WO2017013061A1

WO2017013061A1 - Biomarkers associated with lsd1 inhibitors and uses thereof

Info

Publication number: WO2017013061A1
Application number: PCT/EP2016/067053
Authority: WO
Inventors: Tamara Maes; Cristina MASCARÓ CRUSAT; David ROTLLANT POZO
Original assignee: Oryzon Genomics, S.A.
Priority date: 2015-07-17
Filing date: 2016-07-18
Publication date: 2017-01-26

Abstract

The invention relates to biomarkers associated with LSD1 inhibitors and uses thereof to assess target engagement and to follow patient response to treatment.

Description

BIOMARKERS ASSOCIATED WITH LSD1 INHIBITORS AND USES THEREOF

FIELD OF THE INVENTION

The invention relates to biomarkers associated with LSD1 inhibitors and uses thereof. In particular, the invention relates to the use of the biomarkers as disclosed herein to assess target engagement and to follow patient response to treatment. The invention further relates to novel therapeutic uses for LSD1 inhibitors based on said biomarkers.

BACKGROUND

Aberrant gene expression in affected tissue as compared to normal tissue is a common characteristic of many human diseases. This is true for cancer and many neurological diseases which are characterized by changes in gene expression patterns. Gene expression patterns are controlled at multiple levels in the cell. Control of gene expression can occur through modifications of DNA: DNA promoter methylation is associated with suppression of gene expression. Another class of modifications involve histones, which are proteins, present in the nucleus of eukaryotic cells, that organize DNA strands into nucleosomes by forming molecular complexes around which the DNA winds. Histones play a critical role in modulating chromatin structure and DNA accessibility for replication, repair, and transcription. The covalent modification of histones is closely associated with regulation of gene transcription. Chromatin modifications have been suggested to represent an epigenetic code that is dynamically 'written' and 'erased' by specialized proteins, and 'read' or interpreted by proteins that translate the code into gene expression changes. A number of histone modifications have been discovered including histone acetylation, histone lysine methylation, histone arginine methylation, histone ubiquinylation, and histone sumoylation.

A group of enzymes known as histone lysine methyl transferases and histone lysine demethylases are involved in histone lysine modifications. One particular human histone lysine demethylase enzyme called Lysine Specific Demethylase-1 (LSD1) (Shi et al. (2004) Cell 119:941) has been reported to be involved in this crucial histone modification. LSD1 has a fair degree of structural similarity, and amino acid identity/homology to polyamine oxidases and monoamine oxidases, all of which (i.e., MAO-A, MAO-B and LSD1) are flavin dependent amine oxidases which catalyze the oxidation of nitrogen-hydrogen bonds and/or nitrogen carbon bonds.

LSD1 has been recognized as an interesting target for the development of new drugs to treat cancer, neurological diseases and other conditions, and a number of LSD1 inhibitors are currently under preclinical or clinical development for use in human therapy.

Finding pharmacodynamic (PD) biomarkers which indicate that a drug is active can be very valuable for use during clinical trials or in clinical practice. PD biomarkers can be used to monitor target engagement, i.e. to see if the drug is inhibiting the target against which the drug is designed to act in a subject receiving such drug. They can also be used to monitor the response of those patients receiving the drug. If the biomarker indicates that the patient is not responding appropriately to the drug treatment, then the dosage administered can be increased, reduced or treatment can be discontinued. Biomarkers can also be used to identify particular groups of patients that would benefit, or that would benefit the most, from receiving the drug treatment.

There are no well established PD markers currently available for use in combination with LSD1 inhibitors. There is thus a need to develop biomarkers associated with LSD1 inhibitors.

SUMMARY OF THE INVENTION

The invention relates to the identification of biomarkers associated with LSD1 inhibitors and their use. The present invention is based, in part, on the discovery that a set of genes, as described in more detail below, act as PD markers for the activity of LSD1 inhibitors (henceforth "LSD1 i") and are thus useful to monitor the responsiveness of human subjects to LSD1 inhibition. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the restoration of the discrimination index (Dl) after 2h retention test in female SAMP8 mice when treated for 2 (Fig 1A) and 4 (Fig 1 B) months with compound 1 (Compl ) as described in Example 3.

Figure 2 shows the restoration of the discrimination index (Dl) after 2h retention test in male SAMP8 mice when treated for 2 (Fig 2A) and 4 (Fig 2B) months with compound 1 (Compl ) as described in Example 3.

Figure 3 shows the restoration of the discrimination index (Dl) after 24h retention test in male SAMP8 mice when treated for 2 (Fig 3A) and 4 (Fig 3B) months with compound 1 (Compl ) as described in Example 3.

Figure 4 shows no changes in the platelet blood count of SAMP8 mice treated for 4 months with vehicle or compound 1 (Compl ) as described in Example 3.

Figure 5 shows the reduction of S100A9 expression (Δ Cp) in female (Fig 5A) and male (Fig 5B) SAMP8 mice when treated with compound 1 (Compl) as described in Example 5.

Figure 6 shows the effects of Compound 1 on Baiap3 expression (Δ Cp) in female (Fig 6A) and male (Fig 6B) SAMP8 mice determined by qRT-PCR as described in Example 12.

Figure 7 shows the effects of Compound 1 on Npw expression (Δ Cp) in female (Fig 7A) and male (Fig 7B) SAMP8 mice determined by qRT-PCR as described in Example 12.

Figure 8 shows the effects of Compound 1 on Prph expression (Δ Cp) in female (Fig 8A) and male (Fig 8B) SAMP8 mice determined by qRT-PCR as described in Example 12.

Figure 9 shows S100A9 mRNA levels (Δ Cp S100A9-GADPH) in human cerebrospinal fluid samples from Alzheimer's disease donors determined as described in Example 13. DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the disclosure relates to the analysis of genes that can act as PD markers for LSD1 i and the identification of a group of genes that can be used as such PD markers for monitoring LSD1 inhibition. As disclosed in more detail in the Examples below, the expression of S100A9, S100A8, Prph, Npw and Baiap3 has been found to be modulated by treatment with LSD1 inhibitors in vivo. In particular, S100A9 and S100A8 have been found to be downregulated by treatment with LSD1 i in vivo in various tissues, including brain. Treatment with LSD1 i also causes upregulation of Prph, Npw and Baiap3 in the brain. Importantly, these genes are modulated by LSD1 inhibitors irrespective of gender, i.e. they are modulated in the same direction in both males and females. Moreover, modulation of the expression of these genes by LSD1 i has been confirmed by several techniques, including microarray, RNA sequencing and/or quantitative reverse transcriptase polymerase chain reaction (qRT-PCT),as shown in the Examples below.

Accordingly, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro.

In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein the degree of change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the LSD1 inhibitor. Preferably, the method is performed in vitro.

In another aspect, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in the sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro.

In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein the degree of change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the LSD1 inhibitor. Preferably, the method is performed in vitro.

As used herein, a "change" in the level of the biomarker(s) in relation to S100A9 or S100A8 refers to a decrease in the level of the biomarker(s) as compared to a control, and in relation to Prph, Npw and Baiap3, it refers to an increase in the level of the biomarker(s) as compared to a control.

S100A8 and S100A9 are mammalian calcium- and zinc-binding proteins which play a prominent role in the regulation of inflammatory processes and immune response, among others, as disclosed in more detail below. S100A8, also known as S100 Calcium Binding Protein A8, has the following aliases according to GeneCards:

S100 Calcium Binding Protein A8 CGLA

CAGA CP-10

CFAG L1Ag

S100 Calcium-Binding Protein A8 (Calgranulin A) MA387

Calprotectin L1L Subunit MIF

Cystic Fibrosis Antigen NIF

Leukocyte L1 Complex Light Chain P8

Migration Inhibitory Factor-Related Protein 8 Calgranulin A

Urinary Stone Protein Band A calgranulin-A

MRP-8 Protein S100-A8

MRP8 Calgranulin-A

S100 Calcium Binding Protein A8 (Calgranulin A) p8

60B8AG S100 Calcium-Binding Protein A8

S100A9, also known as S100 Calcium Binding Protein A9, has the following aliases according to GeneCards:

S100 Calcium Binding Protein A9 L1AG

CAGB LI AG

CFAG MAC387

S100 Calcium-Binding Protein A9 (Calgranulin B) MIF Calprotectin L1 H Subunit NIF

Leukocyte L1 Complex Heavy Chain P14

Migration Inhibitory Factor-Related Protein 14 Calgranulin B

MRP-14 calgranulin-B

MRP14 Protein S100-A9

S100 Calcium Binding Protein A9 (Calgranulin B) Calgranulin-B

60B8AG p14

CGLB S100 Calcium-Binding Protein A9

S100A8 and S100A9 are preferentially found in humans as a S100A8/S100A9 heterodimer (i.e. a dimer formed by the protein monomers S100A8 and S100A9), also known as Calprotectin. Calprotectin S100A8/S100A9 heterodimers can non-covalently pair with one another to form heterotetramers.

Prph, also known as Peripherin, has the following aliases according to GeneCards:

Peripherin

NEF4

PRPH1

Neurofilament 4 (57kD)

Neurofilament 4

Peripherin is a neuronal intermediate filament protein that is expressed chiefly in motor neurons and other nerve cells that project into the peripheral nervous system. It is not normally expressed in the hippocampus, but can be induced by certain factors and injury/isquemia and may increase plasticity.

Npw, also known as Neuropeptide W, has the following aliases according to GeneCards:

Neuropeptide W PPNPW

Prepro-Neuropeptide W hPPL8

Preproprotein L8 L8

PPL8 L8C

Npw plays a regulatory role in the organization of neuroendocrine signals accessing the anterior pituitary gland. Stimulates water drinking and food intake. It may play a role in regulating stress responses, emotion, anxiety, and fear.

Baiap3, also known as Brain-specific angiogenesis inhibitor associated protein 3, has the following aliases according to GeneCards:

BAM -Associated Protein 3 I BAP3

BAI-Associated Protein 3

KIAA0734

Baiap3 is a member of the secretin receptor family. It contains two C2 domains, which are often found in proteins involved in signal transduction or membrane trafficking. Its expression pattern and similarity to other proteins suggest that it may be involved in synaptic functions. Deletion of Baiap3 in mice leads to enhanced seizure propensity and increased anxiety, with the latter being more pronounced in female than in male animals.

DNA and protein sequences of human and murine S100A9, S100A8, Prph, Npw and Baiap3 have been previously reported, see GenBank Numbers (NCBI-GenBank Flat File Release 207.0, April 15, 2015) and UniProtKB/Swiss-Prot Numbers (Knowledgebase Release 2015_06) listed below, each of which is incorporated herein by reference in its entirety for all purposes. Such sequences can be used to design procedures for detection of and analysis of the level of S100A9, S100A8, Prph, Npw and/or Baiap3 by ways known to one skilled in the art.

Exemplary amino acid sequences and nucleotide sequences of human and murine S100A9, S100A8, Prph, Npw and Baiap3 are shown in the present application in SEQ ID NO: 1 to 20.

Preferably, the biomarkers of the invention relate to the human forms of S100A9, S100A8, Prph, Npw and Baiap3. In another aspect, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Prph in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.

In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Prph in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Prph in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.

In another aspect, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Prph in the sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.

In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Prph in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Prph in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3. In another aspect, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Npw in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.

In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Npw in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Npw in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.

In another aspect, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Npw in the sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3. In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Npw in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Npw in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3. In another aspect, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Npw.

In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Npw.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Npw.

In another aspect, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Baiap3 in the sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Npw. In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Npw.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Npw.

In another aspect, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is S100A9 and/or S100A8 in a sample obtained from the subject, wherein a decrease in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like Prph, Npw or Baiap3.

In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is S100A9 and/or S100A8 in a sample obtained from the subject, wherein the degree of decrease in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like Prph, Npw or Baiap3.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising determining the level of a biomarker which is S100A9 and/or S100A8 in a sample obtained from the subject, wherein a decrease in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like Prph, Npw or Baiap3.

In another aspect, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is S100A9 and/or S100A8 in the sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein a decrease in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like Prph, Npw or Baiap3.

In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is S100A9 and/or S100A8 in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein the degree of decrease in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like Prph, Npw or Baiap3.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is S100A9 and/or S100A8 in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein a decrease in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like Prph, Npw or Baiap3.

In the methods described herein, the level of the biomarker(s) can be determined using any method known in the art to measure gene expression product levels, including mRNA and protein levels.

As used herein, the term "biomarker which is S100A9 and/or S100A8" encompasses any of S100A9 and/or S100A8 in any of the forms in which they can be found, including without limitation all monomeric forms and all heterodimeric or heterotetrameric forms thereof, such as Calprotectin.

As used herein, the term "determining the level of a biomarker which is S100A9 and/or S100A8" encompasses determining the level of any of S100A9 and/or S100A8 (in any of the forms in which each of them can be found) using any method known in the art to measure gene expression product levels, including mRNA and protein levels.

In the methods for monitoring described herein, the level of the biomarker(s) can be determined as mRNA. In the methods for monitoring described herein, the level of the biomarker(s) can be determined as protein. In the methods for monitoring according to the present invention, the sample obtained from the subject to be compared to a control can be obtained at different time points, i.e. after the subject has been treated or has received a first, second, third etc dosage of the LSD1 inhibitor. The "subject receiving treatment with an LSD1 inhibitor", i.e. the subject being monitored using the methods for monitoring according to the invention, can be either a subject under active treatment with the LSD1 inhibitor or a subject within a treatment break when the treatment with an LSD1 inhibitor may consist of multiple cycles of drug administration separated by break periods during which the subject may also be monitored.

As used in context of the methods for monitoring according to the present invention, a non-limiting example of a "control" is preferably a sample obtained from the to be monitored subject before the start of the treatment or at an earlier time point.

In the methods for monitoring described herein the sample is preferably a peripheral sample. The peripheral sample can be e.g. cerebrospinal fluid (CSF), blood, plasma, serum, stool, saliva, sputum, gingival crevicular fluid, hair follicle or skin biopsy.

In the methods for monitoring described herein the LSD1 inhibitor can be an irreversible LSD1 inhibitor or a reversible LSD1 inhibitor. Preferably, the LSD1 inhibitor is an irreversible LSD1 inhibitor.

In the methods for monitoring described herein the LSD1 inhibitor is preferably a 2- (hetero)arylcyclopropylamino compound.

In the methods for monitoring described herein the LSD1 inhibitor is preferably a compound disclosed in WO2010/043721 , WO2010/084160, WO201 1/035941 , WO201 1/042217, WO201 1/131697, WO2012/013727, WO2012/013728, WO2012/045883, WO2013/057320, WO2013/057322, WO2012/135113, WO2013/022047, WO2014/058071 , WO2010/143582, US2010-0324147, WO201 1/131576, WO2014/084298, WO2014/086790, WO2014/164867, or WO2015/021 128.

In the methods for monitoring described herein the LSD1 inhibitor is preferably a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII), as described in more detail below. More preferably, the LSD1 inhibitor is a compound of formula (III), (VI), (VIII), (IX), (X), (XI), (XII) or (XIII). Still more preferably, the LSD1 inhibitor is a compound from the lists of examples provided below for compounds of formulae (III), (VI), (VIII), (IX), (X) or (XI).

Preferably, in the methods for monitoring described herein the LSD1 inhibitor is (-) 5-((((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof.

In the methods for monitoring described herein, the subject is preferably a human.

In the methods for monitoring described herein, the subject can be a patient or a healthy individual.

In the methods for monitoring described herein the subject can be a subject that has a CNS disease.

In the methods for monitoring described herein the subject can be a subject that has a neurodegenerative disease, for example Alzheimer's disease, Mild Cognitive Impairment, Parkinson's disease, difuse Lewy body disease, synucleinopathies, Huntington's disease, Down syndrome, or Amyotrophic lateral sclerosis, preferably Alzheimer's disease or Mild Cognitive Impairment.

In the methods for monitoring described herein the subject can be a subject that has a cognitive function related disease, for example dementia (such as vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia), delirium, amnesia, Rett disease, schizophrenia, attention- deficit/hyperactivity disorder, or postoperative cognitive dysfunction.

In the methods for monitoring described herein the subject can be a subject that has an autoimmune disease. For example, the autoimmune disease can be an acute or chronic autoimmune neuropathy such as multiple sclerosis.

In the methods for monitoring described herein the subject can be a subject that has an infection or a disease caused by an infection, preferably a bacterial infection, a fungal infection, a protozoan infection, an influenza infection, or a disease caused by any of said infections.

In the methods for monitoring described herein the subject can be a subject that has cancer.

In the methods for monitoring described herein the subject can be a subject that has a cardiovascular disease. Preferably, in the methods for monitoring described herein the subject is a subject that has a CNS disease. In another aspect, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro.

In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2- amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein the degree of change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the LSD1 inhibitor, i.e. response to the treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof. Preferably, the method is performed in vitro.

In another aspect, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Npw in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.

In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2- amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Npw in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Npw in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor, i.e. response to the treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4- oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Prph or Baiap3.

In another aspect, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Prph in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.

In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2- amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Prph in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Prph in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor, i.e. response to the treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4- oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Baiap3.

In another aspect, the invention provides a method for monitoring LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that LSD1 is being inhibited in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Prph.

In another aspect, the invention provides a method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2- amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of LSD1 inhibition in the subject. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Prph.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, comprising determining the level of a biomarker which is Baiap3 in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the LSD1 inhibitor, i.e. response to the treatment with (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof. Preferably, the method is performed in vitro. The method can optionally comprise the detection of further biomarkers like S100A9, S100A8, Npw or Prph.

In the methods for monitoring described herein, the subject can be a patient or a healthy individual. If the subject is a patient, preferably it is a patient that has a CNS disease, for example a neurodegenerative disease or a cognitive function related disease such as the ones disclosed above.

In addition to S100A9, S100A8, Prph, Npw and Baiap3, a further biomarker has been identified, Avp, which targets the MAO-B component of dual LSD1/MAO-B inbibitors since it has been found to be upregulated by treatment with a dual LSD1/MA0-B inhibitor like Compound 1 and with a compound with potent MAO-B inhibitory activity and weak LSD1 inhibitory activity like Compound 2, while not being upregulated by selective LSD1 inhibitors, as discussed in more detail in the Examples. Avp can thus be used as a PD marker for MAO-B inhibitors and dual LSD1/MAO-B inhibitors.

Avp, also known as Arginine vasopressin, has the following aliases according to Gene Cards:

Arginine Vasopressin AVP-NPII

ARVP AVRP

VP Diabetes Insipidus

Antidiuretic Hormone Neurophysin II

Neurohypophyseal ADH

Prepro-Arginine-Vasopressin-Neurophysin II Vasopressin-Neurophysin 2-Copeptin

Prepro-AVP-NP II Vasopressin-Neurophysin ll-Copeptin

Arginine vasopressin is a posterior pituitary hormone which is synthesized in the supraoptic nucleus and paraventricular nucleus of the hypothalamus. Avp is found predominantly in the hypothalamus, but is also located in other brain regions. Avp influences complex social behavior and emotional states, including, but not limited to, aggression, fear, and anxiety. It is also involved in cognition and affiliative behaviors in human. DNA and protein sequences of human and murine Avp have been previously reported, see GenBank Numbers (NCBI-GenBank Flat File Release 207.0, April 15, 2015) and UniProtKB/Swiss-Prot Numbers (Knowledgebase Release 2015_06) listed below, each of which is incorporated herein by reference in its entirety for all purposes. Such sequences can be used to design procedures for detection of and analysis of the level of Avp by ways known to one skilled in the art.

Exemplary amino acid sequences and nucleotide sequences of human and murine Avp are shown in the present application in SEQ ID NO: 21 to 24.

Preferably, the biomarker Avp relates to the human form of Avp.

Accordingly, in another aspect the invention relates to a method for monitoring MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor, comprising determining the level of a biomarker which is Avp in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that MAO-B is being inhibited in the subject. Preferably, the method is performed in vitro.

In another aspect, the invention provides a method for monitoring the degree of MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor, comprising determining the level of a biomarker which is Avp in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of MAO-B inhibition in the subject. Preferably, the method is performed in vitro.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with a MAO-B inhibitor, comprising determining the level of a biomarker which is Avp in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the MAO-B inhibitor. Preferably, the method is performed in vitro.

In another aspect, the invention provides a method for monitoring MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor, comprising (i) administering a MAO-B inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Avp in the sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that MAO-B is being inhibited in the subject. Preferably, the method is performed in vitro. In another aspect, the invention provides a method for monitoring the degree of MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor, comprising (i) administering a MAO-B inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Avp in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of MAO-B inhibition in the subject. Preferably, the method is performed in vitro.

In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with a MAO-B inhibitor, comprising (i) administering a MAO-B inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Avp in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the MAO-B inhibitor. Preferably, the method is performed in vitro. A "MAO-B inhibitor", as used herein, is a compound that inhibits MAO-B (i.e. monoamine oxidase-B). Preferably, the MAO-B inhibitor is a dual LSD1/MAO-B inhibitor as defined below. Still more preferably, the dual LSD1/MAO-B inhibitor is a compound of formula (VIII) as defined below. A particularly preferred dual LSD1/MAO-B inhibitor is (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2- amine or a pharmaceutically acceptable salt or solvate thereof. In yet another aspect, the invention provides a method for monitoring the response of a subject to treatment with a dual LSD1/MAO-B inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw, Baiap3 and Avp in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the dual LSD1/MAO-B inhibitor. Preferably, the method is performed in vitro. Preferably, the dual LSD1/MAO-B inhibitor is a compound of formula (VIII) as defined below. More preferably, the dual LSD1/MAO-B inhibitor is (-) 5-((((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the invention provides a method for monitoring the response of a subject to treatment with a dual LSD1/MAO-B inhibitor, comprising (i) administering a dual LSD1/MAO-B to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw, Baiap3 and Avp in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the dual LSD1/MAO-B inhibitor. Preferably, the dual LSD1/MAO-B inhibitor is a compound of formula (VIII) as defined below. More preferably, the dual LSD1/MAO-B inhibitor is (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof.

As used in context of the methods described above, a non-limiting example of a "control" is preferably a sample obtained from the to be monitored subject before the start of the treatment or at an earlier time point.

In the methods for monitoring described herein, the level of the biomarker can be determined as mRNA.

In the methods for monitoring described herein, the level of the biomarker can be determined as protein. In the methods for monitoring described herein the sample is preferably a peripheral sample. The peripheral sample can be e.g. cerebrospinal fluid (CSF), blood, plasma, serum, stool, saliva, sputum, gingival crevicular fluid, hair follicle or skin biopsy.

In a certain aspect, the present invention relates to the use of a primer / a primer pair in the in vitro methods of the present invention. In a certain aspect, he present invention relates to a primer / a primer pair for use in the in vitro methods of the present invention. The primer / primer pair can be used for determining the level of a biomarker which is S100A9, S100A8, Npw Prph and/or Baiap3. For example, the primer / primer pair can specifically bind to the nucleotide sequence of a biomarker which is S100A9 , S100A8, Npw, Prph and/or Baiap3. In a certain aspect, the present invention relates to the use of a primer / a primer pair for a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3 in the in vitro methods of the present invention. The primer / primer pair can, for example, be used in amplifying the nucleotide sequence of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3, or in amplifying a part of the sequence. Thus, the primer / a primer pair can, for example, be useful to determine the mRNA level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3. The term "primer pair" as used herein refers normally to a forward primer and a reverse primer that are used to amplify a nucleotide sequence of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3, or a part of that sequence. It is understood that the forward primer normally binds to the strand that is complementary to the strand that the reverse primer binds to.

In a further aspect, the present invention relates to an in vitro use of a primer / a primer pair for monitoring the response of a subject to treatment with an LSD1 inhibitor, wherein the primer / primer pair is for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3. For example, the primer / primer pair can specifically bind to the nucleotide sequence of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3.

In a further aspect, the present invention relates to a primer / a primer pair for use in monitoring the response of a subject to treatment with an LSD1 inhibitor, wherein the primer / primer pair is for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3. For example, the primer / primer pair can specifically bind to the nucleotide sequence of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3.

In a certain aspect, the present invention relates to the use of a binding molecule in the in vitro methods of the present invention. In a certain aspect, the present invention relates to a binding molecule for use in the in vitro methods of the present invention. The binding molecule specifically binds to a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3 wherein the biomarker is a protein. The binding molecule can be an antibody. In a certain aspect, the present invention relates to the use of an antibody in the in vitro methods of the present invention.

In a further aspect, the present invention relates to an in vitro use of a binding molecule specifically binding to a biomarker which is S100A9 protein, S100A8 protein, Npw protein, Prph protein and/or Baiap3 protein for monitoring the response of a subject to treatment with an LSD1 inhibitor. The binding molecule can be for example an antibody.

In a further aspect, the present invention relates to a binding molecule specifically binding to a biomarker which is S100A9 protein, S100A8 protein, Npw protein, Prph protein and/or Baiap3 protein for use in monitoring the response of a subject to treatment with an LSD1 inhibitor. The binding molecule can be for example an antibody.

In a certain aspect, the present invention relates to the use of a kit in the in vitro methods of the present invention, wherein the kit comprises means and methods for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3 in accordance with the present invention. In a certain aspect, the present invention relates to a kit for use in the in vitro methods of the present invention, wherein the kit comprises means and methods for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3 in accordance with the present invention. The kit can, for example, comprise a primer/a primer pair for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3. The kit can, for example, comprise a binding molecule, such as an antibody, specifically binding to a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3, wherein the biomarker is a protein.

In a further aspect, the invention provides an in vitro use of a kit comprising a primer / a primer pair for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3 for monitoring the response of a subject to treatment with an LSD1 inhibitor. For example, the primer / primer pair can specifically bind to the nucleotide sequence of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3.

In a further aspect, the invention provides an in vitro use of a kit comprising a binding molecule specifically binding to a biomarker which is S100A9 protein, S100A8 protein, Npw protein, Prph protein and/or Baiap3 protein for monitoring the response of a subject to treatment with an LSD1 inhibitor. The binding molecule can be for example an antibody.

In a further aspect, the invention provides a use of a primer / a primer pair for the preparation of a kit for monitoring the response of a subject to treatment with an LSD1 inhibitor, wherein the primer / primer pair is for determining the level of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3. For example, the primer / primer pair can specifically bind to the nucleotide sequence of a biomarker which is S100A9, S100A8, Npw, Prph and/or Baiap3.

In a further aspect, the invention provides a use of a binding molecule for the preparation of a kit for monitoring the response of a subject to treatment with an LSD1 inhibitor, wherein the binding molecule is specifically binding to a biomarker which is S100A9 protein, S100A8 protein, Npw protein, Prph protein and/or Baiap3 protein. The binding molecule can be for example an antibody.

In the context of the methods for monitoring of the invention, the following non-limiting examples of diseases apply:

1) CNS diseases: including neurodegenerative diseases (including Alzheimer's disease, Mild Cognitive Impairment, Parkinson's disease, difuse Lewy body disease, synucleinopathies, Huntington's disease, Down syndrome, and Amyotrophic lateral sclerosis); autism spectrum disease (including autism, Asperger syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), and childhood disintegrative disorder); cognitive function related disease (including dementia such as vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia, delirium, amnesia, Rett disease, schizophrenia, attention-deficit/hyperactivity disorder, and postoperative cognitive dysfunction); mood disorders (including anxiety, stress disorder, post-traumatic stress disorder, panic disorder, phobia, mania, depressive disorders such as major depression, recurrent depression and postpartum disorder, bipolar disorders, and obsessive- compulsive disorder); and stroke and lesion-related diseases (including Traumatic Brain Injury, brain ischemia, intracranial hemorrhage, intracranial aneurysm, and Cerebral Amyloid Angiopathy);

2) autoimmune diseases: including arthritis (including rheumatoid arthritis, psoriatic arthritis, reactive arthritis and juvenile idiopathic arthritis); inflammatory bowel disease (including Crohn's disease and ulcerative colitis); sclerosis (including systemic sclerosis); acute and chronic autoimmune neuropathies (including autoimmune encephalomyelitis and multiple sclerosis); lupus (including lupus erythematosus, glomerulonephritis, and vasculitis); autoimmune pancreas disease (including autoimmune pancreatitis and diabetes mellitus type 1); autoimmune skin diseases (including psoriasis); autoimmune muscle disease (including dermatomyositis, polymyositis, and inclusion body myositis); and Kawasaki disease;

3) infections: particularly bacterial, fungal, protozoan and viral infections and diseases caused by said infections: including bacterial infections (for example caused by E. coli, Pneumococcus, Helicobacter pylori, Salmonella, Staphylococcus aureus, Pseudomonas aeruginosa, Ureaplasma parvum, Francisella tularensis, and Porphyromonas gingivalis), and diseases caused by said bacterial infections such as acute bacterial infections (including acute appendicitis, meningitis, caries, gastritis, gastric ulceration, and acne) and sepsis (including Severe sepsis, septic shock, perinatal and neonatal sepsis); fungal infections (for example Candidiasis or Aspergillosis) and diseases caused by said fungal infections, protozoan infections (for example caused by Plasmodium or Trypanomoma cruzi) and diseases caused by said protozoan infections (for example malaria or Chagas' disease); and viral infections (influenza virus) and diseases caused by said viral infections (for example Influenza).

4) cancer: including carcinomas such as colorectal cancer, bladder cancer, prostate cancer, anaplastic thyroid carcinoma, cutaneous squamous cell carcinoma, gastric cancer, lung cancer and breast cancer (including metastatic breast cancer to brain); and sarcomas such as glioma (for example astrocytoma); and

5) cardiovascular diseases: including arteriosclerotic vascular disease (including atherosclerosis and atherogenesis), acute coronary syndromes (like myocardial infarction) and vascular injury (including thrombosis, embolism, vasculitis, venous ulcers, and aortic aneurysms).

Analysis of S100A9, S100A8, Npw, Prph, Baiap3 and/or Avp in human subjects, for example patients enrolled in a clinical trial, can be performed following the methods described in the present specification.

When used in methods for monitoring the response of a subject to treatment with an LSD1 inhibitor, typically samples (for example peripheral samples) are collected from each subject following standard procedures at different time points, starting with a sample obtained prior to the start of the treatment with the LSD1 inhibitor. Samples are then processed to prepare them for biomarker analysis following standard procedures, and the level of the biomarker(s) of interest, i.e. S100A9, S100A8, Npw, Prph, and/or Baiap3, is determined in each sample by measuring mRNA levels thereof (for example by qRT-PCR) or protein levels thereof (for example by ELISA).

Typically when measuring mRNA levels, expression levels are normalized relative to the expression level of an endogenous reference gene. Said reference gene is selected following standard criteria, typically among housekeeping genes whose expression is unchanged over a wide range of conditions. An example of a suitable endogenous reference gene is GADPH (glyceraldehyde phosphate dehydrogenase, also known as GAPDH), as disclosed in the Examples. Typically, when measuring protein levels of a protein of interest, for example by ELISA, a standard curve (obtained using samples with known concentrations of the target protein) can be used to quantify the concentration of target protein in the test sample.

An example of a peripheral sample, for example for use in patients having a CNS disease, is CSF.CSF samples are collected by lumbar puncture using standard procedures in participating healthcare facilities. Typically, a CSF volume ranging from 1 to 10 mL is obtained from each subject.

Fresh CSF samples are processed by centrifugation in order to obtain cell pellets and supernatant, which can either be analyzed then or be frozen and maintained at -80°C until further analysis.

Cell pellets can be used to obtain RNA to analyze S100A9, S100A8, Npw, Prph and/or Baiap3 expression levels using methods as described herein, for example by qRT-PCR. Liquid supernatant can be used to analyze S100A9, S100A8, Npw, Prph and/or Baiap3 protein levels using methods as described herein, for example by ELISA. S100A9 protein levels can be analyzed as S100A9 monomer and/or S100A8/S100A9 heterodimer protein concentration, for example by ELISA. In addition, the invention relates to the following items:

1. A method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative that LSD1 is being inhibited in the subject.

2. A method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein the degree of change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative of the degree of LSD1 inhibition in the subject.

3. A method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the LSD1 inhibitor.

4. A method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in the sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative that LSD1 is being inhibited in the subject. 5. A method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein the degree of change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative of the degree of LSD1 inhibition in the subject.

6. A method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw and Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the LSD1 inhibitor.

7. The method of any of items 1 to 6, wherein the level of the biomarker is determined as mRNA.

8. The method of any of items 1 to 6, wherein the level of the biomarker is determined as protein.

9. The method of any of items 1 to 8, wherein the sample is a peripheral sample.

10. The method of item 9, wherein the peripheral sample is cerebrospinal fluid (CSF), blood, plasma, serum, urine, stool, saliva, sputum, gingival crevicular fluid, hair follicle or skin biopsy.

1 1. The method of any of items 1 to 10, wherein the LSD1 inhibitor is an irreversible LSD1 inhibitor.

12. The method of any of items 1 to 1 1 , wherein the LSD1 inhibitor is a 2-(hetero)arylcyclopropylamino compound.

13. The method of any of items 1 to 12, wherein the LSD1 inhibitor is a compound disclosed in WO2010/043721 , WO2010/084160, WO201 1/035941 , WO201 1/042217, WO201 1/131697, WO2012/013727, WO2012/013728, WO2012/045883, WO2013/057320, WO2013/057322, WO2012/135113, WO2013/022047, WO2014/058071 , WO2010/143582, US2010-0324147, WO201 1/131576, WO2014/084298, WO2014/086790, WO2014/164867, or WO2015/021 128.

14. The method of any of items 1 to 12, wherein the LSD1 inhibitor is a compound of formula (I), (II), (III), (IV), (V). (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII).

15. The method of any of items 1 to 12, wherein the LSD1 inhibitor is a compound of formula (III).

16. The method of any of items 1 to 12, wherein the LSD1 inhibitor is a compound of formula (VI).

17. The method of any of items 1 to 12, wherein the LSD1 inhibitor is a compound of formula (VIII).

18. The method of any of items 1 to 12, wherein the LSD1 inhibitor is a compound of formula (IX).

19. The method of any of items 1 to 12, wherein the LSD1 inhibitor is a compound of formula (X).

20. The method of any of items 1 to 12, wherein the LSD1 inhibitor is a compound of formula (XI). 21. The method of any of items 1 to 10, wherein the LSD1 inhibitor is (-) 5-((((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof.

22. The method of any of items 1 to 10, wherein the LSD1 inhibitor is (trans)-N1-((1 R,2S)-2- phenylcyclopropyl)cyclohexane-1 ,4-diamine or a pharmaceutically acceptable salt or solvate thereof.

23. The method of any of items 1 to 10, wherein the LSD1 inhibitor is 4-((4-((((1 R,2S)-2- phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid or a pharmaceutically acceptable salt or solvate thereof.

24. The method of any of items 1 to 23, wherein the subject is a human.

25. The method of any of items 1 to 23, wherein the subject has a CNS disease

26. The method of item 25, wherein the CNS disease is a neurodegenerative disease (e.g. Alzheimer's disease, Mild Cognitive Impairment, Parkinson's disease, difuse Lewy body disease, synucleinopathies, Huntington's disease, Down syndrome, and Amyotrophic lateral sclerosis); an autism spectrum disease (e.g. autism, Asperger syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), and childhood disintegrative disorder); a cognitive function related disease (e.g. dementia such as vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia, delirium, amnesia, Rett disease, schizophrenia, attention-deficit/hyperactivity disorder, and postoperative cognitive dysfunction); a mood disorder (e.g. anxiety, stress disorder, post-traumatic stress disorder, panic disorder, phobia, mania, depressive disorders such as major depression, recurrent depression and postpartum disorder, bipolar disorders, and obsessive-compulsive disorder); stroke or a lesion-related disease (e.g. Traumatic Brain Injury, brain ischemia, intracranial hemorrhage, intracranial aneurysm, and Cerebral Amyloid Angiopathy).

27. The method of any of items 1 to 24, wherein the subject has a neurodegenerative disease, preferably Alzheimer's disease, Mild Cognitive Impairment, Parkinson's disease, difuse Lewy body disease, synucleinopathies, Huntington's disease, Down syndrome, or Amyotrophic lateral sclerosis, more preferably Alzheimer's disease or Mild Cognitive Impairment.

28. The method of any of items 1 to 24, wherein the subject has a cognitive function related disease, preferably a dementia (e.g. vascular dementia, Lewy body dementia, senile dementia, frontotemporal dementia and mixed dementia), delirium, amnesia, Rett disease, schizophrenia, attention-deficit/hyperactivity disorder, or postoperative cognitive dysfunction.

29. The method of any of items 1 to 24, wherein the subject has an autoimmune disease.

30. The method of item 29, wherein the autoimmune disease is arthritis (e.g. rheumatoid arthritis, psoriatic arthritis, reactive arthritis or juvenile idiopathic arthritis); inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis); sclerosis (e.g. systemic sclerosis); an acute or chronic autoimmune neuropathy (e.g. autoimmune encephalomyelitis or multiple sclerosis); lupus (e.g. lupus erythematosus, glomerulonephritis, or vasculitis); an autoimmune pancreas disease (e.g. autoimmune pancreatitis or diabetes mellitus type 1); an autoimmune skin disease (e.g. psoriasis); an autoimmune muscle disease (e.g. dermatomyositis, polymyositis, or inclusion body myositis); or Kawasaki disease.

31. The method of item 29, wherein the autoimmune disease is an acute or chronic autoimmune neuropathy (e.g. autoimmune encephalomyelitis or multiple sclerosis).

32. The method of any of items 1 to 24, wherein the subject has an infection or a disease caused by an infection, preferably a bacterial infection, a fungal infection, a protozoan infection, an influenza infection, or a disease caused by any of said infections.

33. The method of item 32, wherein the infection is a bacterial infection (e.g. caused by E. coli, Pneumococcus, Helicobacter pylori, Salmonella, Staphylococcus aureus, Pseudomonas aeruginosa, Ureaplasma parvum, Francisella tularensis, and Porphyromonas gingivalis) or a disease caused by a bacterial infection such as an acute bacterial infection (e.g. acute appendicitis, meningitis, caries, gastritis, gastric ulceration, and acne) or sepsis (e.g. Severe sepsis, septic shock, perinatal or neonatal sepsis); a fungal infection (e.g. Candidiasis or Aspergillosis) or a disease caused by a fungal infection, a protozoan infection (e.g. caused by Plasmodium or Trypanomoma cruzi) or a disease caused by a protozoan infection (e.g. malaria or Chagas' disease); a viral infection (e.g. influenza virus) or a disease caused by a viral infection (e.g. Influenza).

34. The method of any of items 1 to 24, wherein the subject has cancer.

35. The method of item 34, wherein the cancer is a carcinoma, preferably colorectal cancer, bladder cancer, prostate cancer, anaplastic thyroid carcinoma, cutaneous squamous cell carcinoma, gastric cancer, lung cancer or breast cancer (including metastatic breast cancer to brain); or a sarcoma, preferably glioma (e.g. astrocytoma).

36. The method of any of items 1 to 24, wherein the subject has a cardiovascular disease.

37. The method of item 36, wherein the cardiovascular disease is arteriosclerotic vascular disease (e.g. atherosclerosis and atherogenesis), acute coronary syndromes (e.g. myocardial infarction) or vascular injury (e.g. thrombosis, embolism, vasculitis, venous ulcer, or aortic aneurysm

38. A method for monitoring MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor, comprising determining the level of a biomarker which is Avp in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that MAO-B is being inhibited in the subject.

39. A method for monitoring the degree of MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor, comprising determining the level of a biomarker which is Avp in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of MAO-B inhibition in the subject.

40. A method for monitoring the response of a subject to treatment with a MAO-B inhibitor, comprising determining the level of a biomarker which is Avp in a sample obtained from the subject, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the MAO-B inhibitor. 41. A method for monitoring MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor, comprising (i) administering a MAO-B inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Avp in the sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative that MAO-B is being inhibited in the subject.

42. A method for monitoring the degree of MAO-B inhibition in a subject receiving treatment with a MAO-B inhibitor, comprising (i) administering a MAO-B inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Avp in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein the degree of increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control is indicative of the degree of MAO-B inhibition in the subject.

43. A method for monitoring the response of a subject to treatment with a MAO-B inhibitor, comprising (i) administering a MAO-B inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of a biomarker which is Avp in a sample obtained from the subject, and (iv) comparing the level of the biomarker in the sample with the level of the biomarker in a control, wherein an increase in the level of the biomarker in the sample as compared to the level of the biomarker in a control indicates response to the treatment with the MAO-B inhibitor.

44. A method for monitoring the response of a subject to treatment with a dual LSD1/MAO-B inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of S100A9,

S100A8, Prph, Npw, Baiap3 and Avp in a sample obtained from the subject, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the dual LSD1/MAO-B inhibitor.

45. A method for monitoring the response of a subject to treatment with a dual LSD1/MAO-B inhibitor, comprising (i) administering a dual LSD1/MAO-B to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of S100A9, S100A8, Prph, Npw, Baiap3 and Avp in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein a change in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the dual LSD1/MAO-B inhibitor.

46. The method of any of items 38 to 43 wherein the MAO-B inhibitor is a dual LSD1/MAO-B inhibitor.

47. The method of any of items 44 to 46, wherein the dual LSD1/MAO-B inhibitor is (-) 5-((((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof.

48. The methof of any of items 38 to 47, wherein the sample is a peripheral sample.

49. The method of any of items 38 to 48, wherein the level of the biomarker is determined as mRNA. 50. The method of any of items 38 to 48, wherein the level of the biomarker is determined as protein.

As used herein, determining the level of a biomarker in a sample is used interchangeably with determining or measuring the level of gene expression of the biomarker in the sample. The level of a biomarker in a sample can be determined by any suitable method known in the art to measure gene products, including mRNA and protein. Non-limiting examples of such methods include detecting the quantity of mRNA transcribed from the gene, the quantity of cDNA produced from the reverse transcription of the mRNA transcribed from the gene, or the quantity of protein encoded by the gene.

In the methods according to the invention, mRNA from a sample can be directly used in determining the level of the biomarker. In the methods according to the present invention, the level can be determined by hybridization. In the methods according to the present invention, the RNA can be transformed into cDNA (complementary DNA) copy using methods known in the art. Methods for detecting can include but are not limited to quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), gene expression analyses, microarray analyses, gene expression chip analyses, hybridization techniques and chromatography as well as any other techniques known in the art, e.g. those described in Ralph Rapley, "The Nucleic Acid Protocols Handbook", published 2000, ISBN: 978-0-89603-459-4. Methods for detecting DNA can include but are not limited to PCR, real-time PCR, digital PCR, hybridization, microarray analyses, as well as any other techniques known in the art, e.g. those described in Leland et al, "Handbook of Molecular and cellular Methods in Biology and Medicine", published 2011 , ISBN 9781420069389.

In the methods according to the invention, the method can comprise detecting the protein expression level of a biomarker. Any suitable methods of protein detection, quantization and comparison can be used, such as those described in John M. Walker, "The Protein Protocols Handbook", published 2009, ISBN 978-1-59745-198-7. The protein expression level of a biomarker can be detected by immune assays which include the recognition of the protein or protein complex by anti antibody or antibody fragment, comprising but not limited to enzyme linked immunosorbent assays (ELISA), "sandwich" immunoassays, immunoradiometric assays, in situ immunoassays, alphaLISA immunoassays, protein proximity assays, proximity ligation assay technology (e.g. protein qPCR), western blot analysis, immunoprecipitation assays, immunofluorescent assays, flow cytometry, immunohistochemistry (IHC), immuneeletrophoresis, protein immunestaining, confocal microscopy; or by similar methods in which the antibody or antibody fragment is substituted by a chemical probe, aptamer, receptor, interacting protein or other by another biomolecule recognizing the biomarker protein in a specific manner; or by Forster / fluorescence resonance energy transfer (FRET), differential scanning fluorimetry (DSF), microfluidics.spectrophotometry, mass spectrometry, enzymatic assays, surface plasmon resonance, or combinations thereof. Immunoassays may be homogeneous assays or heterogeneous assays. In a homogeneous assay the immunological reaction usually involves the specific antibody, a labeled analyte, and the sample of interest. The signal arising from the label is modified, directly or indirectly, upon the binding of the antibody to the labeled analyte. Both the immunological reaction and detection of the extent thereof can be carried out in a homogeneous solution. Immunochemical labels which may be employed include free radicals, radioisotopes, fluorescent dyes, enzymes, bacteriophages, or coenzymes. In a heterogeneous assay approach, the reagents are usually the sample, the antibody, and means for producing a detectable signal. The antibody can be immobilized on a support, such as a bead, plate or slide, and contacted with the specimen suspected of containing the antigen in a liquid phase. The support is then separated from the liquid phase and either the support phase or the liquid phase is examined for a detectable signal employing means for producing such signal. The signal is related to the presence of the analyte in the sample. Means for producing a detectable signal include the use of radioactive labels, fluorescent labels, or enzyme labels.

In the methods according to the invention, an antibody to the biomarker of interest can be used. In the methods according to the present invention, a kit for detection can be used. Such antibodies and kits are available from commercial sources such as EMD Millipore, R&D Systems for biochemical assays, Thermo Scientific Pierce Antibodies, Novus Biologicals, Aviva Systems Biology, Abnova Corporation, AbD Serotec or others. Alternatively, antibodies can also be synthesized by any known method. The term "antibody" as used herein is intended to include monoclonal antibodies, polyclonal antibodies, and chimeric antibodies. Antibodies can be conjugated to a suitable solid support (e.g., beads such as protein A or protein G agarose, microspheres, plates, slides or wells formed from materials such as latex or polystyrene) in accordance with known techniques, such as passive binding. Antibodies as described herein may likewise be conjugated to detectable labels or groups such as radiolabels (e.g., ³⁵S), enzyme labels (e.g., horseradish peroxidase, alkaline phosphatase), fluorescent labels (e.g., fluorescein, Alexa, green fluorescent protein, rhodamine), can generated by release of singlet oxygen by phthalocyanine containing beads after irradiation at 680 nM and subsequent absorption and emission of light by acceptor beads containing Europium or Therbium, and oligonucleotide labels. Labels can generate signal directly or indirectly. Signal generated can include fluorescence, radioactivity, luminescence, in accordance with known techniques.

Preferably, in the methods according to the invention the level of the biomarker is measured either as mRNA using qRT-PCT or as protein using an ELISA assay or a proximity ligation assay technology such as a protein qPCR.

As used herein, an LSD1 inhibitor (LSD1 i) is a compound which inhibits LSD1. Any LSD1 inhibitor known in the art can be used in the methods and therapeutic uses of the invention. Both irreversible and reversible LSD1 i have been reported. Most LSD1 i reported to date are irreversible LSD1 i, which exert their inhibitory activity by becoming covalently bound to the FAD cofactor within the LSD1 active site and are generally based on a 2- (hetero)arylcyclopropylamino moiety. Some reversible inhibitors of LSD1 have also been reported in the literature (see e.g. DP Mould et al, Med. Res. Rev., 2015,35:586-618. doi:10.1002/med.21334, epub 24-nov- 2014).

Non-limiting examples of LSD1 i are disclosed e.g. in: WO2010/043721 , WO2010/084160, WO2011/035941 , WO2011/042217, WO2011/131697, WO2012/013727, WO2012/013728, WO2012/045883, WO2013/057320, WO2013/057322, WO2010/143582, US2010-0324147, WO2011/022489, WO2011/131576, WO2012/034116, WO2012/135113, WO2013/022047, WO2013/025805, WO2014/058071 , WO2014/084298, WO2014/086790, WO2014/164867,WO2014/205213,WO2015/021128, WO2015/031564, US2015-0065434, WO2007/021839, WO2008/127734, WO2015/089192, CN104119280, CN103961340, CN103893163, CN103319466, CN103054869, K Taeko et al, Bioorg Med Chem Lett 2015, 25(9):1925-8. doi: 10.1016/j.bmcl.2015.03.030. Epub 2015 Mar 20, PMID: 25827526; S Valente et al, Eur J Med Chem. 2015, 94:163-74. doi: 10.1016/j.ejmech.2015.02.060. Epub 2015 Mar 3, PMID:25768700; MN Ahmed Khan et al Med. Chem. Commun., 2015,6, 407-412, DOI: 10.1039/C4MD00330F epub 29 Sep 2014; M Pieroni et al, Eur J Med Chem. 2015 ;92:377-386. doi: 10.1016/j.ejmech.2014.12.032. Epub 2015 Jan 7. PMID:25585008; V Rodriguez et al, Med. Chem. Commun., 2015,6, 665-670 DOI: 10.1039/C4MD00507D, Epub 23 Dec 2014; P Vianello et al, Eur J Med Chem. 2014, 86:352-63. doi: 10.1016/j.ejmech.2014.08.068. Epub 2014 Aug 27; DP Mould et al, Med. Res. Rev., 2015,35:586-618. doi:10.1002/med.21334, epub 24-nov-2014; LY Ma et al, 2015, 58(4): 1705-16. doi: 10.1021/acs.jmedchem.5b00037. Epub 2015 Feb 6; SL Nowotarski et al, 2015, 23(7):1601-12. doi: 10.1016 j.bmc.2015.01.049. Epub 2015 Feb 7. PMID:25725609; CJ Kutz et al Medchemcomm. 2014, 5(12): 1863-1870 PMID: 25580204; C Zhou et al, Chemical Biology & Drug Design,2015, 85(6):659-671. doi:10.1111/cbdd.12461 , epub 22-dec-2014; P Prusevich et al, ACS Chem Biol. 2014, 9(6):1284-93. doi: 10.1021/cb500018s. Epub 2014 Apr 7; B Dulla et al, Org Biomol Chem 2013,11 , 3103-3107, doi: 10.1039/c3ob40217g; JR Hitchin et al, MedChemCommun,2013, 4, 1513-1522 DOI: 10.1039/c3md00226h; and Y Zhou et al," Synthesis and biological evaluation of novel (E)-N'-(2, 3-dihydro-1 H-inden-1-ylidene) benzohydrazides as potent LSD1 inhibitors", Biorg Med Chem Lett, 2015, online publication 20-Jun-2015, doi: 10.1016/j.bmcl.2015.06.054, WO2014/194280.WO2015/120281 , WO2015/123465, WO2015/123437, WO2015/123424, WO2015/123408, WO2015/134973, WO2015/156417, WO2015/168466, WO2015/181380, WO2015/200843, WO2016/003917, WO2016/004105, WO2016/007722, WO2016/007727, WO2016/007731 , WO2016/007736,WO2016/034946, WO2016/037005.

Among the references listed above, the following disclose irreversible LSD1 i: WO2010/043721 , WO2010/084160, WO2011/035941 , WO2011/042217, WO2011/131697, WO2012/013727, WO2012/013728, WO2012/045883, WO2013/057320, WO2013/057322, WO2010/143582, US2010-0324147, WO2011/131576, WO2012/135113, WO2013/022047, WO2014/058071 , WO2014/084298, WO2014/086790, WO2014/164867, WO2015/021128; K Taeko et al, Bioorg Med Chem Lett. 2015, 25(9):1925-8. doi: 10.1016/j.bmcl.2015.03.030. Epub 2015 Mar 20, PMID: 25827526; S Valente et al, Eur J Med Chem. 2015, 94:163-74. doi: 10.1016/j.ejmech.2015.02.060. Epub 2015 Mar 3, PMID:25768700; MN Ahmed Khan et al Med. Chem. Commun., 2015,6, 407-412, DOI: 10.1039/C4MD00330F epub 29 Sep 2014; M Pieroni et al, Eur J Med Chem. 2015 ;92:377-386. doi: 10.1016/j.ejmech.2014.12.032. Epub 2015 Jan 7. PMID:25585008; V Rodriguez et al, Med. Chem. Commun., 2015,6, 665-670 DOI: 10.1039/C4MD00507D, Epub 23 Dec 2014; P Vianello et al, Eur J Med Chem. 2014, 86:352-63. doi: 10.1016/j.ejmech.2014.08.068. Epub 2014 Aug 27, WO2014/194280, WO2015/123465, WO2015/123437, WO2015/123424, WO2015/123408, WO2015/156417, WO2015/181380. In the methods and therapeutic uses of the invention the LSD1 i is preferably an irreversible LSD1 L In the methods and uses according to the invention, the LSD1 inhibitor is preferably a 2-(hetero)arylcyclopropylamino LSD1 L As used herein, a "2-(hetero)arylcyclopropylamino LSD1 i" or a "2-(hetero)arylcyclopropylamino compound" means a LSD1 i whose chemical structure comprises a cyclopropyl ring substituted at position 1 with an amino group, which can be optionally substituted, and substituted at position 2 with an aryl or heteroaryl group (wherein the aryl or heteroaryl group can be optionally substituted). The ability of a compound to inhibit LSD1 can be tested in vitro using any method known in the art to determine LSD1 inhibition, for example the method disclosed in Example 1.

In the methods and uses according to the invention, the LSD1 inhibitor is preferably a 2- (hetero)arylcyclopropylamino LSD1 i as disclosed in any of WO2010/043721, WO2010/084160, WO2011/035941 , WO2011/042217, WO2011/131697, WO2012/013727, WO2012/013728, WO2012/045883, WO2013/057320, WO2013/057322, WO2012/135113, WO2013/022047, WO2014/058071 , WO2010/143582, US2010-0324147, WO2011/131576, WO2014/084298, WO2014/086790, WO2014/164867, WO2015/021128, WO2014/194280, WO2015/123465, WO2015/123437, WO2015/123424, WO2015/123408, WO2015/156417, or WO2015/181380, the disclosure of each of which is incorporated by reference herein in their entirety, and preferably as disclosed in WO2010/043721 , WO2010/084160, WO2011/035941 , WO2011/042217, WO2011/131697, WO2012/013727, WO2012/013728, WO2012/045883, WO2013/057320, WO2013/057322, WO2012/135113, WO2013/022047 or WO2014/058071.

In the methods and uses according to the invention, the LSD1 inhibitor can be a compound of formula (I) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:

(I)

In formula (I), each of R1-R5 is optionally substituted and independently chosen from -H, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heteroaryl, -L-heterocyclyl, -L-carbocycle, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido;

R6 is chosen from -H and alkyl; R7 is chosen from -H, alkyl, and cycloalkyl;

R8 is chosen from -C(=0)NR_xR_y and -C(=0)R_z;

Rx when present is chosen from -H, alkyl, alkynyl, alkenyl, -L-carbocycle, -L-aryl, -L-heterocyclyl, all of which are optionally substituted;

R_y when present is chosen from -H, alkyl, alkynyl, alkenyl, -L-carbocycle, -L-aryl, -L-heterocyclyl, all of which are optionally substituted;

Rz when present is chosen from -H, alkoxy, -L-carbocyclic, -L-heterocyclic, -L-aryl, wherein the aryl, heterocyclyl, or carbocycle is optionally substituted;

each L can be saturated, partially saturated, or unsaturated, and is independently chosen from -(CH2)_n-(CH2)_n-, -(CH₂)nC(=0)(CH₂)n-, -(CH₂)nC(=0)NH(CH₂)n-, -(CH₂)_nNHC(=0)0(CH₂)n-, -(CH₂)_nNHC(=0)NH(CH₂)n-, - (CH₂)_nNHC(=S)S(CH₂)n-, -(CH₂)nOC(=0)S(CH₂)n-, -(CH₂)_nNH(CH₂)n-, -(CH₂)nO(CH₂)_n-, -(CH₂)_nS(CH₂)n-, and - (CH₂)nNHC(=S)NH(CH₂)n-, where each n is independently chosen from 0, 1 , 2, 3, 4, 5, 6, 7, and 8, wherein optionally substituted refers to zero or 1 to 4 optional substituents independently chosen from acylamino, acyloxy, alkenyl, alkoxy, cycloalkoxy, alkyl, alkylthio, cycloalkylthio, alkynyl, amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, carbocyclyl, cyano, cyanato, halo, haloalkyl, haloaryl, hydroxyl, heteroaryl, heteroaryloxy, heterocyclyl, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl,

0- thiocarbamyl, N-thiocarbamyl, and C-amido.

Compounds of formula (I) having a (trans) disposition on the substituents on the cyclopropyl ring are preferred. Preferably, the compound of formula (I) is a compound from the list below:

N-cyclopropyl-2-{[(trans)-2-phenylcyclopropyl]amino}acetamide;

2-{[(trans)-2-phenylcyclopropyl]amino}acetamide;

N-cyclopropyl-2-{[(trans)-2-phenylcyclopropyl]amino}propanamide;

2-{[(trans)-2-phenylcyclopropyl]amino}-N-prop-2-ynylacetamide;

N-isopropyl-2-{[(trans)-2-phenylcyclopropyl]amino}acetamide;

N-(tert-butyl)-2-{[(trans)-2-phenylcyclopropyl]amino}acetamide;

N-(2-morpholin-4-yl-2-oxoethyl)-N-[(trans)-2-phenylcyclopropyl]amine;

2-{[(trans)-2-phenylcyclopropyl]amino}propanamide;

Methyl 2-{[(trans)-2-phenylcyclopropyl]amino}propanoate;

N-cyclopropyl-2-{methyl[(trans)-2-phenylcyclopropyl]amino}acetamide;

2-{methyl[(trans)-2-phenylcyclopropyl]amino}acetamide;

N-methyl-trans-2-(Phenylcyclopropylamino)propanamide;

1- (4-methylpiperazin-1-yl)-2-((trans)-2-phenylcyclopropylamino)ethanone;

1- (4-ethylpiperazin-1-yl)-2-((trans)-2-phenylcyclopropylamino)ethanone;

1 -(4-benzyl piperazin-1 -yl)-2-(( trans)-2-phenylcyclopropylamino)ethanone;

2- ((trans)-2-phenylcyclopropylamino)-1-(4-phenylpiperazin-1-yl)ethanone; 2-((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)-1-(4-methylpiperazin-1-yl)ethanone;

2-((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)-N-cyclopropylacetamide;

2-((trans)-2-(4-(3-fluorobenzyloxy)phenyl)cyclopropylamino)-1-(4-methylpiperazin-1-yl)ethanon

2-((trans)-2-(4-(3-chlorobenzyloxy)phenyl)cyclopropylamino)-1-(4-methylpiperazin-1-yl)ethan

2-((trans)-2-(biphenyl-4-yl)cyclopropylamino)-1-(4-methylpiperazin-1-yl)ethanone;

1- (4-methylpiperazin-1-yl)-2-((trans)-2-(4-phenethoxyphenyl)cyclopropylamino)ethanone;

2- ((trans)-2-(4-(4-fluorobenzyloxy)phenyl)cyclopropylamino)-1-(4-methylpiperazin-1-yl)ethanon

2-((trans)-2-(4-(biphenyl-4-ylmethoxy)phenyl)cyclopropylamino)-1-(4-methylpipe

2-({(trans)-2-[4-(benzyloxy)phenyl]cyclopropyl}amino)-N-cyclopropylacetamide,

N-[(trans)-2-(4-benzyloxyphenyl)cyclopropyl]}-N-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]amine,

N-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]-N-[(trans)-2-phenylcyclopropyl]amine,

N-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]-N-[(trans)-2-phenylcyclopropyl]amine ,

N-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-N-[(trans)-2-phenylcyclopropyl]amine,

N-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-N-[(trans)-2-phenylcyclopropyl]amine,

2-((trans)-2-(4-pyridin-3-ylphenyl) cyclopropylamino)-1-(4-methylpiperazin-1-yl)ethanone, and

2-((trans)-2-(3'-methoxy-1 ,1'-biphenyl-4-yl) cyclopropylamino)-1-(4-methylpiperazin-1-yl)ethanone, and pharmaceutically acceptable salts thereof.

Compounds of formula (I) can be prepared by the methods disclosed in WO2010/043721, the disclosure of which is incorporated by reference herein in its entirety.

In the methods and uses according to the invention, the LSD1 inhibitor can be a compound of formula (II) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutic thereof:

In formula (II), each of R1-R5 is independently chosen from -H, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido;

R6 is chosen from -H and alkyl; R7 is chosen from -H, alkyl, and cycloalkyl;

R8 is a -L-heterocyclyl wherein the ring or ring system of said -L-heterocyclyl has from 0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cydoalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyi, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, 0- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; or

R8 is -L-aryl wherein the ring or ring system of said -L-aryl has from 1-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cydoalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyi, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido;

each L is independently chosen from -(CH₂)n-(CH₂)n-, -(CH₂)nNH(CH₂)n-, -(CH₂)_nO(CH₂)_n-, and -(CH₂)_nS(CH₂)_n-, and where each n is independently chosen from 0, 1 , 2, and 3.

Compounds of formula (II) having a (trans) disposition on the substituents on the cyclopropyl ring are preferred. Preferably the compound of formula (II) is a compound from the list below:

(trans)-N-(4-fluorobenzyl)-2-phenylcyclopropanamine;

(trans)-N-(4-fluorobenzyl)-2-phenylcyclopropanaminium;

4-(((trans)-2-phenylcyclopropylamino)methyl)benzonitrile;

trans)-N-(4-cyanobenzyl)-2-phenylcyclopropanaminium;

trans)-2-phenyl-N-(4-(trifluoromethyl)benzyl)cyclopropanamine;

trans)-2-phenyl-N-(4-(trifluoromethyl)benzyl)cyclopropanaminium;

trans)-2-phenyl-N-(pyridin-2-ylmethyl)cyclopropanamine;

trans)-2-phenyl-N-(pyridin-3-ylmethyl)cyclopropanamine;

trans)-2-phenyl-N-(pyridin-4-ylmethyl)cyclopropanamine;

trans)-N-((6-methylpyridin-2-yl)methyl)-2-phenylcyclopropanamine;

trans)-2-phenyl-N-(thiazol-2-ylmethyl)cyclopropanamine;

trans)-2-phenyl-N-(thiophen-2-ylmethyl)cyclopropanamine;

trans)-N-((3-bromothiophen-2-yl)methyl)-2-phenylcyclopropanamine;

trans)-N-((4-bromothiophen-2-yl)methyl)-2-phenylcyclopropanamine;

trans)-N-(3,4-dichlorobenzyl)-2-phenylcyclopropanamine;

trans)-N-(3-fluorobenzyl)-2-phenylcyclopropanaminium;

trans)-N-(2-fluorobenzyl)-2-phenylcyclopropanamine;

trans)-2-phenyl-N-(quinolin-4-ylmethyl)cyclopropanamine;

trans)-N-(3-methoxybenzyl)-2-phenylcyclopropanamine; (trans)-2-phenyl-N-((6-(trifluoromethyl)pyridin-3- yl)methyl)cyclopropanamine;

(trans)-N-((6-chloropyridin-3-yl)methyl)-2- phenylcyclopropanamine;

(trans)-N-((4-methylpyridin-2-yl)methyl)-2-phenylcyclopropanamine;

(trans)-N-((6-rnethoxypyridin-2-yl)rnethyl)-2-phenylcyclopropanamine;

2-(((trans)-2-phenylcyclopropylamino)methyl)pyridin-3-ol;

(trans)-N-((6-bromopyridin-2-yl)methyl)-2-phenylcyclopropanamine;

4-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)benzonitrile;

(trans)-N-(4-(benzyloxy)benzyl)-2-phenylcyclopropanamine;

(trans)-N-benzyl-2-(4-(benzyloxy)phenyl)cyclopropanamine;

(trans)-2-(4-(benzyloxy)phenyl)-N-(4- methoxybenzyl)cyclopropanamine;

(trans)-2-(4-(benzyloxy)phenyl)-N-(4- fluorobenzyl)cyclopropanamine;

(trans)-2-phenyl-N-(quinolin-2-ylmethyl)cyclopropanamine;

(trans)-2-phenyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropanamine;

(trans)-N-((3-fluoropyridin-2-yl)methyl)-2-phenylcyclopropanamine;

(trans)-2-phenyl-N-(quinolin-3-ylmethyl)cyclopropanamine;

(trans)-N-((6-rnethoxypyridin-3-yl)rnethyl)-2-phenylcyclopropanamine;

(trans)-N-((5-rnethoxypyridin-3-yl)rnethyl)-2-phenylcyclopropanamine;

(trans)-N-((2-rnethoxypyridin-3-yl)rnethyl)-2-phenylcyclopropanamine;

(trans)-N-((3H-indol-3-yl)methyl)-2-phenylcyclopropanamine;

3-(((trans)-2-phenylcyclopropylamino)methyl)benzonitrile;

(trans)-N-(2-methoxybenzyl)-2-phenylcyclopropanamine;

3-(((trans)-2-phenylcyclopropylamino)methyl)pyridin-2-amine;

(trans)-N-((2-chloropyridin-3-yl)methyl)-2-phenylcyclopropanamine;

(trans)-N-(3,4-dimethoxybenzyl)-2-phenylcyclopropanamine;

(trans)-N-((2,3-dihydrobenzofuran-5-yl)methyl)-2-phenylcyclopropanamine;

(trans)-N-(benzo[d][1 ,3]dioxol-5-ylmethyl)-2-phenylcyclopropanamine;

(trans)-N-((2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)methyl)-2-phenylcyclopropanamine;

(trans)-N-(2,6-difluoro-4-methoxybenzyl)-2-phenylcyclopropanamine;

(trans)-2-phenyl-N-(4-(trifluoromethoxy)benzyl)cyclopropanamine;

(trans)-N-(5-fluoro-2-methoxybenzyl)-2-phenylcyclopropanamine;

(trans)-N-(2-fluoro-4-methoxybenzyl)-2-phenylcyclopropanamine;

(trans)-N-((4-methoxynaphthalen-1-yl)rnethyl)-2-phenylcyclopropanamine;

(trans)-N-(2-fluoro-6-methoxybenzyl)-2-phenylcyclopropanamine;

(trans)-N-((2-methoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanamine;

(trans)-N-((4J-dimethoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanamine;

(trans)-N-(4-methoxy-3-methylbenzyl)-2-phenylcyclopropanamine; rans) -N- (3-chloro-4-methoxybenzyl)-2-phenylcyclopropanamine;

rans) -N- (3-fluoro-4-methoxybenzyl)-2-phenylcyclopropanamine;

rans) -N- (4-methoxy-2-methylbenzyl)-2-phenylcyclopropanamine;

rans) -N- ((3,4-dihydro-2H-benzo[b][1 ,4]dioxepin-6-yl)methyl)-2-phenylcyclopropanamine;

rans) -N- ((3,4-dihydro-2H-benzo[b][1 ,4]dioxepin-7-yl)methyl)-2-phenylcyclopropanamine;

rans) -N- ((2,2-dimethylchroman-6-yl)methyl)-2-phenylcyclopropanarnine;

rans) -N- (4-methoxy-2,3-dimethylbenzyl)-2-phenylcyclopropanamine;

rans) -N- (4-methoxy-2,5-dimethylbenzyl)-2-phenylcyclopropanamine;

rans) -N- (2-fluoro-4,5-dimethoxybenzyl)-2-phenylcyclopropanamine;

rans) -N- (3-chloro-4,5-dimethoxybenzyl)-2-phenylcyclopropanamine;

rans) -N- (2-chloro-3,4-dimethoxybenzyl)-2-phenylcyclopropanamine;

rans) -N- (2,4-dimethoxy-6-methylbenzyl)-2-phenylcyclopropanamine;

rans) -N- (2,5-dimethoxybenzyl)-2-phenylcyclopropanamine;

rans) -N- (2,3-dimethoxybenzyl)-2-phenylcyclopropanamine;

rans) -N- (2-chloro-3-methoxybenzyl)-2-phenylcyclopropanamine;

rans) -N- ((1H-indol-5-yl)methyl)-2-phenylcyclopropanamine;

rans) -2- ;4-(benzyloxy)phenyl)-N-(pyridin-2-ylmethyl)cyclopropanamine;

rans) -2- [4-(benzyloxy)phenyl)-N-(2-methoxybenzyl)cyclopropanamine;

rans) -N- (1-(4-methoxyphenyl)ethyl)-2-phenylcyclopropanamine;

rans) -N- (1-(3,4-dimethoxyphenyl)ethyl)-2-phenylcyclopropanamine;

rans) -N- (1-(2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)ethyl)-2-phenylcyclopropanamine;

rans) -N- (1-(5-fluoro-2-methoxyphenyl)ethyl)-2-phenylcyclopropanamine;

rans) -N- (1-(3,4-dimethoxyphenyl)propan-2-yl)-2-phenylcyclopropanamine;

rans) -N- ((3-methyl-1 ,2,4-oxadiazol-5-yl)methyl)-2-phenylcyclopropanamine; and

pharmaceutically acceptable salts thereof.

Compounds of formula (II) can be prepared by the methods disclosed in WO2010/084160, the disclosure of which is incorporated by reference herein in its entirety.

In the methods and uses according to the invention, the LSD1 inhibitor can be a compound of formula (III) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:

(A')x-(A)-(B)-(Z)-(L)-(D)

(III)

In formula (III), (A) is heteroaryl or aryl;

each (Α'), if present, is independently chosen from aryl, arylalkoxy, arylalkyl, heterocyclyl, aryloxy, halo, alkoxy, haloalkyi, cycloalkyi, haloalkoxy, and cyano, wherein each (Α') is substituted with 0, 1 , 2, or 3 substituents independently chosen from halo, haloalkyi, aryl, arylalkoxy, alkyl, alkoxy, cyano, sulfonyl, amido, and sulfinyl; X is O, 1, 2, or 3;

(B) is a cydopropyl ring, wherein (A) and (Z) are covalently bonded to different carbon atoms of (B);

(Z) is -NH-;

(L) is chosen from -CH₂CH₂-, -CH2CH2CH2-, and -CH2CH2CH2CH2-; and

(D) is chosen from -N(-R1)-R2, -0-R3, and -S-R3, wherein:

R1 and R2 are mutually linked to form a heterocyclic ring together with the nitrogen atom that R1 and R2 are attached to, wherein said heterocyclic ring has 0, 1 , 2, or 3 substituents independently chosen from -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(Ci-Ce alkyl), alkyl, halo, cyano, alkoxy, haloalkyi, and haloalkoxy, or

R1 and R2 are independently chosen from -H, alkyl, cydoalkyi, haloalkyi, and heterocydyl, wherein the sum of substituents on R1 and R2 together is 0, 1, 2, or 3, and the substituents are independently chosen from -NH2, -NH(Ci-C₆ alkyl), -N(0-C₆ alkyl)(Ci-C₆ alkyl), and fluoro; and

R3 is chosen from -H, alkyl, cydoalkyi, haloalkyi, and heterocydyl, wherein R3 has 0, 1, 2, or 3 substituents independently chosen from -NH₂, -NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)(Ci-Ce alkyl), and fluoro.

Compounds of formula (III) having a (trans) disposition on the substituents on the cydopropyl ring are preferred.

Preferably the compound of formula (III) is a compound from the list below:

N-[2-(4-methylpiperazin-1-yl)ethyl]-N-[(trans)-2-phenylcyclopropyl] amine;

N-cyclopropyl-N'-[(trans)-2-phenylcyclopropyl]ethane-1 ,2-diamine;

N,N-dimethyl-N'-(2-{[(trans)-2-phenylcyclopropyl]amino}ethyl)ethane-1 ,2-diamine;

(3R)-1-(2-{[(trans)-2-phenylcyclopropyl]amino}ethyl)pyrrolidin-3-amine;

(3S)-N,N-dimethyl-1-(2-{[(trans)-2-phenylcyclopropyl]amino}ethyl) pyrrolidin-3-amine;

(3R)-N,N-dimethyl-1-(2-{[(trans)-2-phenylcyclopropyl]amino}ethyl)pyrrolidin-3-amine;

N-[(trans)-2-phenylcyclopropyl]-N-(2-piperazin-1-ylethyl)amine;

N1 ,N1-diethyl-N2-((trans)-2-phenylcyclopropyl)ethane-1,2-diamine;

N-[(trans)-2-phenylcyclopropyl]-N-(2-piperidin-1-ylethyl)amine;

(trans)-2-(4-(benzyloxy)phenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)

cyclopropanamine;

(trans)-N-(2-(4-methylpiperazin-1-yl)ethyl)-2-(3'-(trifluoromethyl)

biphenyl-4-yl)cyclopropanamine;

(trans)-2-(3'-chlorobiphenyl-4-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)

cyclopropanamine;

(R)-1-(2-((trans)-2-(3'-(trifluoromethyl)biphenyl -yl)cyclopropylamino)ethyl)pyrrolidin-3-amine; and

N¹-cyclopropyl-N²-((trans)-2-(3'-(trifluoromethyl)biphenyl-4-yl)

cyclopropyl)ethane-1 ,2-diamine;

N1-((trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropyl)-N2-cyclopropylethane-1 ,2-diamine;

N1-((trans)-2-(3'-chlorobiphenyl-4-yl)cyclopropyl)-N2-cyclopropylethane-1 ,2-diamine; N1-cyclopropyl-N2-((trans)-2-(4-phenethoxyphenyl)cyclopropyl)ethane-1 ,2-diamine;

N1 ,N1-diethyl-N2-((trans)-2-(4-(3-fluorobenzyloxy)phenyl)cyclopropyl)ethane-1 ,2-diamine;

(trans)-2-(4-bromophenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)cyclopropanarnine;

N1-((trans)-2-(terphenyl-4-yl)cyclopropyl)-N2-cyclopropylethane- ,2-diamine;

(trans)-N-(2-(piperidin-1-yl)ethyl)-2-(3'-(trifluoromethyl)biphenyl-4-yl)cyclopropanamine;

N1 ,N1-diethyl-N2-((trans)-2-(3'-(trifluoromethyl)biphenyl-4-yl)cyclopropyl)ethane-1 ,2-diamine;

(trans)-N-(2-(piperazin-1-yl)ethyl)-2-(3'-(trifluoromethyl)biphenyl-4-yl)cyclopropanamine;

(S)-1-(2-((trans)-2-(3'-(trifluoromethyl)biphenyl-4-yl)cyclopropylamino)ethyl)pyrrolidin-3-arnine;

(R)-1-(2-((trans)-2-(3'-chlorobiphenyl-4-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

(R)-1-(2-((trans)-2-(4'-chlorobiphenyl-4-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

(R)-1-(2-((trans)-2-(3'-methoxybiphenyl-4-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

(R)-1-(2-((trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropylamino)ethyl)pyrrolidin-3-amine; and

(R)-1-(2-((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

N-(trans)-2-(isobutylthio)-ethyl-2-phenylcyclopropanamine,

N-trans-(2-ethoxyethyl)-2-phenylcyclopropanamine, and

N-trans-(2-methoxyethyl)-2-phenylcyclopropanamine,

(R)-1-(2-((trans)-2-(4-(4-bromobenzyloxy)phenyl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

(R)-1-(2-((trans)-2-(4-(4-chlorobenzyloxy)phenyl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

(R)-1-(2-((trans)-2-(4-(biphenyl-4-ylmethoxy)phenyl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

(R)-1-(2-((trans)-2-(3',5'-dichlorobiphenyl-4-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

N1-((trans)2-(2-[1 ,1';4',1"]terphenyl-4"-yl-cyclopropyl)-N2-cyclopropylethane-1 ,2-diamine;

(R)-1-(2-((trans)-2-(6-(benzyloxy)-4'-(trifluoromethyl)biphenyl-3-yl)cyclopropylamino)ethyl)pyrrolidin-3-am and

(R)-1-(2-((trans)-2-(6-(benzyloxy)biphenyl-3-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

(R)-1-(2-((trans)-2-(4-phenethoxyphenyl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

(R)-1-(2-((trans)-2-(6-(3-methoxyphenyl)pyridin-3-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

(R)-1-(2-((trans)-2-(6-(4-chlorophenyl)pyridin-3-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine; and

4-((4-((trans)-2-(2-((R)-3-aminopyrrolidin-1-yl)ethylamino)cyclopropyl)phenoxy)methyl)benzonitrile;

and pharmaceutically acceptable salts thereof.

Compounds of formula (III) can be prepared by the methods disclosed in WO2011/035941 , the disclosure of which is incorporated by reference herein in its entirety.

In the methods and uses according to the invention, the LSD1 inhibitor can be a compound of formula (IV) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:

(A')x-(A)-(B)-(Z)-(L)-C(=0)NH₂ In formula (IV), (A) is heteroaryl or aryl;

each (Α'), if present, is indepedently chosen from aryl, arylalkoxy, arylalkyi, heterocyclyl, aryloxy, halo, alkoxy, haloalkyi, cycloalkyi, haloalkoxy, and cyano, wherein each (Α') is substituted with 0, 1, 2 or 3 substituents independently chosen from halo, haloalkyi, aryl, arylalkoxy, alkyl, alkoxy, cyano, sulfonyl, sulfinyl, and carboxamide;

X is O, 1, 2, or 3;

(B) is a cyclopropyl ring, wherein (A) and (Z) are covalently bonded to different carbon atoms of (B);

(Z) is -NH-; and

(L) is -(CH2)mCRiR2-, wherein m is 0, 1, 2, 3, 4, 5, or 6, and wherein Ri and R2 are each independently hydrogen or C1-C6 alkyl;

provided that, if (L) is -CH₂- or -CH(CH₃)-, then X is not 0.

Compounds of formula (IV having a (trans) disposition on the substituents on the cyclopropyl ring are preferred.

Preferably, the compound of formula (IV) is a compound from the list below:

2-((trans)-2-(4-(4-cyanobenzyloxy)phenyl)cyclopropylamino)acetamide,

2-((trans)-2-(4-(3-cyanobenzyloxy)phenyl)cyclopropylamino)acetamide,

2-((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)acetamide,

2-((trans)-2-(4-(4-fluorobenzyloxy)phenyl)cyclopropylamino)acetamide,

2-((trans)-2-(4-(3-fluorobenzyloxy)phenyl)cyclopropylamino)acetamide,

2-((trans)-2-(4-(3-chlorobenzyloxy)phenyl)cyclopropylamino)acetamide,

2-((trans)-2-(4-(4-chlorobenzyloxy)phenyl)cyclopropylamino)acetamide,

2-((trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropylamino)acetamide,

2-((trans)-2-(4-(3,5-difluorobenzyloxy)phenyl)cyclopropylamino)acetamide,

2-((trans)-2-(4-phenethoxyphenyl)cyclopropylamino)acetamide,

2-((trans)-2-(3'-(trifluoromethyl)biphenyl-4-yl)cyclopropylamino)acetamide,

2-((trans)-2-(3'-chlorobiphenyl-4-yl)cyclopropylamino)acetamide,

2-((trans)-2-(6-(4-chlorophenyl)pyridin-3-yl)cyclopropylamino)acetamide,

(R)-2-((trans)-2-(4-(3-fluorobenzyloxy)phenyl)cyclopropylamino)propanamide,

(S)-2-((trans)-2-(4-(4-fluorobenzyloxy)phenyl)cyclopropylamino)propanamide,

(R)-2-((trans)-2-(4-(4-fluorobenzyloxy)phenyl)cyclopropylamino)propanamide,

(S)-2-((trans)-2-(4-(4-fluorobenzyloxy)phenyl)cyclopropylamino)propanamide,

(R)-2-((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)propanamide,

(S)-2-((trans)-2-(4-(benzyloxy)phenyl) cyclopropylamino)propanamide,

2- (2-[1 ,1';4',1"]Terphenyl-4"-yl-cyclopropylamino)acetamide,

5'-((trans)-2-(2-amino-2-oxoethylamino)cyclopropyl)-2'-(benzyloxy)biphenyl-3-carboxamide,

5-((trans)-2-(4'-chlorobiphenyl-4-yl)cyclopropylamino)pentanamide,

3- ((trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropylamino)propanamide, 4- ((trans)-2-phenylcyclopropylamino)butanamide,

5- ((trans)-2-phenylcyclopropylamino)pentanamide,

5-((trans)-2-(4'-chlorobiphenyl-4-yl)cyclopropylamino)-2-methylpentanamide,

4-((trans)-2-(4'-chlorobiphenyl-4-yl)cyclopropylamino)-2-methylbutanamide,

3-((trans)-2-(4-(3-fluorobenzyloxy)phenyl)cyclopropylamino)-2,2-dimethylpropanamide,

3- ((trans)-2-(4'-chlorobiphenyl-4-yl)cyclopropylamino)propanamide,

4- ((trans)-2-(4'-chlorobiphenyl-4-yl)cyclopropylamino)butanamide,

4- ((trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropylarnino)butanarnide,

5- ((trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropylamino)pentanarriide,

5-((trans)-2-(6-(benzyloxy)biphenyl-3-yl)cyclopropylamino)pentanarriide, and

4-((trans)-2-(6-(benzyloxy)biphenyl-3-yl)cyclopropylamino)butanamide,

and pharmaceutically acceptable salts thereof.

Compounds of formula (IV) can be prepared by the methods disclosed in WO2011/042217, the disclosure of which is incorporated by reference herein in its entirety.

In the methods and uses according to the invention, the LSD1 inhibitor can be a compound of formula (V) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:

(

In formula (V), E is -N(R3)-, -0-, or -S-, or is -X³=X⁴-;

X¹ and X² are independently C(R2) or N;

X³ and X⁴, when present, are independently C(R2) or N;

(G) is a cyclyl group;

each (R1) is independently chosen from alkyl, alkenyl, alkynyl, cyclyl, -L1 -cyclyl, -L1-amino, -L1-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, or carboxyl;

each (R2) is independently chosen from -H, alkyl, alkenyl, alkynyl, cyclyl, -L1-cyclyl, -L1-amino, -L1-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, or carboxyl, wherein each (R2) group has 1 , 2, or 3 independently chosen optional substituents or two (R2) groups can be taken together to form a heterocyclyl or aryl group having 1 , 2, or 3 independently chosen optional substituents, wherein said optional substituents are independently chosen from alkyl, alkanoyl, heteroalkyl, heterocyclyl, haloalkyl, cycloalkyl, carbocyclyl, arylalkoxy, heterocyclylalkoxy, aryl, aryloxy, heterocyclyloxy, alkoxy, haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, carboxamido, cyano, halogen, hydroxyl, amino, aminoalkyi, amidoalkyi, amido, nitro, thiol, alkylthio, arylthio, sulfonamide, sulfinyl, sulfonyl, urea, or carbamate;

R3 is -H or a (Ci-Ce)alkyl group;

each L1 is independently alkylene or heteroalkylene; and

n is 0, 1, 2, 3, 4 or 5.

Compounds of formula (V) having a (trans) disposition on the substituents on the cyclopropyl ring are preferred.

Preferably, the compound of formula (V) is a compound from the list below:

(trans)-2-(3'-(trifluoromethyl)biphenyl-4-yl)cyclopropanamine;

(trans)-2-(terphenyl-4-yl)cyclopropanamine;

4'-((trans)-2-aminocyclopropyl)biphenyl-4-ol;

4'-((trans)-2-aminocyclopropyl)biphenyl-3-ol;

(trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

(Trans)-2-(6-(3,5-dichlorophenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(4-chlorophenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(3-chlorophenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(4-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(3-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

4-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzonitrile;

3- (5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzonitrile;

(Trans)-2-(6-p-tolylpyridin-3-yl)cyclopropanamine;

(Trans)-2-(6-m-tolylpyridin-3-yl)cyclopropanamine;

4- (5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenol;

4- (5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzamide;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzamide;

2- (5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenol;

3- (5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenol;

(Trans)-2-(6-(3-methoxy-4-methylphenyl)pyridin-3-yl)cyclopropanamine;

5- (5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2-fluorophenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-fluorophenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-fluorophenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2-fluorophenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2,4-difluorophenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2,4,6-trifluorophenol; 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-chlorophenol;

(Trans)-2-(6-(2-fluoro-3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

(Trans)-2-(6-(5-chlorothiophen-2-yl)pyridin-3-yl)cyclopropanamine;

(Trans)-2-(6-(5-methylthiophen-2-yl)pyridin-3-yl)cyclopropanamine;

(Trans)-2-(6-(1 H-indol-6-yl)pyridin-3-yl)cyclopropanamine;

(Trans)-2-(6-(benzo[b]thiophen-5-yl)pyridin-3-yl)cyclopropanamine;

3-(5-((trans)-2-aminocyclopropyl)-3-methylpyridin-2-yl)phenol;

(trans)-2-(6-(3-chlorophenyl)-5-methylpyridin-3-yl)cyclopropanamine;

(trans)-2-(5-methyl-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(4-fluoro-3-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(3-fluoro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(2-fluoro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(2-fluoro-3-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(3-chloro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(2-chloro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(3-methoxy-5-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanarnine;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-methoxybenzonitrile;

5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2-methylphenol;

3- (5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-chlorophenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-(trifluoromethyl)phenol;

(trans)-2-(6-(2-fluoro-5-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanarnine;

(trans)-2-(6-(2-chloro-5-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanarnine;

(trans)-2-(6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

N-(3-(5-((trans)-2-aminocyclopropyl)pyndin-2-yl)phenyl)acetamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)methanesulfonamide;

(trans)-2-(6-(benzo[b]thiophen-2-yl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(benzo[b]thiophen-3-yl)pyridin-3-yl)cyclopropanamine;

5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)thiophene-2-carbonitrile;

(trans)-2-(6-(4-methylthiophen-3-yl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(2-chloro-6-(3-(tnfluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(2-(4-chlorophenyl)-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

4- (3-((trans)-2-aminocyclopropyl)-6-(3-(trifluoromethyl)phenyl)pyridin-2-yl)phenol; 4-(3-((trans)-2-aminocyclopropyl)-6-(3-(trifluoromethyl)phenyl)pyridin-2-yl)benzamide; (trans)-2-(2-methyl-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-hydroxybenzonitrile;

(trans)-2-(6-(3,4-difluoro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine; 5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2,3-difluorophenol;

(trans)-2-(6-(3-chloro-4-fluoro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

5- (5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-3-chloro-2-fluorophenol;

(trans)-2-(6-(1H-indazol-6-yl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(9H-carbazol-2-yl)pyridin-3-yl)cyclopropanamine;

6- (5-((trans)-2-aminocyclopropyl)pyridin-2-yl)indolin-2-one;

6-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzofuran-2(3H)-one;

4-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)pyridin-2(1 H)-one;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)benzenesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)propane-2-sulfonamide;

4'-((trans)-2-aminocyclopropyl)-4-fluorobiphenyl-3-ol;

4'-((trans)-2-aminocyclopropyl)-5-chlorobiphenyl-3-ol;

4'-((trans)-2-aminocyclopropyl)-5-chloro-4-fluorobiphenyl-3-ol;

N-(4'-((trans)-2-aminocyclopropyl)biphenyl-3-yl)benzenesulfonamide;

N-(4'-((trans)-2-aminocyclopropyl)biphenyl-3-yl)propane-2-sulfonamide;

N-(4'-((trans)-2-aminocyclopropyl)biphenyl-3-yl)methanesulfonamide;

N-(2-(5-((trans)-2-aminocyclopropyl)pyndin-2-yl)phenyl)methanesulfonamide;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-methoxybenzonitrile;

N-(4'-((trans)-2-aminocyclopropyl)biphenyl-2-yl)methanesulfonamide;

4'-((trans)-2-aminocyclopropyl)-6-methoxybiphenyl-3-carbonitrile;

N-(4'-((trans)-2-aminocyclopropyl)-6-methoxybiphenyl-3-yl)methanesulfonamide;

4'-((trans)-2-aminocyclopropyl)-6-hydroxybiphenyl-3-carbonitrile;

N-(4'-((trans)-2-aminocyclopropyl)-6-hydroxybiphenyl-3-yl)rnethanesulfonamide;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-hydroxybenzonitrile;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-hydroxyphenyl)methanesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-(trifluoromethyl)phenyl)ethanesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide;

3-(6-((trans)-2-aminocyclopropyl)pyridin-3-yl)phenol;

(Trans)-2-(5-(3-methoxyphenyl)pyridin-2-yl)cyclopropanamine;

4-(6-((trans)-2-aminocyclopropyl)pyridin-3-yl)phenol;

2-(6-((trans)-2-aminocyclopropyl)pyridin-3-yl)phenol;

2- (5-((trans)-2-aminocyclopropyl)thiophen-2-yl)phenol;

3- (5-((trans)-2-aminocyclopropyl)thiophen-2-yl)phenol;

4- (5-((trans)-2-aminocyclopropyl)thiophen-2-yl)phenol;

2-(5-((trans)-2-aminocyclopropyl)thiazol-2-yl)phenol;

3-(5-((trans)-2-aminocyclopropyl)thiazol-2-yl)phenol; 4-(5-((trans)-2-aminocyclopropyl)thiazol-2-yl)phenol;

2- (2-((trans)-2-aminocyclopropyl)thiazol-5-yl)phenol;

3- (2-((trans)-2-aminocyclopropyl)thiazol-5-yl)phenol;

2- (2-((trans)-2-aminocyclopropyl)thiazol-5-yl)phenol;

3-(2-((trans)-2-aminocyclopropyl)thiazol-5-yl)phenol;

3- (5-((trans)-2-aminocyclopropyl)pyrimidin-2-yl)phenol;

4- (5-((trans)-2-aminocyclopropyl)pyrimidin-2-yl)phenol;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl) -methoxyphenyl)methane

N-(4'-((trans)-2-aminocyclopropyl)-5-chloro-[1 ,1'-biphenyl]-3-yl)methanesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-chlorophenyl)methanesulfonami

N-(4'-((trans)-2-aminocyclopropyl)-4-fluoro-[1 ,1'-biphenyl]-3-yl)methanesulfonamide;

N-(5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2-fluorophenyl)methanesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)ethanesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)-4-cyanobenzenesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)-3-cyanobenzenesulfonam^

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)-2-cyanobenzenesulfonam

N-(3-(5-((trans)-2-aminocyclopropyl)py^

N-(4'-((trans)-2-aminocyclopropyl)-[1 ,1'-biphenyl]-3-yl)-1 ,1 ,1-trifluoromethanesulfonamide;

4'-((trans)-2-aminocyclopropyl)-6-hydroxy-[1,1'-biphenyl]-3-carbonitrile;

4'-((trans)-2-aminocyclopropyl)-[1 ,1'-biphenyl]-2-ol;

4'-((trans)-2-aminocyclopropyl)-3'-methoxy-[1 ,1'-biphenyl]-3-ol;

N-(3-(5-((trans)-2-aminocyclopropyl)thiazol-2-yl)phenyl)-2-cyanobenzenesulfonam

and pharmaceutically acceptable salts thereof.

Compounds of formula (V) can be prepared by the methods disclosed in WO2012/013727, the disclosure of which is incorporated by reference herein in its entirety.

In the methods and uses according to the invention, the LSD1 inhibitor can be a compound of formula (VI) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:

(A')x-(A)-(B)-(Z)-(L)-(D)

(VI)

In formula (VI), (A) is heteroaryl or aryl;

each (Α'), if present, is independently chosen from aryl, arylalkoxy, arylalkyl, heterocyclyl, aryloxy, halo, alkoxy, haloalkyl, cycloalkyl, haloalkoxy, and cyano, wherein each (Α') is substituted with 0, 1 , 2, or 3 substituents independently chosen from halo, haloalkyl, haloalkoxy, aryl, arylalkoxy, alkyl, alkoxy, amido, -CH2C(=0)NH2, heteroaryl, cyano, sulfonyl, and sulfinyl;

X is O, 1, 2, or 3; (B) is a cyclopropyl ring, wherein (A) and (Z) are covalently bonded to different carbon atoms of (B);

(Z) is -NH-;

(L) is chosen from a single bond, -CH₂-, -CH2CH2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-; and

(D) is an aliphatic carbocyclic group or benzocycloalkyl, wherein said aliphatic carbocyclic group or said benzocycloalkyl has 0, 1 , 2, or 3 substituents independently chosen from -NH₂, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(CrC6 alkyl), alkyl, halo, amido, cyano, alkoxy, haloalkyl, and haloalkoxy.

Preferably in formula (VI),

(A) is aryl or heteroaryl. Said aryl is preferably phenyl. Said heteroaryl is preferably pyridinyl, pyrimidinyl, or thiophenyl; and/or

(Α^'), if present, is aryl or arylalkoxy. Said aryl is preferably phenyl. Said arylalkoxy is preferably benzyloxy, all of which can be optionally substituted as provided above; and/or

(L) is a single bond.

Compounds of formula (VI) having a (trans) disposition on the substituents on the cyclopropyl ring are preferred.

Preferably, the compound of formula (VI) is a compound from the list below:

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-6-methoxy-2,3-dihydro-1 H-inden-1-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-5,6-dimethoxy-2,3-dihydro-1 H-inden-1-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-4,5-dimethoxy-2,3-dihydro-1 H-inden-1-amine;

N-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1 H-inden- -amine;

6-methoxy-N-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1 H-inden-1 -amine;

6- chloro-N-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1 H-inden-1-amine;

N-((trans)-2-phenylcyclopropyl)-6-(trifluoromethyl)-2,3-dihydro-1 H-inden-1-amine;

7- methoxy-N-((trans)-2-phenylcyclopropyl)-1 ,2,3,4-tetrahydronaphthalen-1-amine;

N-((trans)-2-(3'-chlorobiphenyl-4-yl)cyclopropyl)-6-methoxy-2,3-dihydro-1 H-inden-1-amine;

N-((trans)-2-(4'-chlorobiphenyl-4-yl)cyclopropyl)-6-methoxy-2,3-dihydro-1 H-inden-1 -amine;

6-methoxy-N-((trans)-2-(3'-methoxybiphenyl-4-yl)cyclopropyl)-2,3-dihydro-1 H-inden-1-amine;

N-trans-(2-cyclohexylethyl)-2-phenylcyclopropanamine;

(Trans)-N-(3-cyclohexylpropyl)-2-phenylcyclopropanamine;

(Trans)-N-(2-cycloheptylethyl)-2-phenylcyclopropanamine;

(Trans)-2-(4-(3-bromobenzyloxy)phenyl)-N-(2-cyclohexylethyl) cyclopropanamine;

N-((trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropyl)-6-methoxy-2,3-dihydro-1 H-inden-1-amine;

(Trans)-2-(3'-chlorobiphenyl-4-yl)-N-(2-cyclohexylethyl)cyclopropanamine;

(Trans)-2-(4'-chlorobiphenyl-4-yl)-N-(2-cyclohexylethyl)cyclopropanamine;

(Trans)-N-(2-cyclohexylethyl)-2-(3'-methoxybiphenyl-4-yl)cyclopropanamine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-7-methoxy-1 ,2,3,4-tetrahydronaphthalen-1-amine; and

1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)cyclopropanecarboxamide; and pharmaceutically acceptable salts thereof.

Compounds of formula (VI) can be prepared by the methods disclosed in WO2011/131697, the disclosure of which is incorporated by reference herein in its entirety.

In the methods and uses according to the invention, the LSD1 inhibitor can be a compound of formula (VII) or

(VII)

In formula (VII), E is -X³=X⁴-,-N(R3)-, -S-, or -0-;

X¹ and X²are each independently C(R2) or N;

X³and X⁴, when present, are each independently C(R2) or N;

L1 is -NH- or -NH-CH₂-;

G is a cyclyl group;

each R1 is independently chosen from alkyl, alkenyl, alkynyl, cyclyl, -L2-cyclyl, -L2-amino, -L2-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, or carboxyl;

each R2 is independently chosen from -H, alkyl, alkenyl, alkynyl, cyclyl, -L2-cyclyl, -L2-amino, -L2-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, or carboxyl, wherein each R2 group has 1 , 2, or 3 independently chosen optional substituents, and further wherein two R2 groups bound to adjacent carbon atoms can be taken together to form a heterocyclyl or aryl group having 1 , 2, or 3 independently chosen optional substituents; wherein said optional substituents are each independently chosen from alkyl, alkanoyl, heteroalkyl, heterocyclyl, haloalkyl, cycloalkyl, carbocyclyl, arylalkoxy, heterocyclylalkoxy, aryl, aryloxy, heterocyclyloxy, alkoxy, haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, carboxamido, cyano, halogen, hydroxyl, amino, aminoalkyl, amidoalkyl, amido, nitro, thiol, alkylthio, arylthio, sulfinyl, sulfonyl, sulfonamide, urea or carbamate;

R3 is -H or an (C1-C6)alkyl group;

each L2 is independently chosen from alkylene or heteroalkylene; and

n is 0, 1, 2, 3, 4 or 5.

Compounds of formula (VII) having a (trans) disposition on the substituents on the cyclopropyl ring are preferred. Preferably, the compound of formula (VII) is a compound from the list below: 5-((trans)-2-aminocyclopropyl)-N-(3-chlorophenyl)pyridin-2-amine;

5-((trans)-2-aminocyclopropyl)-N-(4-chlorophenyl)pyridin-2-amine;

5-((trans)-2-aminocyclopropyl)-N-(4-(trifluoromethyl)phenyl)pyridin-2-amine; 5-((trans)-2-aminocyclopropyl)-N-(3-methoxyphenyl)pyridin-2-amine;

5-((trans)-2-aminocyclopropyl)-N-(4-methoxyphenyl)pyridin-2-amine;

5-((trans)-2-aminocyclopropyl)-N-p-tolylpyridin-2-amine;

5-((trans)-2-aminocyclopropyl)-N-m-tolylpyridin-2-amine;

4-(5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)benzonitrile;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)benzonitrile;

3- (5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)benzamide;

4- (5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)benzamide;

5- ((trans)-2-aminocyclopropyl)-N-(3-chlorobenzyl)pyridin-2-amine;

5-((trans)-2-aminocyclopropyl)-N-(4-chlorobenzyl)pyridin-2-amine;

5-((trans)-2-aminocyclopropyl)-N-(3-(trifluoromethyl)benzyl)pyridin-2-amine; 5-((trans)-2-aminocyclopropyl)-N-(4-(trifluoromethyl)benzyl)pyridin-2-amine; 5-((trans)-2-aminocyclopropyl)-N-(3-methylbenzyl)pyridin-2-amine;

5-((trans)-2-aminocyclopropyl)-N-(4-methylbenzyl)pyridin-2-amine;

3- ((5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)methyl)benzonitrile; 4-((5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)methyl)benzonitrile;

5-((trans)-2-aminocyclopropyl)-N-(3-methoxybenzyl)pyridin-2-amine;

5-((trans)-2-aminocyclopropyl)-N-(4-methoxybenzyl)pyridin-2-amine;

4- (5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)phenol;

3- ((5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)methyl)benzamide; 4-((5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)methyl)benzamide;

4- ((5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)methyl)phenol;

5- ((trans)-2-aminocyclopropyl)-N-(3-ethynylphenyl)pyridin-2-amine;

N-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-1 H-indol-7-amine;

N-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-1H-indazol-7-amine;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)phenol;

4-((trans)-2-aminocyclopropyl)-N-(4-methylbenzyl)aniline;

4-((trans)-2-aminocyclopropyl)-N-(4-(trifluoromethyl)benzyl)aniline;

4-((trans)-2-aminocyclopropyl)-N-(3-chlorobenzyl)aniline;

3- (((4-((trans)-2-aminocyclopropyl)phenyl)amino)methyl)benzonitrile;

4-((trans)-2-aminocyclopropyl)-N-(p-tolyl)aniline;

4- ((trans)-2-aminocyclopropyl)-N-(4-chlorophenyl)aniline; 3-((4-((trans)-2-arninocyclopropyl)phenyl)arnino)benzonitrile;

N-(4-((trans)-2-aminocyclopropyl)phenyl)-3-methoxyaniline;

3-((4-((trans)-2-aminocyclopropyl)phenyl)amino)benzamide;

and pharmaceutically acceptable salts thereof.

Compounds of formula (VII) can be prepared by the methods disclosed in WO2012/045883, the disclosure of which is incorporated by reference herein in its entirety.

In the methods and uses according to the invention, the LSD1 inhibitor can be a compound of formula (VIII) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:

(VIII)

In formula (VIII), (A) is a cyclyl group having n substituents (R3);

(B) is a cyclyl group or an -(U)-cyclyl group, wherein said cyclyl group or the cyclyl moiety comprised in said -(U)-cyclyl group has n substituents (R2);

(L1) is -0-, -NH-, -N(alkyl)-, alkylene or heteroalkylene;

(D) is a heteroaryl group or an -(L2)-heteroaryl group, wherein said heteroaryl group or the heteroaryl moiety comprised in said -(L2)-heteroaryl group has one substituent (R1), and further wherein said heteroaryl group is covalently bonded to the remainder of the molecule through a ring carbon atom or the heteroaryl moiety comprised in said -(L2)-heteroaryl group is covalently bonded to the (L2) moiety through a ring carbon atom; (L2) is -0-, -NH-, -N(alkyl)-, alkylene or heteroalkylene;

(R1) is a hydrogen bonding group, including but not limited to -OH, -NH2, amido, -S(0)2NH2, -C(=0)NH2, -CH₂-C(=0)NH₂, -NH-C(=0)CH₃, -NHCH3, -N(CH₃)2 or -CH₂-NH₂;

each (R2) is independently selected from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea;

each (R3) is independently selected from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate, or urea; and

n is independently 0, 1 , 2, 3 or 4.

Preferably in formula (VIII),

(A) is aryl or heteroaryl. Said aryl is preferably phenyl. Said heteroaryl is preferably pyridinyl, and/or;

(B) is -0-CH2-phenyl or phenyl, each of which can be optionally substituted with n substituents R2, and/or; (D) is a monocyclic heteroaryl, preferably thiazolyl, oxadiazolyl or pyrimidinyl, and more preferably oxadiazolyl; and/or;

(R1) is -NH₂ or -NHCH₃and more preferably -NH₂.

Compounds of formula (VIII) having a (trans) disposition on the substituents on the cyclopropyl ring are preferred.

Preferably, the compound of formula (VIII) is a compound from the list below:

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin-2-amine;

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine;

5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)pynmi

5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)thia

3-(5-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol;

3- (5-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol;

4'-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;

4'-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1 ,2,4-oxadiazol-3-amine;

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1 ,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1 ,3,4-oxadiazol-2-amine;

N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-yl)acetamide;

4'-((trans)-2-(((5-amino-1 ,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[1 ,1'-biphenyl]-3-ol;

5-((((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 , 3,4-th iadiazol-2-amine;

2- ((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazol-5-amine;

4- ((((trans)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl] -yl)cyclopropyl)amino)methyl)thiazol-2-amin

2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine;

3- ((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine;

5- ((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N,N-dimethyl-1 ,3,4-oxadiazol-3-amine;

3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,2,4-oxadiazol-5-amine;

5- ((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 , 2,4-th iadiazol-3-amine;

5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridin-2-amine;

6- ((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridazin-3-amine; 5- ((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrazin-2-amine;

2- ((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-5-amine;

6- ((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,2,4-tnazin-3-amine;

3- ((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,2,4-tnazin-6-amine;

4'-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1 ,2,4-oxadiaz^

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1 ,3,4-oxadiazol-2-am

5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-ami

5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-ami

(-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1 ,3,4-oxadiazol-2-amine;

(-) 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-ami

(-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3^-oxadiazol-2-am

(-) N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-yl)acetamide;

(-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2-amine;

(-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;

(-) 5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-ami

4'-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1 ,2,4-oxadiazol-3-am

5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amin

5-((((trans)-2-(4-((3 luorobenzyl)oxy)phenyl)cyclopropyl^^

(-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1 ,3^-oxadiazol-2-ami

(-) 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amin

(-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclo^

and pharmaceutically acceptable salts thereof.

Still more preferably, the compound of formula (VIII) is (-) 5-((((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine, or a pharmaceutically acceptable salt thereof.

Compounds of formula (VIII) can be prepared by the methods disclosed in WO2012/013728, the disclosure of which is incorporated by reference herein in its entirety. In the methods and uses according to the invention, the LSD1 inhibitor can be a compound of formula (IX) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:

(IX)

wherein:

A is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R¹;

B is hydrogen, R¹ or -L-E;

E is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more R²;

L is a bond, -0-, -NH-, -N(Ci-4 alkyl)-, C1-4 alkylene or heteroCi-4 alkylene;

D is a cycloalkyi group having from 4 to 7 C atoms, wherein said cycloalkyi group has one or two substituents R³ and is further optionally substituted with one or more R⁴, and wherein the cycloalkyi group optionally:

(a) is fused to a phenyl or a 5- or 6-membered aromatic heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S, wherein said fused phenyl or said fused aromatic heterocyclic ring is optionally substituted with one or more R⁵; or

(b) is bonded to a linker group -(C(R^a)2)_P- linking together any two non-adjacent ring carbon atoms of the cycloalkyi group, wherein p is 1 or 2 and each R^a independently is hydrogen or C1-4 alkyl; or

(c) is linked to a second ring that is either a 3- to 7-membered saturated carbocyclic ring or a 3- to 7-membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S, wherein said second ring is linked together with the cycloalkyi group via a single carbon atom common to both rings, and wherein said second ring is optionally substituted with one or more R⁶;

each R¹ is independently selected from C1-3 alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloCi-8 alkyl, haloCi-e alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C1-8 alkoxy, acyl, carboxyl, 0- carboxy, C-carboxy, carbamate and urea;

each R² is independently selected from C1-3 alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloCi-e alkyl, haloCi-e alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C1.8 alkoxy, acyl, carboxyl, 0- carboxy, C-carboxy, carbamate and urea;

each R³ is independently selected from -NR⁷R⁸, -NHOH, -NR⁹COR¹⁰, -NR⁹S0₂R¹°, -NR⁹COOR¹⁰, - NR⁹CONR⁷R«, -NR S0₂NR⁷R«, -OH, -CONR⁷R⁸ oxo, -C₁.₄ alkylene-NR R⁸, -C^ alkylene-NHOH, -C^ alkyene- NR COR¹⁰, -C1-4 alkylene-NR S0₂R¹°, -C1-4 alkylene-NR COOR¹⁰, -C1-4 alkylene-NR CONR R⁸, -C1-4 alkylene- NR S0₂NR R⁸, -Cu alkylene-OH and -C₁.₄alkylene-CONR R⁸; each R⁴ and each R⁶ is independently selected from Ci-e alkyl, halo, haloCi-e alkyl, haloCi-e alkoxy and Ci-e alkoxy;

each R⁵ is independently selected from Ci-e alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloCi-e alkyl, haloCi-e alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C1.8 alkoxy, acyl, carboxyl, 0- carboxy, C-carboxy, carbamate and urea;

each R⁷ and each R⁸ is independently selected from hydrogen, C1.8 alkyl, R ²R ³N-Ci-8 alkyl and hydroxyC-i-e alkyl, or R⁷ and R⁸ are linked together to form, along with the N atom to which they are bound, a saturated 3- to 7-membered heterocyclic ring which optionally contains one further heteroatom selected from N, 0 and S, wherein one or more C atoms in said heterocyclic ring are optionally oxidized to form CO groups, wherein one or more S atoms in said heterocyclic ring, if present, are optionally oxidized to form independently SO groups or SO2 groups, and wherein said heterocyclic ring is optionally substituted with one or more R¹¹;

each R⁹ is independently selected from hydrogen and C1-4 alkyl;

each R¹⁰ is independently selected from Ci-e alkyl, haloCi-e alkyl, cyclyl and cyclylC -s alkyl, wherein said cyclyl or the cyclyl moiety comprised in said cyclylCi-s alkyl is optionally substituted with one or more R¹⁴;

each R¹¹ is independently selected from C1.8 alkyl, halo, C1.8 alkoxy, hydroxyl and -NR¹²R¹³;

each R¹² and each R¹³ is independently selected from hydrogen and Ci-e alkyl;

each R¹⁴ is independently selected from Ci-e alkyl, C2-8 alkenyl, C2-8 alkynyl, amino, amido, hydroxyl, nitro, halo, haloCi-e alkyl, haloCi-e alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C1.8 alkoxy, acyl, carboxyl, O-carboxy, C- carboxy, carbamate and urea; and

each R^w, R^x, Ry and R^z is independently selected from hydrogen, halo and C1-4 alkyl.

Preferably in formula (IX),

(A) is phenyl, thiazolyl or pyridyl, preferably phenyl, which rings can be optionally substituted with one or more R¹, and/or

(B) is H , and/or

(R¹) is C1-8 alkyl, amino, amido, hydroxyl, halo, haloCi-e alkyl, haloCi-ealkoxy, cyano, sulfonamide, C1.8 alkoxy, acyl, carboxyl, carbamate, and urea, and more preferably halo, Cu alkyl, haloCi-4 alkyl, Cu alkoxy and C3-6 cycloalkyl; and/or

(D) is selected from D1 , D2, D3 and D4:

D1 D2 D3 D4

and more preferably D3; and/or

(R³) is selected from -NR R⁸, -NHOH, -NR⁹COR¹⁰, -NR⁹S0₂R¹°, -NR COOR¹⁰, -NR CONR R⁸, -NR S0₂NR R⁸, -OH, -CONR⁷R⁸ oxo, -C1-4 alkylene-NR⁷R⁸, -C1-4 alkylene-OH and -C1-4 alkylene-CONR⁷R⁸, more preferably from -NR⁷R⁸, -OH, -Ci-₄ alkylene-NR⁷R⁸, and -C1-4 alkylene-OH, still more preferably -NR⁷R⁸ (such as -NH₂); and/or

each R^w, R^x, R^ and R^z is hydrogen.

Compounds of formula (IX) having a (trans) disposition on the substituents on the cyclopropyl ring are preferred.

Preferably, the compound of formula (IX) is a compound from the list below:

N1-((trans)-2-phenylcyclopropyl)cyclohexane-1 ,4-diamine;

(cis)-N1-((1S,2R)-2-phenylcyclopropyl)cyclohexane-1 ,4-diamine;

(trans)-N1-((1S,2R)-2-phenylcyclopropyl)cyclohexane-1 ,4-diamine;

(cis)-N1-((1 R,2S)-2-phenylcyclopropyl)cyclohexane-1 ,4-diamine;

(trans)-N1-((1 R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

N1-((trans)-2-(thiazol-5-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexanol;

4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexanecarboxamide;

N-(4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexyl)acetamide;

N-(4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexyl)methanesulfonamide;

(R)-1-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)pyrrolidin-3-amine;

N1-((trans)-2-(4'-chloro-[1 ,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-(3'-chloro-[1 ,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

4'-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1 ,1'-biphenyl]-3-ol;

N-(4'-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1 ,1'-biphenyl]-3-yl)methanesulfonamide;

N1-((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1 ,4-diamine;

N1-methyl-N4-((trans)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-N4-methylcyclohexane-1 ,4-diamine;

N1-((trans)-2-phenylcyclopropyl)cyclobutane-1,3-diamine;

N1-((trans)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropyl)cyclobutane-1,3-diamine;

N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)cyclobutane-1 ,3-diamine;

N1-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1H-indene-1 ,3-diamine;

N1-((trans)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropyl)-2,3-dihydro-1 H-indene-1 ,3-diamine; N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-2,3-dihydro-1 H-indene-1,3-diamine;

N1-((trans)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1 ,4-diamine;

N1-((1S,2S)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

N1-((1 R,2R)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1 ,4-diamine;

1-methyl-N4-((irans)-2-phenylcyclopropyl)cyclohexane-1 ,4-diamine;

4-(aminomethyl)-N-((irans)-2-phenylcyclopropyl)cyclohexanamine;

N1-((frans)-2-phenylcyclopropyl)cyclohexane-1 ,3-diamine;

N1-((c/s)-2-phenylcyclopropyl)cyclohexane-1 ,4-diamine;

Teri-butyl (4-(((irans)-2-phenylcyclopropyl)amino)cyclohexyl)carbamate;

1-ethyl-3-(4-(((irans)-2-phenylcyclopropyl)amino)cyclohexyl)urea;

4-morpholino-N-((irans)-2-phenylcyclopropyl)cyclohexanamine;

N1-((frans)-2-(4-bromophenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-(2-(o-tolyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-(2-(4-(trifluoromethyl)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-(2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine;

4- (2-((4-aminocyclohexyl)amino)cyclopropyl)phenol;

N1-(2-(2-fluorophenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-(2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-(2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;

N1-(2-methyl-2-phenylcyclopropyl)cyclohexane-1 ,4-diamine;

(R)-1-(4-(((irans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl) amino)cyclohexyl)pyrrolidin-3-amine;

(C/^'s)-N1-((1S,2R)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

(7rans)-N1-((1S,2R)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclo-propyl)cyclohexane-1 ,4-diamine;

(C/^'s)-N1-((1 R,2S)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclo-propyl)cyclohexane-1 ,4-diamine;

(7rans)-N1-((1 R,2S)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclo-propyl)cyclohexane-1 ,4-diamine;

N1-((irans)-2-(4-cyclopropylphenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((frans)-2-(4-(pyridin-3-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

N1-((irans)-2-(4-(1H-indazol-6-yl)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((irans)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

3-(5-((frans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiophen-2-yl)phenol;

3-(5-(( irans)-2-((4-a mi nocyclo hexyl)am i no)cyclo pro pyl)th iazol-2-yl) phe nol ;

3-(5-((irans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)-5-methoxybenzonitrile;

5- (5-((irans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)-2-methylphenol;

N-(4 (frans)-2-((4-aminocyclohexyl)amino)cyd

N-(3-(5-((irans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiazol-2-yl)phenyl)-2-cyanobenzenesulfonamide ; N-(4 (irans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1 ,1'-biphenyl]-3-yl)-2-cyanobenzenesulfonamide; 6-amino-N-(4'-((irans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1 ,1'-biphenyl]-3-yl)pyridine-3-sulfonamide;

N-(4'-((irans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1 ,1'-biphenyl]-3-yl)piperazine-1-sulfonamide;

N1-((c/s)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1 ,4-diamine;

N1-((irans)-2-(4-((3-(piperazin-1-yl)benzyl)oxy)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((irans)-2-(4-(pyridin-3-ylmethoxy)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((irans)-2-(6-((3-methylbenzyl)amino)pyridin-3-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

3-((5-((irans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl) amino)benzonitrile;

N1-((trans)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-(o-tolyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-(2-fluorophenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N1-((trans)-2-methyl-2-phenylcyclopropyl)cyclohexane-1 ,4-diamine;

(c/s)-N1-(( 7S,-?R)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1 ,4-diamine ;

(irans)-N1-(( iR,-?S)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

(c/s)-N1-(( iR,-?S)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

(irans)-N1-(( iS,-?R)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

(c/s)-N1-(( iS,-?R)-2-phenylcyclopropyl)cyclobutane-1 ,3-diamine ;

(irans)-N1-(( iR,-?S)-2-phenylcyclopropyl)cyclobutane-1 ,3-diamine;

(c/s)-N1-(( iR,-?S)-2-phenylcyclopropyl)cyclobutane-1 ,3-diamine ;

(irans)-N1-(( iS,-?R)-2-phenylcyclopropyl)cyclobutane-1 ,3-diamine;

(c/s)-N1-(( iS,-?R)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

(irans)-N1-(( iR,-?S)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

(c/s)-N1-(( iR,-?S)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

(irans)-N1-(( iS,-?R)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

(c/s)-N1-(( iS,-?R)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

(irans)-N1-(( iR,-?S)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

(c/s)-N1-(( iR,-?S)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

(irans)-N1-(( iS,-?R)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1 ,4-diamine;

(c/s)-N1-(( iS,-?R)-2-(4-(1 H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

(irans)-N1-(( iR,-?S)-2-(4-(1 H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

(c/s)-N1-(( iR,-?S)-2-(4-(1 H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

(irans)-N1-(( iS,-?R)-2-(4-(1 H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

N-(4'-(( 7R,_?S)-2-(((c/s)-4-aminocyclohexyl)amino)cyclopropyl)-[1 ,1'-biphenyl]-3-yl)piperazine-1-sulfonamide;

N-(4'-(( 7S,-?R)-2-(((irans)-4-aminocyclohexyl)amino)cyclopropyl)-[1 ,1'-biphenyl]-3-yl)piperazine-1-sulfonamide; N-(4 ( /S,2fl)-2-(((c/s)-4-aminocyclohexyl)amino)cyclopropyl)-[1 ,1'-biphenyl]-3-yl)piperazine-1-sulfonamide;

N-(4'-((iR,-?S)-2-(((irans)-4-aminocyclohexyl)amino)cyclopropyl)-[1 ,1'-biphenyl]-3-yl)piperazine-1 -sulfonamide;

(c/s)-N1-(( iS,2R)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

(irans)-N1-((iR,2S)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

(c/s)-N1-((iR,-?S)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

(irans)-N1-((iS,-?R)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1 ,4-diamine;

and pharmaceutically acceptable salts thereof.

Still more preferably, the compound of formula (IX) is (trans)-N1-((1 R,2S)-2-phenylcyclopropyl)cyclohexane- 1 ,4-diamine; or a pharmaceutically acceptable salt thereof.

Compounds of formula (IX) can be prepared by the methods disclosed in WO2013/057322, the disclosure of which is incorporated by reference herein in its entirety.

In the methods and uses according to the invention, the LSD1 inhibitor can be a compound of formula (X) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmace thereof:

wherein:

A is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R¹;

B is H, R¹ or -L¹-E;

L¹ is a bond, -0-, -NH-, -N(Ci-4 alkyl)-, C1-4 alkylene or heteroCi-₄alkylene;

L² is a bond and D is a cyclic group selected from:

(i) a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, 0 and S, and

(ii) a 7- to 15-membered polycyclic ring system which comprises at least one saturated heterocyclic ring, wherein the polycyclic ring system contains from 1 to 4 heteroatoms independently selected from N, 0 and S,

wherein the cyclic group (i) or (ii) is linked to the remainder of the compound of Formula I through a ring C atom,

wherein one or more ring C atoms in the cyclic group (i) or (ii) are optionally oxidized to form CO groups, wherein one or more S atoms in the cyclic group (i) or (ii), if present, are optionally oxidized to form independently SO groups or SO2 groups, and

wherein the cyclic group (i) or (ii) is optionally substituted with one or more R³; or L² is C1-4 alkylene and D is a cyclic group selected from:

(iii) a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, 0 and S, and

(iv) a 7- to 15-membered polycyclic saturated ring system which comprises at least one heterocyclic ring, wherein the polycyclic saturated ring system contains from 1 to 4 heteroatoms independently selected from N, 0 and S,

wherein the cyclic group (iii) or (iv) is linked to the remainder of the compound of Formula I through a ring C atom,

wherein one or more ring C atoms in the cyclic group (iii) or (iv) are optionally oxidized to form CO groups, wherein one or more S atoms in the cyclic group (iii) or (iv), if present, are optionally oxidized to form independently SO groups or SO2 groups, and

wherein the cyclic group (iii) or (iv) is optionally substituted with one or more R³;

each R³ is independently selected from C1-3 alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo, haloCi-e alkyl, haloCi-e alkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, C1.8 alkoxy, acyl, carboxyl, 0- carboxy, C-carboxy, carbamate and urea; and

Preferably in formula (X),

(B) is H, and/or

(R¹) is C1-8 alkyl, amino, amido, hydroxyl, halo, haloCi-e alkyl, haloCi-ealkoxy, cyano, sulfonamide, C1.8 alkoxy, acyl, carboxyl, carbamate, and urea and more preferably halo, Cu alkyl, haloCi-4 alkyl, Cu alkoxy and C3-6 cycloalkyl; and/or

L² is a bond and (D) is a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from N, 0 and S wheren D is linked to the remainder of the compound of formula (X) through a C, more preferably a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 N atom wherein D is linked to the remainder of the compound of formula (X) through a C, and even more preferably D is 4- piperidinyl, or L² is a bond and (D) is a ring system selected from (a), (b), (c) and (d)

(c) (d)

wherein any D is optionally substituted with one or more R³; and/or

each R^w, R^x, R^ and R^z is hydrogen.

Compounds of formula (X) having a (trans) disposition on the substituents on the cydopropyl ring are preferred.

Preferably.the compound of formula (X) is a compound from the list below:

N-((trans)-2-phenylcyclopropyl)piperidin-4-amine;

N-((1S,2R)-2-phenylcyclopropyl)piperidin-4-amine;

N-((1 R,2S)-2-phenylcyclopropyl)piperidin-4-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)tetrahydro-2H-pyran-4-amine;

N-((trans)-2-(pyridin-3-yl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-(thiazol-5-yl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-phenylcyclopropyl)piperidin-3-amine;

N-((trans)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropyl)piperidin-3-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidin-3-amine;

N-((trans)-2-phenylcyclopropyl)pyrrolidin-3-amine;

N-((trans)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropyl)pyrrolidin-3-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)pyrrolidin-3-amine;

N-((trans)-2-phenylcyclopropyl)azetidin-3-amine;

N-((trans)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropyl)azetidin-3-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)azetidin-3-amine;

N-((trans)-2-phenylcyclopropyl)azepan-3-amine;

N-((trans)-2-phenylcyclopropyl)-8-azabicyclo[3.2.1 ]octan-3-amine;

N-((trans)-2-phenylcyclopropyl)-3-azabicyclo[3.2.1]octan-8-amine;

N-((trans)-2-phenylcyclopropyl)decahydroquinolin-4-amine;

N-((trans)-2-phenylcyclopropyl)-1 ,2,3,4-tetrahydroquinolin-4-amine;

N-((trans)-2-phenylcyclopropyl)-3-azaspiro[5.5]undecan-9-amine;

N-((trans)-2-phenylcyclopropyl)-2-azaspiro[4.5]decan-8-amine; N-((trans)-2-phenylcyclopropyl)-2,3-dihydrospiro[indene-1 ,4'-piperidin]-3-amine;

N-((1S,2R)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidin-4-amine;

N-((1 R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidin-4-amine ;

N-((1S,2R)-2-(pyridin-3-yl)cyclopropyl)piperidin-4-amine;

N-((1 R,2S)-2-(pyridin-3-yl)cyclopropyl)piperidin-4-amine;

N-((1S,2S)-2-(thiazol-5-yl)cyclopropyl)piperidin-4-amine;

N-((1 R,2R)-2-(thiazol-5-yl)cyclopropyl)piperidin-4-amine;

N-((1S,2R)-2-(3'-(trifluoromethyl)-[1 , 1 '-b i phe ny l]-4-yl)cycl o pro pyl ) pi pe rid i n-4-a mine;

N-((1 R,2S)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropyl)piperidin-4-amine;

N-((irans)-2-phenylcyclopropyl)-7-azaspiro[3.5]nonan-2-amine;

N-(2-(o-tolyl)cyclopropyl)piperidin-4-amine;

N-(2-(2-fluorophenyl)cyclopropyl)piperidin-4-amine;

N-(2-(3,4-difluorophenyl)cyclopropyl)piperidin-4-amine;

N-(2-(4-methoxyphenyl)cyclopropyl)piperidin-4-amine;

N-(2-(naphthalen-2-yl)cyclopropyl)piperidin-4-amine;

N-(2-methyl-2-phenylcyclopropyl)piperidin-4-amine;

N-(6-methoxy-4 (ira/7s)-2-(piperidin-4-ylamino)cyclopropyl)-[1 ,1'-biphenyl]-3-yl)metha

N-(4'-((irans)-2-(piperidin-4-ylamino)cyclopropyl)-[1 ,1'-biphenyl]-3-yl)propane-2-sulfonamide;

1-(methylsulfonyl)-N-((irans)-2-phenylcyclopropyl)piperidin-4-amine;

1-(4-(((irans)-2-(4-bromophenyl)cyclopropyl)amino)piperidin-1-yl)ethanone;

4-(((irans)-2-(4-bromophenyl)cyclopropyl)amino)piperidine-1-carboxarriide;

N-((irans)-2-(4-bromophenyl)cyclopropyl)tetrahydro-2H-pyran-4-amine;

2,2,6, 6-tetramethyl-N-((irans)-2-phenylcyclopropyl)piperidin-4-amine;

1-methyl-N-((irans)-2-phenylcyclopropyl)piperidin-4-amine;

1-isopropyl-N-((irans)-2-phenylcyclopropyl)piperidin-4-amine;

N-((frans)-2-phenylcyclopropyl)-1-(2,2,2-trifluoroethyl)piperidin-4-amine;

N-((irans)-2-phenylcyclopropyl)-1-(pyridin-4-yl)piperidin-4-amine;

4-(((irans)-2-(4-bromophenyl)cyclopropyl)amino)tetrahydro-2H-thiopyran 1 ,1-dioxide;

N-((trans)-2-fluoro-2-phenylcyclopropyl)piperidin-4-amine;

N-((1 S,2S)-2-fluoro-2-phenylcyclopropyl)piperidin-4-amine;

N-((1 R,2R)-2-fluoro-2-phenylcyclopropyl)piperidin-4-amine;

N-((trans)-2-(naphthalen-2-yl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-methyl-2-phenylcyclopropyl)piperidin-4-amine;

N-((trans)-2-(o-tolyl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-(2-fluorophenyl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-(3,4-difluorophenyl)cyclopropyl)piperidin-4-amine; N-((trans)-2-(4-methoxyphenyl)cyclopropyl)piperidin-4-amine;

(Trans)-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine;

(Trans)-2-phenyl-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

(Trans)-2-phenyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)cyclopropanamine;

(Trans)-2-(4'-chloro-[1 , -biphenyl]-4-yl)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)cyclopropanamine;

(Trans)-N-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)cyclopropanamine;

(Trans)-N-(piperidin-4-ylmethyl)-2-(thiazol-5-yl)cyclopropanamine;

(Trans)-N-(piperidin-4-ylmethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine;

(Trans)-2-(4-(benzyloxy)phenyl)-N-(pipendin-4-ylmethyl)cyclopropanamine;

(Trans)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)cyclopropanamine;

(Trans)-N-(2-(piperidin-4-yl)ethyl)-2-(thiazol-5-yl)cyclopropanamine;

(Trans)-N-(2-(piperidin-4-yl)ethyl)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropanamine;

(Trans)-2-(4-(benzyloxy)phenyl)-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

(1 S,2R)-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine ;

(1 R,2S)-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine ;

(1S,2R)-2-phenyl-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

(1 R,2S)-2-phenyl-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine ;

(1S,2R)-N-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)cyclopropanamine;

(1 R,2S)-N-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)cyclopropanamine;

(1S,2S)-N-(piperidin-4-ylmethyl)-2-(thiazol-5-yl)cyclopropanamine;

(1 R,2R)-N-(piperidin-4-ylmethyl)-2-(thiazol-5-yl)cyclopropanamine;

(1S,2R)-N-(piperidin-4-ylmethyl)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropanamine;

(1 R,2S)-N-(piperidin-4-ylmethyl)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropanamine;

(1S,2R)-2-(4-(benzyloxy)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

(1 R,2S)-2-(4-(benzyloxy)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

(1S,2R)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)cyclopropanamine;

(1 R,2S)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)cyclopropanamine;

(1S,2S)-N-(2-(piperidin-4-yl)ethyl)-2-(thiazol-5-yl)cyclopropanamine;

(1 R,2R)-N-(2-(piperidin-4-yl)ethyl)-2-(thiazol-5-yl)cyclopropanamine;

(1S,2R)-N-(2-(piperidin-4-yl)ethyl)-2-(3'-(trifluoromethyl)-[1 '-biphenyl]-4-yl)cyclopropanam

(1 R,2S)-N-(2-(piperidin-4-yl)ethyl)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl]-4-yl)cyclopropanamine;

(1S,2R)-2-(4-(benzyloxy)phenyl)-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

(1 R,2S)-2-(4-(benzyloxy)phenyl)-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

(7rans)-2-phenyl-N-(pyrrolidin-3-ylmethyl)cyclopropanamine;

(rrans)-2-(4-((2-fluorobenzyl)oxy)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

(7rans)-N-(azetidin-3-ylmethyl)-2-phenylcyclopropanamine; (7rans)-2-(4-cyclopropylphenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

(Trans)-N-(piperidin-4-ylmethyl)-2-(4-(pyridin-3-yl)phenyl)cyclopropanamine;

(Trans)-2-(4-(1 H-pyrazol-5-yl)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

(Trans)-2-(naphthalen-2-yl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

2-methyl-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine;

(trans)-2-methyl-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine;

(irans)-2-(4-(benzyloxy)phenyl)-N-((1-methylpiperidin-4-yl)methyl)cyclopropanamine;

and pharmaceutically acceptable salts thereof.

Still more preferably, the compound of formula (X) is a compound from the list below:

N-((trans)-2-phenylcyclopropyl)piperidin-4-amine;

N-((1S,2R)-2-phenylcyclopropyl)piperidin-4-amine;

N-((1 R,2S)-2-phenylcyclopropyl)piperidin-4-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)tetrahydro-2H-pyran-4-amine; N-((trans)-2-(pyridin-3-yl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-(thiazol-5-yl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-phenylcyclopropyl)piperidin-3-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidin-3-amine;

N-((trans)-2-phenylcyclopropyl)pyrrolidin-3-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)pyrrolidin-3-amine;

N-((trans)-2-phenylcyclopropyl)azetidin-3-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)azetidin-3-amine;

N-((trans)-2-phenylcyclopropyl)azepan-3-amine;

N-((trans)-2-phenylcyclopropyl)-8-azabicyclo[3.2.1]octan-3-amine;

N-((trans)-2-phenylcyclopropyl)-3-azabicyclo[3.2.1]octan-8-amine;

N-((trans)-2-phenylcyclopropyl)decahydroquinolin-4-amine;

N-((trans)-2-phenylcyclopropyl)-1 ,2,3,4-tetrahydroquinolin-4-amine;

N-((trans)-2-phenylcyclopropyl)-3-azaspiro[5.5]undecan-9-amine;

N-((trans)-2-phenylcyclopropyl)-2-azaspiro[4.5]decan-8-amine;

N-((trans)-2-phenylcyclopropyl)-2,3-dihydrospiro[indene-1 ,4'-piperidin]-3-amine;

N-((1S,2R)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidin-4-amine;

N-((1 R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidin-4-amine ; N-((1S,2R)-2-(pyridin-3-yl)cyclopropyl)piperidin-4-amine;

N-((1 R,2S)-2-(pyridin-3-yl)cyclopropyl)piperidin-4-amine;

N-((1S,2S)-2-(thiazol-5-yl)cyclopropyl)piperidin-4-amine;

N-((1 R,2R)-2-(thiazol-5-yl)cyclopropyl)piperidin-4-amine;

N-((1 S,2R)-2-(3'-(trifluoromethyl)-[1 , 1 '-biphenyl]-4-yl)cyclopropyl)piperidin-4-amine;

N-((irans)-2-phenylcyclopropyl)-7-azaspiro[3.5]nonan-2-amine;

N-(2-(o-tolyl)cyclopropyl)piperidin-4-amine;

N-(2-(2-fluorophenyl)cyclopropyl)piperidin-4-amine;

N-(2-(3,4-difluorophenyl)cyclopropyl)piperidin-4-amine;

N-(2-(4-methoxyphenyl)cyclopropyl)piperidin-4-amine;

N-(2-(naphthalen-2-yl)cyclopropyl)piperidin-4-amine;

N-(2-methyl-2-phenylcyclopropyl)piperidin-4-amine;

N-(6-methoxy-4'-((irans)-2-(piperidin-4-ylamino)cyclopropyl)-[1 ,1'-biphenyl]-3-yl)methanesulfonamide; N-(4'-((irans)-2-(piperidin-4-ylamino)cyclopropyl)-[1 ,1'-biphenyl]-3-yl)propane-2-sulfonamide;

1-(methylsulfonyl)-N-((irans)-2-phenylcyclopropyl)piperidin-4-amine;

1-(4-(((irans)-2-(4-bromophenyl)cyclopropyl)amino)piperidin-1-yl)ethanone;

4-(((irans)-2-(4-bromophenyl)cyclopropyl)amino)piperidine-1-carboxamide;

N-((irans)-2-(4-bromophenyl)cyclopropyl)tetrahydro-2H-pyran-4-amine;

2,2,6, 6-tetramethyl-N-((irans)-2-phenylcyclopropyl)piperidin-4-amine;

1-methyl-N-((irans)-2-phenylcyclopropyl)piperidin-4-amine;

1-isopropyl-N-((irans)-2-phenylcyclopropyl)piperidin-4-amine;

N-((irans)-2-phenylcyclopropyl)-1-(2,2,2-trifluoroethyl)piperidin-4-amine;

N-((irans)-2-phenylcyclopropyl)-1-(pyridin-4-yl)piperidin-4-amine;

N-((trans)-2-fluoro-2-phenylcyclopropyl)piperidin-4-amine;

N-((1S,2S)-2-fluoro-2-phenylcyclopropyl)piperidin-4-amine;

N-((1 R,2R)-2-fluoro-2-phenylcyclopropyl)piperidin-4-amine;

N-((trans)-2-(naphthalen-2-yl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-methyl-2-phenylcyclopropyl)piperidin-4-amine;

N-((trans)-2-(o-tolyl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-(2-fluorophenyl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-(3,4-difluorophenyl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-(4-methoxyphenyl)cyclopropyl)piperidin-4-amine;

or a pharmaceutically acceptable salt thereof. Compounds of formula (X) can be prepared by the methods disclosed in WO2013/057320, the disclosure of which is incorporated by reference herein in its entirety.

In the methods and uses according to the invention, the LSD1 inhibitor can be a compound of formula (XI) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:

wherein

Ri is selected from the group consisting of: d-dalkyl, -NSC^Me, -NSC^Ph, arylalkoxy, C3-C7cycloalkyl, - NC(0)R_a, 1 -methyl-1 H-pyrazol-4-yl, hydroxyl, CrC4alkoxy, halogen, amide, amino, substituted amino, and - C(0)OR_a;

R2 is hydrogen or COOH;

each R3 is independently selected from the group consisting of: aryl, heteoaryl, hydrogen, d-dalkyl,

- NC(0)R_a, -CH₂C(0)OR_a, -C(0)OR_a, -C(0)R_a, -C(0)NR_aR_b, substituted amino, amino, urea, amide, sulfonamide, arylalkyl, and heteroarylalkyl;

each R_a is independently hydrogen, phenyl, phenylmethyl, 3,5-dimethylisoxazol-4-yl, 1 ,2-dimethyl-1 H-imidazol- 4-yl, C3-C7cycloalkyl, d-dalkyl, Ci-C4alkoxy, Ci-C3alkylamino, or -NHPh;

Rb is hydrogen or d-dalkyl, or when attached to the same atom; or

R_a and Rb together form a 5- or 6-membered hetercycloalkyl ring;

R4 is d-dalkyl, acyl, -C(0)CF3 or hydrogen;

W is -(CH₂)i-4, or -CH(Rc)(CH₂)o-3, in which R_c is CN or d-dalkyl;

Y is N or C;

X is N or C;

Z is 0 or (CH2)q, wherein q is 0-2, when q is 0, Z represents a bond;

m is 0-3, n is 0-3;

provided that when Z is O, Y is N and X is C;

also provided that when X is C, at least one of the R3 groups attached to X is not hydrogen.

Compounds of formula (XI) can be prepared by the methods disclosed in WO2012/135113, the disclosure of which is incorporated by reference herein in its entirety. Preferably, the compound of formula (XI) is a compound from examples 1 to 150 in WO2012/135113 or a pharmaceutically acceptable salt thereof. Still more preferably, the compound of formula (XI) is 4-((4-((((1 R,2S)- 2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

In the methods and uses according to the invention, the LSD1 inhibitor can be a compound of formula (XII) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:

A compound represented by the formula (XII):

(XII)

wherein A is a hydrocarbon group optionally having substituent(s), or a heterocyclic group optionally having substituent(s);

B is a benzene ring optionally having further substituent(s);

R¹, R² and R³ are each independently a hydrogen atom, a hydrocarbon group optionally having substituent(s), or a heterocyclic group optionally having substituent(s);

A and R¹ are optionally bonded to each other to form, together with te adjacent nitrogen atom, a cyclic group optionally having substituent(s); and

R² and R³ are optionally bonded to each other to form, together with the adjacent nitrogen atom, a cyclic group optionally having substituent(s).

Compounds of formula (XII) can be prepared by the methods disclosed in WO2014/058071 , the disclosure of which is incorporated by reference herein in its entirety.

Preferably, the compound of formula (XII) is a compound from examples 1 to 273 in WO2014/058071 or a pharmaceutically acceptable salt thereof. More preferably, the compound of formula (XII) is 3-(trans-2- ((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)benzamide, 3-(trans-2-((1- cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide, 3-(trans-2- ((cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide, or a salt thereof.

In the methods and uses according to the invention, the LSD1 inhibitor can be a compound of formula (XIII) or an enantiomer, a diastereomer or a mixture of stereoisomers (such as a racemic mixture or a diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:

R is a hydrogen atom, a hydrocarbon group optionally having substituent(s), or a heterocyclic group optionally having substituent(s); or

A and R are optionally bonded to each other to form a ring optionally having substituent(s);

Q¹, Q², Q³ and Q⁴ are each independently a hydrogen atom or a substituent; Q¹ and Q², and Q³ and Q⁴, are each optionally bonded to each other to form a ring optionally having substituent(s);

X is a hydrogen atom, an acyclic hydrocarbon group optionally having substituent(s), or a saturated cyclic group optionally having substituent(s);

Y¹, Y² and Y³ are each independently a hydrogen atom, a hydrocarbon group optionally having substituent(s), or a heterocyclic group optionally having substituent(s);

X and Y¹, and Y¹ and Y², are each optionally bonded to each other to form a ring optionally having substituent(s); and

Z¹, Z²and Z³are each independently a hydrogen atom or a substituent,

Compounds of formula (XIII) can be prepared by the methods disclosed in WO2013/022047, the disclosure of which is incorporated by reference herein in its entirety.

Preferably, the compound of formula (XIII) is a compound from examples 1 to 166 in WO2013/022047, or a pharmaceutically acceptable salt thereof. More preferably, the compound of formula (XIII) is N-(4-(trans-2- [(cyclopropylmethyl)amino]cyclopropyl)phenyl)biphenyl-4-carboxamide, N-(4-(trans-2-[(1-methylpiperidin-4- yl)amino]cyclopropyl)phenyl)-3-(trifluoromethyl)benzamide, N-(4-(trans-2- [(cyclopropylmethyl)amino]cyclopropyl)phenyl)-1 H-pyrazole-4-carboxamide, or a salt thereof. Preferably, the LSD1 inhibitor to be used in the methods of the present invention is a selective LSD1 inhibitor or a dual LSD1/MAO-B inhibitor.

As used herein, a selective LSD1 inhibitor is a compound that inhibits LSD1 and has an IC50 value for LSD1 which is at least two-fold lower (i.e. more potent) than the IC50 value for MAO-A and MAO-B. More preferably, a selective LSD1 inhibitor has an IC50 value for LSD1 which is at least five-fold lower than the IC50 value for MAO-A and MAO-B. Even more preferably, selective LSD1 inhibitor have IC50 values for LSD1 which are at least ten-fold lower than the IC50 value for MAO-A and MAO-B. As used herein, a dual LSD1/MA0-B inhibitor is a compound that inhibits LSD1 and MAO-B and has IC50 values for LSD1 and MAO-B which are at least two-fold lower (i.e. more potent) than the IC50 value for MAO-A. More preferably, dual LSD1/MAO-B inhibitors have IC50 values for LSD1 and MAO-B which are at least five-fold lower than the IC50 value for MAO-A. Even more preferably, dual LSD1/MAO-B inhibitors have IC50 values for LSD1 and MAO-B which are at least ten-fold lower than the IC50 value for MAO-A.

The ability of a compound to inhibit LSD1 , MAO-A and MAO-B and its IC50 values for LSD1 , MAO-A and MAO- B can be determined in accordance with the methods described in Example 1.

Preferred LSD1 inhibitors for use in the methods of the invention are the compounds of formulae (I) to (XIII), preferably the compounds of formulae (III), (VI), (VIII), (IX), (X), (XI), (XII) and (XIII), more preferably the compounds recited in the lists of examples provided above for compounds of formulae (III), (VI), (VIII), (IX), (X) and (XI), and still more preferably the compounds recited in the lists of examples provided above for compounds of formulae (VIII), (IX), (X) and (XI).

A particularly preferred LSD1 inhibitor for use in the methods of the invention is (-) 5-((((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof.

Other preferred LSD1 inhibitors for use in the methods of the invention are:

(trans)-N1-((1 R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine, or

4-((4-((((1 R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid,

or a pharmaceutically acceptable salt or solvate thereof.

While it is possible that an active compound, i.e. the LSD1 inhibitor, may be administered for use in therapy directly as such, it is typically administered in the form of a pharmaceutical composition, which comprises said compound as active pharmaceutical ingredient together with one or more pharmaceutically acceptable excipients or carriers.

The active compounds may be administered by any means that accomplish their intended purpose. Examples include administration by the oral, parenteral, intravenous, subcutaneous or topical routes.

For oral delivery, the active compounds can be incorporated into a formulation that includes pharmaceutically acceptable carriers such as binders {e.g., gelatin, cellulose, gum tragacanth), excipients {e.g., starch, lactose), lubricants {e.g., magnesium stearate, silicon dioxide), disintegrating agents {e.g., alginate, Primogel, and corn starch), and sweetening or flavoring agents {e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). The formulation can be orally delivered in the form of enclosed gelatin capsules or compressed tablets. Capsules and tablets can be prepared in any conventional techniques. The capsules and tablets can also be coated with various coatings known in the art to modify the flavors, tastes, colors, and shapes of the capsules and tablets. In addition, liquid carriers such as fatty oil can also be included in capsules.

Suitable oral formulations can also be in the form of suspension, syrup, chewing gum, wafer, elixir, and the like. If desired, conventional agents for modifying flavors, tastes, colors, and shapes of the special forms can also be included. In addition, for convenient administration by enteral feeding tube in patients unable to swallow, the active compounds can be dissolved in an acceptable lipophilic vegetable oil vehicle such as olive oil, corn oil and safflower oil.

The active compounds can also be administered parenterally in the form of solution or suspension, or in lyophilized form capable of conversion into a solution or suspension form before use. In such formulations, diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used. Other conventional solvents, pH buffers, stabilizers, anti-bacteria agents, surfactants, and antioxidants can all be included. For example, useful components include sodium chloride, acetates, citrates or phosphates buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like. The parenteral formulations can be stored in any conventional containers such as vials and ampoules.

Routes of topical administration include nasal, bucal, mucosal, rectal, or vaginal applications. For topical administration, the active compounds can be formulated into lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Thus, one or more thickening agents, humectants, and stabilizing agents can be included in the formulations. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, and the like. A special form of topical administration is delivery by a transdermal patch. Methods for preparing transdermal patches are disclosed, e.g., in Brown, et al. (1988) Ann. Rev. Med. 39:221-229 which is incorporated herein by reference.

Subcutaneous implantation for sustained release of the active compounds may also be a suitable route of administration. This entails surgical procedures for implanting an active compound in any suitable formulation into a subcutaneous space, e.g., beneath the anterior abdominal wall. See, e.g., Wilson et al. (1984) J. Clin.

Psych. 45:242-247. Hydrogels can be used as a carrier for the sustained release of the active compounds.

Hydrogels are generally known in the art. They are typically made by crosslinking high molecular weight biocompatible polymers into a network, which swells in water to form a gel like material. Preferably, hydrogels are biodegradable or biosorbable. For purposes of this invention, hydrogels made of polyethylene glycols, collagen, or poly(glycolic-co-L-lactic acid) may be useful. See, e.g., Phillips et al. (1984) J. Pharmaceut. Sci.,

73: 1718-1720.

The active compounds can also be conjugated, to a water soluble non- immunogenic non-peptidic high molecular weight polymer to form a polymer conjugate. For example, an active compound is covalently linked to polyethylene glycol to form a conjugate. Typically, such a conjugate exhibits improved solubility, stability, and reduced toxicity and immunogenicity. Thus, when administered to a patient, the active compound in the conjugate can have a longer half-life in the body, and exhibit better efficacy. See generally, Burnham (1994) Am. J. Hosp. Pharm. 15:210-218. PEGylated proteins are currently being used in protein replacement therapies and for other therapeutic uses. For example, PEGylated interferon (PEG-INTRON A®) is clinically used for treating Hepatitis B. PEGylated adenosine deaminase (ADAGEN®) is being used to treat severe combined immunodeficiency disease (SCIDS). PEGylated L-asparaginase (ONCAPSPAR®) is being used to treat acute lymphoblastic leukemia (ALL). It is preferred that the covalent linkage between the polymer and the active compound and/or the polymer itself is hydrolytically degradable under physiological conditions. Such conjugates known as "prodrugs" can readily release the active compound inside the body. Controlled release of an active compound can also be achieved by incorporating the active ingredient into microcapsules, nanocapsules, or hydrogels generally known in the art. Other pharmaceutically acceptable prodrugs of the compounds of this invention include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters.

Liposomes can also be used as carriers for the active compounds. Liposomes are micelles made of various lipids such as cholesterol, phospholipids, fatty acids, and derivatives thereof. Various modified lipids can also be used. Liposomes can reduce the toxicity of the active compounds, and increase their stability. Methods for preparing liposomal suspensions containing active ingredients therein are generally known in the art. See, e.g., U.S. Patent No. 4,522,81 1 ; Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y. (1976).

In the herein disclosed methods, the LSD1 i can also be administered in combination with another active agent that synergistically treats the same symptoms or is effective for another disease or symptom in the patient treated so long as the other active agent does not interfere with or adversely affect the effects of the active compounds of this invention. Such other active agents include but are not limited to anti-inflammatory agents, antibiotics, antifungal agents, antithrombotic agents, cardiovascular drugs, cholesterol lowering agents, anticancer drugs, hypertension drugs, and the like.

Combination therapy includes administration of a single pharmaceutical dosage formulation which contains an LSD1 inhibitor and one or more additional active agents, as well as administration of the LSD1 inhibitor and each additional active agent in its own separate pharmaceutical dosage formulation. If administered separately, the administration can be simultaneous, sequential or separate, and the LSD1 i and the additional therapeutic agent(s) can be administered via the same administration route or using different administration routes, for example one compound can be administered orally and the other intravenously.

It is to be understood that the present invention specifically relates to each and every combination of features or embodiments described herein, including any combination of general and/or preferred features/embodiments. In particular, the invention specifically relates to all combinations of preferred features/embodiments (including all degrees of preference) of the methods and uses provided herein.

The following definitions apply throughout the present specification and claims, unless specifically indicated otherwise. As used herein, the term "sample" refers to a sample obtained from a subject. The sample may be of any biological tissue, cell or fluid. Such samples include but are not limited to Cerebrospinal fluid, Blood, Plasma, Serum, Stool, Urine, Saliva, Sputum, Gingival crevicular fluid, Hair follicles and tissue biopsy (skin, liver, etc). A sample is preferably a peripheral sample.

The sample to be assessed in accordance with the present invention (i.e. samples whose level of a biomarker selected from S100A9 S100A8, Npw, Prph, and/or Baiap3 is to be determined), can be obtained from a subject or a patient as defined herein.

Non-limiting examples of peripheral samples from patients having an infection or an infectious disease include Cerebrospinal fluid (CSF), Blood, Plasma, Serum, Stool, Urine, Saliva, Sputum, and Gingival crevicular fluid. Non- limiting examples of peripheral samples from patients having an autoimmune disease include Cerebrospinal fluid (CSF), Blood, Plasma, Serum, Stool, Urine.Saliva, Sputum, Gingival crevicular fluid, skin biopsy and hair follicles. Non-limiting examples of peripheral samples from patients having cancer include Cerebrospinal fluid (CSF), Blood, Plasma, Serum, Stool, Urine, skin biopsy and hair follicles. Non-limiting examples of peripheral samples from patients having a cardiovascular disease include Blood, Plasma, and Serum. Non-limiting examples of peripheral samples from patients having a CNS disease include Cerebrospinal fluid (CSF), Blood, Plasma, and Serum.

A "patient" or "subject" for the purposes of the present invention includes both humans and other animals, particularly mammals, and other organisms. Thus, the methods are applicable to both human therapy and veterinary applications. In a preferred aspect the subject or patient is a mammal, and in the most preferred aspect the subject or patient is human.

As used herein a "subject" is an individual (preferably a human) from which samples are obtained for analysis of biomarker levels. Thus, the term "subject" encompasses both a healthy individual (like a healthy volunteer enrolled in clinical trials) and a patient.

A "patient" is a subject with a presymptomatic, prodromal, incipient, mild, severe, active, or dormant disease. As used herein "patient" also includes subjects identified to have a high risk for the development of a disease. As used herein, the term "a patient having a disease" refers to a patient suffering from a disease as defined herein, a patient suspected to suffer from a disease as defined herein or being prone to suffer from a disease as defined herein. A patient that is prone to suffer from a disease as defined herein refers to a patient that is at risk of developing a disease as defined herein.

As used in the methods for monitoring of the invention, a "decrease" in relation to the level of a biomarker means that the level of S100A9 and/or S100A8 in a test sample is lower than the level of the same biomarker in a control. Preferably, the decrease is a significant decrease. As used herein, a "significant decrease" of the biomarker level in a test sample means a decrease with a probability p < 0.05 to fit the null hypothesis; i.e. that the biomarker levels measured before treatment have not varied after treatment (between and/or within subjects) but not excluding other comparisons (Fisher, 1925, Statistical Methods for Research Workers). As used in the methods for monitoring of the invention, an "increase" in relation to the level of a biomarker which is Prph, Npw, Baiap3 or Avp means that the level of the biomarker in a test sample is higher than the level of the same biomarker in a control. Preferably, the increase is a significant increase. As used herein, a "significant increase" of the biomarker level in a test sample means an increase with a probability p < 0.05 to fit the null hypothesis; i.e. that the biomarker levels measured before treatment have not varied after treatment (between and/or within subjects) but not excluding other comparisons (Fisher, 1925, Statistical Methods for Research Workers).

A non-limiting example of a "control" is a healthy control, which can be either samples obtained from healthy subjects, as well as samples obtained from biobanks and similar sources. A further non-limiting example of a "control" are data published in the scientific literature relating to such healthy subjects. As used herein, a "healthy subject" is a subject with matched age and gender as a patient and showing neither presymptomatic, prodromal, incipient, mild, severe, active, nor dormant disease nor a high risk for the development of the disease. A further non-limiting example of a "control" may be a sample obtained from a subject prior to the initiation of treatment with the LSD1 inhibitor. Prior to the initiation of treatment means that no LSD1 inhibitor has been administered to the subject at least 1 week, but preferentially 2 weeks prior to obtaining the control sample.

Preferentially, controls are of the same type as the sample to be compared with, and cover the expected range in that sample type.

As mentioned herein, the herein provided biomarkers can be used as monitoring biomarkers. Thus, the biomarkers can be used to monitor the response to an LSD1 inhibitor after treatment has started (e.g. during treatment with an LSD1 inhibitor, encompassing treatment breaks).

It is to be understood that the term "in vitro" is used in relation to methods in the sense of experiments, methods or procedures performed "outside of a living human or animal body". Accordingly, as used herein "in vitro" encompasses ex-vivo.

The terms "treatment", "treating" and the like are used herein to generally mean obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of partially or completely curing a disease and/or adverse effect attributed to the disease. The term "treatment" as used herein covers any treatment of a disease in a patient and includes: (a) preventing a disease in a patient which may be predisposed/at risk of developing the disease; (b) inhibiting the disease, i.e. arresting its development; or (c) relieving the disease, i.e. causing regression of the disease. As used herein, the term "treating a disease" or "treatment of a disease" refers particularly to a slowing of or a reversal of the progress of the disease. Treating a disease includes treating a symptom and/or reducing the symptoms of the disease.

As used herein, the term "therapeutically effective amount", such as the therapeutically effective amount of a compound of the present invention, refers to the amount sufficient to produce a desired biological effect (e.g., a therapeutic effect) in a subject. Accordingly, a therapeutically effective amount of a compound may be an amount which is sufficient to treat a disease, and/or delay the onset or progression of a disease, and/or alleviate one or more symptoms of the disease, when administered to a subject suffering from or susceptible to that disease.

As used herein, a "pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. A compound for use in the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, such as hydrochlorides, hydrobromides, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, nitrates, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4 dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, ethane-sulfonates, propanesulfonates, benzenesulfonates, toluenesulfonates, trifluoromethansulfonates, naphthalene-1 -sulfonates, naphthalene-2-sulfonates, mandelates, pyruvates, stearates, ascorbates, or salicylates. When the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine and the like. Pharmaceutically acceptable salts are well known in the art.

As used herein, a "pharmaceutically acceptable solvate" refers to a complex of variable stoichiometry formed by a solute (like a compound of formula I to XIII or a salt thereof) and a pharmaceutically acceptable solvent such as water, ethanol and the like. A complex with water is known as a hydrate.

As used herein, a "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a non-API (API refers to Active Pharmaceutical Ingredient) substances such as disintegrators, binders, fillers, and lubricants used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration and the European Medical Agency. Pharmaceutically acceptable carriers or excipients are well known to those skilled in the art. In the definitions of LSD1 i provided above, particularly in the definitions of compounds of formula (I) to (XIII), the following definitions apply, when applicable: Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group cyclylC -s alkyl would represent a cyclyl group attached to the parent molecule through a Ci-e alkyl group.

As used herein, the term "acyl" refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, or any other moiety where the atom attached to the carbonyl is carbon. Preferably, the term "acyl" refers to a group of formula -C(=0)R", wherein R" represents alkenyl, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl. An "acetyl" group refers to a -C(=0)CH3 group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include, but are not limited to, methylcarbonyl or ethylcarbonyl. Examples of acyl groups include, but are not limited to, formyl, alkanoyl or aroyl.

As used herein, the term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon group having one or more double bonds and containing from 2 to 20 carbon atoms. A C2-8 alkenyl is an alkenyl group having from 2 to 8 carbon atoms.

As used herein, the term "alkoxy" refers to an alkyl ether group (ie a group of formula alkyl-O-), wherein the term alkyl is as defined below. Examples of suitable alkyl ether groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, or n-pentoxy. The term Ci-_Z alkoxy refers to an alkoxy group wherein the alkyl moiety has from 1 to z carbon atoms; for example a C1.8 alkoxy is an alkoxy group wherein the alkyl moiety is C1.8 alkyl, i.e. a group of formula C1.8 alkyl-O-.

As used herein, the term "alkyl" refers to a straight-chain or branched-chain alkyl group containing from 1 to 20 carbon atoms. A Ci_-Z alkyl is an alkyl from 1 to z carbon atoms; thus, a C1.8 alkyl has from 1 to 8 carbon atoms, a C1-4 alkyl has from 1 to 4 carbon atoms and a C1-2 alkyl has from 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neo-pentyl, iso-amyl, hexyl, heptyl, octyl, or nonyl.

As used herein, the term "C1-4 alkylene" refers to a Cu alkyl group attached at two positions, i.e. an alkanediyl group. Examples include, but are not limited to, methylene (i.e. a group of formula -CH2-), ethylene (including ethane-1 ,2-diyl and ethane-1 ,1-diyl), propylene (e.g. propane-1 ,3-diyl, propane-1 ,2-diyl and propane-1 ,1-diyl) and butylene (e.g. butane-1 ,4-diyl, butane-1 ,3-diyl or butane-1 ,1-diyl). Accordingly, the term "C1-4 alkylene" may refer to a straight-chain or branched-chain alkylene group having from 1 to 4 carbon atoms. A "linear C1-4 alkylene" refers to a straight chain alkylene group having from 1 to 4 carbon atoms, i.e. a -(Chb group wherein y is 1 , 2, 3 or 4.

As used herein, the term "alkylamino," refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups including, but not limited to N-methylamino, N-ethylamino, Ν,Ν-dimethylamino, N,N-ethylmethylamino, Ν,Ν-diethylamino, N- propylamino, and N,N-methylpropylamino. As used herein, the term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon group having one or more triple bonds and containing from 2 to 20 carbon atoms. A C2-8 alkynyl has from 2 to 8 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, or hexyn-2-yl.

As used herein, the term "amido" and "carbamoyl" refers to an amino group as described below attached to the parent molecular moiety through a carbonyl group (e.g., -C(=0)NRR') , or vice versa (-N(R)C(=0)R'). "Amido" and "carbamoyl" encompasses "C-amido" and "N-amido" as defined herein. R and R' are as defined herein. As used herein, the term "C-amido" refers to a -C(=0)NRR' group with R and R' as defined herein.

As used herein, the term "N-amido" refers to a -N(R)C(=0)R' group with R and R' as defined herein.

As used herein, the term "amino" refers to -NRR', wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, carbocyclyl, and heterocyclyl. Additionally, R and R' may be combined to form a heterocyclyl. Exemplary "amino" groups include, without being limited thereto, -NH2, -NH(d-₄ alkyl) and -N(d-₄ alkyl)(Ci_-4 alkyl).

As used herein, the term "aryl" refers to a carbocyclic aromatic system containing one ring, or two or three rings fused together where in the ring atoms are all carbon. The term "aryl" includes, but is not limited to groups such as phenyl, naphthyl, or anthracenyl. The term "monocyclic aryl" refers to phenyl.

As used herein, the term "arylalkoxy" or "aralkoxy," refers to an aryl group attached to the parent molecular moiety through an alkoxy group. Examples of arylalkoxy groups include,

but are not limited to, benzyloxy or phenethoxy.

As used herein, the term "arylalkyl" or "aralkyi," refers to an aryl group attached to the parent molecular moiety through an alkyl group.

As used herein, the term "aryloxy" refers to an aryl group attached to the parent molecular moiety through an oxy (-0-).

As used herein, the term "carbamate" refers to an O-carbamyl or N-carbamyl group as defined herein. An N- carbamyl group refers to -NR-COOR', wherein R and R' are as defined herein. An O-carbamyl group refers to -OCO-NRR', wherein R and R' are as defined herein.

As used herein, the term "carbonyl" when alone includes formyl -C(=0)H and in combination is a -C(=0)- group.

As used herein, the term "carboxyl" or "carboxy" refers to -C(=0)OH or the corresponding "carboxylate" anion, such as is in a carboxylic acid salt.

An "O-carboxy" group refers to a RC(=0)0- group, where R is as defined herein.

A "C-carboxy" group refers to a -C(=0)OR groups where R is as defined herein.

As used herein, the term "cyano" refers to -CN.

As used herein, the term "carbocyclyl" refers to a saturated or partially saturated monocyclic or a fused bicyclic or tricyclic group wherein the ring atoms of the cyclic system are all carbon and wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. "Carbocyclyl" encompasses benzo fused to a carbocyclyl ring system. One group of carbocyclyls have from 5 to 7 carbon atoms. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1 H-indenyl, or adamantyl.

As used herein, the term "cycloalkyl", unless otherwise specified, refers to a saturated monocyclic, bicyclic or tricyclic group wherein the ring atoms of the cyclic system are all carbon and wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. A C3-6 cycloalkyl is a cycloalkyl that has from 3 to 6 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. A cycloalkyl containing from 4 to 7 C atoms includes cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.

As used herein, the term "cycloalkenyl" refers to a partially saturated monocyclic, bicyclic or tricyclic group wherein the ring atoms of the cyclic system are all carbon and wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. One group of carboalkenyls has from 5 to 7 carbon atoms. Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, or cyclohexenyl.

As used herein, the term "cyclyl" refers to an aryl, heterocyclyl, or carbocyclyl group as defined herein.

As used herein, the term "cyclylC -s alkyl" refers to a C1.8 alkyl as defined above wherein one hydrogen atom in the C1-8 alkyl group has been replaced with one cyclyl group as defined above.

As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

As used herein, the term "haloalkoxy" refers to a haloalkyi group (as defined below) attached to the parent molecular moiety through an oxygen atom. A haloC-i-e alkoxy group refers to a haloalkoxy group wherein the haloalkyi moiety has from 1 to 8 C atoms. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2-fluoroethoxy, pentafluoroethoxy, or 3-chloropropoxy.

As used herein, the term "haloalkyi" refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. A haloC-i-e alkyl group refers to a haloalkyi group wherein the alkyl moiety has from 1 to 8 C atoms. Specifically embraced are monohaloalkyl, dihaloalkyl or polyhaloalkyi groups. A monohaloalkyl group, for one example, may have an iodo, bromo, chloro or fluoro atom within the group. Dihalo or polyhaloalkyi groups may have two or more of the same halo atoms or a combination of different halo groups. Examples of haloalkyi groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl or dichloropropyl.

As used herein, the term "heteroalkyl" refers to a straight or branched alkyl chain, wherein one, two, or three carbons forming the alkyl chain are each replaced by a heteroatom independently selected from the group consisting of 0, N, and S, and wherein the nitrogen and/or sulfur heteroatom(s) (if present) may optionally be oxidized and the nitrogen heteroatom(s) (if present) may optionally be quaternized. The heteroatom(s) 0, N and S may, for example, be placed at the end(s) or at an interior position of the heteroalkyl group, i.e., the heteroalkyl may be bound to the remainder of the molecule via a heteroatom or a carbon atom. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3. Accordingly, a further example for a "heteroalkyl" group is a straight or branched alkyl group, in which two consecutive carbon atoms are replaced by the heteroatoms S and N, respectively, and the sulfur heteroatom is furthermore oxidized, resulting in moieties such as, e.g., -S(=0)₂-NH₂, -S(=0)₂-NH(alkyl) or -S(=0)₂-N(alkyl)(alkyl).

As used herein, the term "heteroalkylene" refers to a heteroalkyl group attached at two positions. Examples include, but are not limited to, -CH₂OCH₂-, -CH₂SCH₂-, and -CH₂NHCH₂-, -CH₂S-, or -CH₂NHCH(CH₃)CH₂-. Accordingly, the term "heteroalkylene" may, e.g., refer to a straight or branched alkylene group (i.e., a straight or branched alkanediyl group) having from 1 to 6 carbon atoms, wherein 1 , 2 (if present) or 3 (if present) of said carbon atoms are each replaced by a heteroatom independently selected from 0, N or S. It is to be understood that the presence of hydrogen atoms will depend on the valence of the heteroatom replacing the respective carbon atom. If, for example, the carbon atom in a -CH₂- group is replaced by 0 or S, the resulting group will be -0- or -S-, respectively, while it will be -N(H)- when the carbon atom replaced by N. Likewise, if the central carbon atom in a group -CH₂-CH(-CH3)-CH₂- is replaced by N, the resulting group will be -CH₂-N(-CH3)-CH₂-. An example for a "heteroalkylene" group is a straight or branched alkylene group, in which two consecutive carbon atoms are replaced by the heteroatoms S and N, respectively, and the sulfur heteroatom is furthermore oxidized, resulting in moieties such as, e.g., -S(=0)₂-N(H)- or -S(=0)₂-N(alkyl)-. Accordingly, the groups -S(=0)₂-N(H)- and -S(=0)₂-N(alkyl)- (e.g.,

alkyl)-) are exemplary "heteroalkylene" groups. As used herein, the term "heteroCi-4 alkylene" refers to a straight or branched Cu alkylene group (i.e., a straight or branched C-u alkanediyl group) linked to one heteroatom selected from 0, N and S and also refers to a straight or branched Cu alkylene group wherein one or more (e.g., 1, 2 (if present) or 3 (if present)) of the carbon atoms of said alkylene group are each replaced by a heteroatom independently selected from 0, N or S. The nitrogen and/or sulfur heteroatom(s) (if present) may optionally be oxidized and the nitrogen heteroatom(s) (if present) may optionally be quaternized. The heteroatom(s) 0, N and S may be placed at the end(s) and/or at an interior position of the heteroC-u alkylene group. It is to be understood that the presence of hydrogen atoms will depend on the valence of the heteroatom replacing the respective carbon atom. If, for example, the carbon atom in a -CH₂- group is replaced by 0 or S, the resulting group will be -0- or -S-, respectively, while it will be -N(H)- when the carbon atom is replaced by N. Likewise, if the central carbon atom in a group -CH₂-CH(-CH3)-CH₂- is replaced by N, the resulting group will be -CH₂-N(-CH3)-CH₂-. An example for a "heteroCi-4 alkylene" group is a straight or branched Cu alkylene group, in which two consecutive carbon atoms are replaced by the heteroatoms S and N, respectively, and the sulfur heteroatom is furthermore oxidized, resulting in moieties such as, e.g., -S(=0)₂-N(H)- or -S(=0)₂-N(CH3)-.

As used herein, the term "heteroaryl" refers to a 5 to 6 membered unsaturated monocyclic ring, or a fused bicyclic or tricyclic ring system in which the rings are aromatic and in which at least one ring contains at least one heteroatom selected from the group consisting of 0, S, and N. Preferred heteroaryl groups are 5- to 6- membered monocyclic or 9- to 10-membered bicyclic heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridinyl. As used herein, the term "heterocyclyl" or "heterocycle" each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur wherein the nitrogen or sulfur atoms may be oxidized (e.g., -N=0, -S(=0)-, or -S(=0)2-). Additionally, 1 , 2, or 3 of the carbon atoms of the heterocyclyl may be optionally oxidized (e.g., to give an oxo group or =0). One group of heterocyclyls has from 1 to 4 heteroatoms as ring members. Another group of heterocyclyls has from 1 to 2 heteroatoms as ring members. One group of heterocyclyls has from 3 to 8 ring members in each ring. Yet another group of heterocyclyls has from 3 to 7 ring members in each ring. Again another group of heterocyclyls has from 5 to 6 ring members in each ring. "Heterocyclyl" is intended to encompass a heterocyclyl group fused to a carbocyclyl or benzo ring systems. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, or imidazolidinyl. Examples of heteroaryls that are heterocyclyls include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridinyl.

As used herein, the term "heterocycloalkyl" refers to a heterocyclyl group that is not fully unsaturated e.g., one or more of the rings systems of a heterocycloalkyl is not aromatic. Examples of heterocycloalkyls include piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl.

As used herein, the term "hydroxyl" or "hydroxy" refers to -OH.

As used herein, the term "hydroxyalkyl," as used herein, refers to a hydroxyl group attached to the parent molecular moiety through an alkyl group.

As used herein, the term "hydroxyC-i-e alkyl" refers to a Ci-e alkyl group, wherein one or more hydrogen atoms (preferably one or two) have been replaced by hydroxy groups.

As used herein, the term "R¹²R¹³N-Ci-8 alkyl" refers to a Ci-e alkyl group, wherein one or more hydrogen atoms (preferably one or two, more preferably one) have been replaced by -NR¹²R¹³. As used herein, the phrase "in the main chain," refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of any one of the formulas disclosed herein.

As used herein, the term phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.

As used herein, the term "lower" where not otherwise specifically defined, means containing from 1 to and including 6 carbon atoms.

As used herein, the term "lower aryl," means phenyl or naphthyl.

As used herein, the term "nitro" refers to -NO2.

As used herein, the term "saturated" in relation to a ring means that the ring does not contain any unsaturation. As used herein, the terms "sulfonate" "sulfonic acid" and "sulfonic" refer to the -SO3H group and its anion as the sulfonic acid is used in salt formation.

As used herein, the term "sulfanyl," to -S-.

As used herein, the term "sulfinyl" refers to -S(=0)(R), with R as defined herein.

As used herein, the term "sulfonyl" refers to -S(=0)2R, with R as defined herein.

As used herein, the term "sulfonamide" refers to an N-sulfonamido or S-sulfonamido group as defined herein. As used herein, the term "N-sulfonamido" refers to a RS(=0)2N(R')- group with R and R' as defined herein. Preferred N-sulfonamido groups are -NHSO2R, wherein R is as defined herein, preferably R is alkyl, cycloalkyi, heteroalkyi, aryl, heteroaryl or heterocycloalkyi, more preferably R is alkyl, aryl, heteroaryl or heterocycloalkyi, wherein said alkyl, said cycloalkyi, said heteroalkyi, said aryl, said heteroaryl and said heterocycloalkyi are each optionally substituted. The optional substituents on said alkyl, said cycloalkyi, said heteroalkyi, said aryl, said heteroaryl and said heterocycloalkyi may be selected independently from lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyi, lower heterocycloalkyi, lower haloalkyl, lower cycloalkyi, phenyl, aryl, heteroaryl, pyridyl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, halogen, hydroxyl, amino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(0)CH3, CO2CH3, CO2H, carbamate, and urea. Preferably, the optional substituents are independently selected from hydroxyl, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, -N(Ci-3 alkyl)2, -NH(Ci-3 alkyl), -

alkyl), -C(=0)OH, alkyl), -C(=0)NH₂, -C(=0)NH(Ci_-3 alkyl), -C(=0)NH(cycloalkyl), -C(=0)N(Ci_-3 alkyl)₂, -S(=0)₂(Ci_-3 alkyl), -S(=0)₂NH₂, -S(=0)₂N(Ci_-3 alkyl)₂, -S(=0)₂NH(Ci-3 alkyl), -CHF₂, -OCF3, -OCHF2, -SCF₃, -CF₃, -CN, -NH₂, -NO2, or tetrazolyl. Particularly preferred N-sulfonamido groups are -NHSO2R, wherein R is alkyl, cycloalkyi, heteroalkyi, aryl, heteroaryl or heterocycloalkyi, and preferably R is alkyl, aryl, heteroaryl or heterocycloalkyi, and -NHS02(optionally substituted aryl). Still more preferred N-sulfonamido groups are -NHS02alkyl and -NHS02(optionally substituted aryl). Exemplary, non-limiting N-sulfonamido groups are -NHSC>2alkyl such as -NHSO2CH3, -NHSO2CH2CH3 or -NHS0₂(isopropyl), and -NHS0₂(optionally substituted aryl) such as -NHS0₂-phenyl, - NHS0₂-(2-cyanophenyl), -NHS0₂-(3-cyanophenyl), -NHS0₂-(4-cyanophenyl), -NHS0₂-(2-aminophenyl), - NHS0₂-(3-aminophenyl) or -NHS0₂-(4-aminophenyl). Other exemplary N-sulfonamido groups are - NHS0₂(optionally substituted heterocycloalkyl) such as -NHS0₂-(piperazin-1-yl) and -NHS0₂(optionally substituted heteroaryl) such as -NHS0₂-(optionally substituted pyridyl) like -NHS0₂-(3-pyridyl) or -NHS0₂-(6- amino-3-pyridyl).

As used herein, the term "S-sulfonamido" refers to a -S(=0)₂NRR', group, with R and R' as defined herein. As used herein, the term "urea" refers to a -N(R)C(=0)N(R)(R') group wherein R and R' are as defined herein. As used herein, "hydrogen bonding group" refers to a substituent group, which is capable of taking part in a non-covalent bonding between hydrogen and another atom (usually nitrogen or oxygen). Examples include, but are not limited to, -NH₂, -OH, amido, -S(0)₂NH₂, -C(=0)NH₂, -CH₂-C(=0)NH₂, - and -CH₂-NH₂. Other non- limiting examples include NHC(=0)CH₃ or -NHCH₃.

As used herein, the term "amide isostere" refers to a monocyclic or bicyclic ring system that is isosteric or bioisosteric with an amide moiety. Examples of amide isoteres include but are not limited to those disclosed in, e.g., Meanwell (2011) J. Med. Chem. PMID: 21413808,

The term R or the term R', appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl. Both unsubstituted and substituted forms of the above groups are encompassed.

Whether an R group has a number designation or not, every R group, including R, R' and R^z where z=(1, 2, 3, . . . z), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as -C(=0)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen.

As used herein, the term "optionally substituted" means the preceding or anteceding group may be substituted or unsubstituted. When substituted and unless otherwise specified, the substituents of an "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower cycloalkyl, phenyl, aryl, heteroaryl, pyridyl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, halogen, hydroxyl, amino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(0)CH3, C0₂CH3, C0₂H, carbamate, and urea. Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted {e.g., -CH2CH3), fully substituted {e.g., -CF2CF3), monosubstituted {e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted {e.g., -CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, "optionally substituted with." In one specific definition, the optional substituents are chosen from hydroxyl, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, -N(d-₃ alkyl)₂, -NH(d-₃ alkyl), -NHC(=0)(Ci-₃ alkyl), -C(=0)OH, -C(=0)0(d-₃ alkyl), -C(=0)(Ci-₃ alkyl), -C(=0)NH₂, -C(=0)NH(d-₃ alkyl), -C(=0)NH(cycloalkyl), -C(=0)N(d-₃ alkyl)₂, -S(=0)₂(d-₃ alkyl), - S(=0)₂NH₂, -S(=0)₂N(Ci-3 alkyl)₂, - S(=0)₂NH(d-₃ alkyl), -CHF₂, -OCF3, -OCHF2, -SCF₃, -CF₃, -CN, -NH₂, -NO2, or tetrazolyl.

As used herein, the term "optional substituent" denotes that the corresponding substituent may be present or may be absent. Accordingly, a compound having 1 , 2 or 3 optional substituents may be unsubstituted or may be substituted with 1 , 2 or 3 substituents, which may be the same or different.

The following examples illustrate various aspects of the invention. The examples should, of course, be understood to be merely illustrative of only certain embodiments of the invention and not to constitute limitations upon the scope of the invention. EXAMPLES

Example 1 : LSD1 inhibitors and in vitro biochemical assays

This example describes the LSD1 inhibitors used in the subsequent examples and methods to assess the activity of test compounds against LSD1 and related enzymes MAO-A and MAO-B. 1.1 LSD1 INHIBITORS USED

Compound 1 is the compound (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4- oxadiazol-2-amine, which can be obtained as disclosed in WO2012/013728.

Compound 2 is the enantiomer of compound 1 and it is the compound (+) 5-((((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1 ,3,4-oxadiazol-2-amine. It can be obtained as disclosed in WO2012/013728.

Compound 3 is the compound with the following chemical name and structure, and can be obtained as disclosed in WO2011/042217:

2-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)acetamide.

Compound 4 is the compound with the following chemical name and structure, and can be obtained as disclosed in WO2010/043721 :

2-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)-1-(4-methylpiperazin-1-yl)ethan-1-one.

Compound 5 is the compound with the following chemical name and structure, and can be obtained as disclosed in WO2011/035941 :

(S)-1-(2-(((trans)-2-(3'-(trifluoromethyl)-[1 ,1'-biphenyl] -yl)cyclopropyl)amino)ethyl)pyrrolidm

Compounds 1 and 2 are optically active stereoisomers, whereas compounds 3 to 5 are "trans" racemic mixtures. The stereochemistry shown in the chemical structures depicted above for the cyclopropyl moiety in compounds 3 to 5 is thus only intended to show that the compounds have a "trans" configuration in respect to the substituents on the cyclopropyl ring, it does not indicate absolute stereochemistry for said carbon atoms. 1.2 IN VITRO BIOCHEMICAL ASSAYS

1.2.1 LSD1

The inhibitory activity of a compound of interest against LSD1 can be tested using the method described below: Human recombinant LSD1 protein from BPS Bioscience Inc (catalog reference number 50100: human recombinant LSD1 , GenBank accession no. NM_015013, amino acids 158-end with N-terminal GST tag, MW: 103 kDa) was used. In order to monitor LSD1 enzymatic activity and/or its inhibition rate by a test compound, di-methylated H3-K4 peptide (Anaspec) was chosen as a substrate. The demethylase activity was estimated, under aerobic conditions, by measuring the release of H2O2 produced during the catalytic process, using the Amplex® Red hydrogen peroxide/peroxidase assay kit (Invitrogen).

Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, in the absence and/or in the presence of at least eight 3-fold serial dilutions of the respective inhibitor (e.g., from 0 to 75 μΜ, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. Within the experiment, each concentration of inhibitor was tested in duplicate. After leaving the enzyme interacting with the inhibitor, KM of di-methylated H3-K4 peptide was added to each reaction and the experiment was left for 30 minutes at 37°C in the dark. The enzymatic reactions were set up in a 50 mM sodium phosphate, pH 7.4 buffer. At the end of the incubation, Amplex® Red reagent and horseradish peroxidase (HPR) solution were added to the reaction according to the recommendations provided by the supplier (Invitrogen), and left to incubate for 5 extra minutes at room temperature in the dark. A 1 μΜ H2O2 solution was used as a control of the kit efficiency. The conversion of the Amplex® Red reagent to resorufin due to the presence of H2O2 in the assay, was monitored by fluorescence (excitation at 540 nm, emission at 590 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure level of H2O2 produced in the absence and/or in the presence of inhibitor. The maximum demethylase activity of LSD1 was obtained in the absence of inhibitor and corrected for background fluorescence in the absence of LSD1. The IC50 value of each inhibitor was calculated with GraphPad Prism Software.

1.2.2 MONOAMINE OXIDASE A (MAO-A) AND B (MAO-B)

LSD1 has a fair degree of structural similarity and amino acid identity/homology with the flavin-dependent amine oxidases monoamine oxidase A (MAO-A) and B (MAO-B). To determine the level of selectivity of a LSD1 inhibitor versus MAO-A and MAO-B, the inhibitory activity of a compound of interest against MAO-A and MAO-B can be tested using the method described below:

Human recombinant monoamine oxidase proteins MAO-A and MAO-B were purchased from Sigma Aldrich. MAOs catalyze the oxidative deamination of primary, secondary and tertiary amines. In order to monitor MAO enzymatic activities and/or their inhibition rate by inhibitor(s) of interest, a fluorescence-based (inhibitor- screening assay was set up. 3-(2-Aminophenyl)-3-oxopropanamine (kynuramine dihydrobromide, Sigma Aldrich), a non fluorescent compound was chosen as a substrate. Kynuramine is a non-specific substrate for both MAO-A and MAO-B activities. While undergoing oxidative deamination by MAO activities, kynuramine is converted into 4-hydroxyquinoline (4-HQ), a resulting fluorescent product.

The monoamine oxidase activity was estimated by measuring the conversion of kynuramine into 4- hydroxyquinoline. Assays were conducted in 96-well black plates with clear bottom (Corning) in a final volume of 100 μί. The assay buffer was 100 mM HEPES, pH 7.5. Each experiment was performed in duplicate within the same experiment. Briefly, a fixed amount of MAO was incubated on ice for 15 minutes in the reaction buffer, in the absence and/or in the presence of at least eight 3-fold serial dilutions each. Clorgyline and Deprenyl (Sigma Aldrich) was used as a control for specific inhibition of MAO-A and MAO-B respectively.

After leaving the enzyme(s) interacting with the inhibitor, KM of kynuramine was added to each reaction for MAO-B and MAO-A assay respectively, and the reaction was left for 1 hour at 37°C in the dark. The oxidative deamination of the substrate was stopped by adding 50 μί. of NaOH 2N. The conversion of kynuramine to 4- hydroxyquinoline, was monitored by fluorescence (excitation at 320 nm, emission at 360 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure levels of fluorescence produced in the absence and/or in the presence of inhibitor.

The maximum of oxidative deamination activity was obtained by measuring the amount of 4-hydroxyquinoline formed from kynuramine deamination in the absence of inhibitor and corrected for background fluorescence in the absence of MAO enzymes. The IC50 values of each inhibitor were calculated with GraphPad Prism Software. 1.2.3 RESULTS

Exemplary IC50 values against LSD1 , MAO-A and MAO-B obtained using the above methods for compounds 1 to 5 are shown in the table below:

As can be seen from the above data, Compound 1 is a potent dual LSD1/MAO-B inhibitor, whereas its enantiomer, Compound 2, is a much weaker LSD1 inhibitor while retaining potent MAO-B inhibitory activity. Compound 3 exhibits LSD1 and MAO-B inhibitory activity, and Compounds 4 and 5 are potent LSD1 inhibitors with selectivity versus MAO-A and MAO-B.

Example 2: Gene expression analysis by microarray hybridization This example describes the general method used in subsequent examples to perform microarray gene expression analysis. 2.1 RNA EXTRACTION AND LABELING METHOD

Total RNA was extracted from samples using the RNeasy extraction kit (Qiagen). The quality and concentration of the RNA was analyzed using the Agilent 2100 bioanalyzer and NanoDrop™ ND-1000 (Thermo Scientific). Samples with RNA integrity number (RIN) < 6.0 were discarded. Total RNA (0.5 g) amplification and labelling with Cy3 or Cy5 was carried out using the Eberwein mRNA amplification procedure (Van Gelder et al, Proc Natl Acad Sci USA 1990,87:1663-1667) employing the MessageAmp™ aRNA amplification kit from Ambion (Applied Biosystems) following the manufacturer's instructions with minor modifications. As hybridization controls, plant mRNAs were transcribed from a plasmid containing the Zea mays Xet (xyloglucan endo- transglycosylase) cDNA and from a plasmid containing the Zea mays Zmmyb42 cDNA, independently prepared Cy3 and Cy5 labelled aRNA from these two RNAs using the Eberwein mRNA amplification procedure (as disclosed in Cerda et al, Gen Comp Endocrinol 2008, 156:470-481).

2.2 HYBRIDIZATION AND DATA ACQUISITION

The Cy3- and Cy5-labelled cRNAs and spikes were combined and hybridized to the microarray described in Example 2.6 for 17 h at 60°C using Agilent's gaskets G2534-60002, G2534A hybridization chambers and DNA Hybridization Oven G2545A, according to the manufacturer's instructions. More specifically, equal amounts of Cy3 and Cy5 labeled Xet aRNA as well as equal amounts of Cy3 and Cy5 labeled Zmmyb42 aRNA were spiked into each mixture hybridized to the array. Arrays were washed and raw data were obtained using Agilent's DNA Microarray Scanner G2505B and Feature Extraction software (v10.1). The raw fluorescence intensity data were processed using applicant's proprietary software, and consists in the following operations: 1) spatial data compensation based on the hybridization pattern of the spiked-in controls, 2) global data filtering, and 3) data normalization.

Data compensation was performed based on the behavior of the plant aRNAs spiked into the array. Briefly, the labeled spike aRNAs hybridized to its corresponding spike i.e. control probes, represented in multiple copies and distributed strategically over the array, generates signals distributed over the expected dynamic range. The signal intensities derived from each specific repeated probe, form a data surface (x_arra_y,y array, Zsignal intensity). The data compensation algorithm uses these data surfaces to calculate a function that corrects all data surface to horizontal ity, and then applies the same operation to the total gene probe dataset. This data compensation can absorb most systematic spatial deviation generated by array synthesis, hybridization defects or scanner deviations between Cy3 and Cy5.

Global data filtering: using the specific controls and comparing all the samples in an experiment, the probes which are not expressed in any sample are systematically removed in order not to bias the posterior statistics. The decision on which probes are not expressed is based on the background probes and the negative control probes, designed to recognize maize expansin RNA (not included in the spikes) but not any mouse RNA. 2.3 MICROARRAY DATA NORMALIZATION

Data normalization was carried out by an improved version of the nonlinear Q-splines normalization method (Workman et al., Genome Biol 2002, 3(9): research0048.1-0048.16). Normalization results were presented graphically as MA plots, as first described by Dudoit et al (Dudoit et al, Statistica Sinica, 2002, 12:111-139). Each point corresponds to a probe of the DNA array. M values (vertical axis) are the log-differential expression ratios. A values (horizontal axis) are the log-intensities of the spots. M and A are calculated from the Cy5 and Cy3 intensity values as of each spot. The DNA Array data is normalized using an improved version of nonlinear Q-Splines normalization described by Workman et al., Genome Biol 2002, 3(9): research0048.1-0048.16. This process is useful to correct the deviation of the M values from the statistical assumption that most of the spots have M=0 in MA plots. The method allows the adjustment of all M values to form a cloud centered at M=0 in all intensity ranges. The data used to calculate the normalization fitting curve is the totality of the raw measurement dataset, excluding the signals for the probes for the spiked-in plant RNA controls and negative controls. In order to be able to normalize properly the data among all the experiments, the probe-set must include an important group of genes that should have no change (M=0) in the experiment. The normalization function is then applied to all the data, including controls.

Normalized and log-transformed data were used to calculate log2(sample/control) and Fold Change (FC) values. No background subtraction was applied to the signal intensity values during data processing, permitting robust selection of differentially expressed genes with low expression levels at the cost of potential sub- estimation of change when intensity levels are close to the array background level.

2.4 REPLICA ANALYSIS

The technical replicate analysis is the statistical processing of the microarray data. Replicates were calculated to measure oligo replicates on an array or between replicates of experiments on different arrays (i.e. hybridization of the same sample). The output of the Replicate Analysis is a list of selected genes with associated mean log2 (sample/control), Fold Change values (presented as the sample /control ratio when expression is induced and control/sample ratio when expression is reduced in the sample), and their corresponding p- values.

During replica analysis, datapoints may be identified which appear to lie outside the group of datapoints being analyzed, the so called outliers. Outliers are data that differ in a statistically important manner from the rest of a group of data for a given gene oligo. Outlier exclusion was applied to technical replicates. Outlier data on technical replicates can be caused by array imperfections like dust or synthesis defects. Outlier data can also be caused simply by errors, for example mislabeling or mixing up of a sample. What is to be considered "statistically different" was defined by comparison of the observed variation for the replicas of a gene probe with the expected variation for a given experiment, which was calculated based on the variation in Fold Changes observed for the control values yielded by the spike signals. In no case more than 20% of the data in a replica group was eliminated as outliers.

2.5 CALCULATION OF P VALUES FOR MICROARRAY DATA The p-values were calculated based on the absolute value of the regularized t-statistic (Baldi et al, Bioinformatics 2001 , 17(6):509-519), which uses a Bayesian framework to derive the algorithm, using internal replica controls to assess the minimum technical variability of the process. The inherent experimental variation was assessed by the FC of internal controls and/or self-to-self hybridizations. 2.6 MICROARRAY DESIGN AND RELEVANT PROBES

The microarrays employed were designed using applicant's proprietary software based on thermodynamic simulation of hybridization. The basic parameter used for the design of oligo with a length of 50-60 bases was the melting temperature (Tm), calculated using the "Nearest-Neighbours" and applying the parameters provided by Sugimoto et a/ (N Sugimoto et al, Biochemistry 1995, 34:11211-11216) for DNA/RNA interactions in defined salt concentrations. To calculate the folding of the oligo the minimum free energy algorithm of Zuker & Stiegler (M Zuckler and P Stiegler, Nucleic Acids Research 1981 , 9(1): 133-148) was used, and for cases where the minimum free energy equaled 0, the algorithms of Wutchy et al were used (S Wutchy et al, Biopolymers 1999, 49:145-165). The secondary structures of oligonucleotides and (fragmented) nucleic acids in solution were calculated. To model the hybridization process, the candidate oligonucleotide probes were first aligned with the transcriptome using the BLAST (http://www.ncbi.nlm.nih.gov/BLAST) algorithm (Altschul et al, J Mol Biol 1990, 215:403-410). The software performed total alignment (no mismatches allowed), mismatch alignment, and partial alignment (i.e. partial overlap) and calculated the Tm of all interactions based the sequence of all nucleic acids (sample, oligos, spiked in controls) and other relevant parameters (nucleic acid and salt concentration, temperature) of the hybridization reaction.

Next, Tm range limitations were applied, aiming for a narrow Tm distribution and homogeneous behavior of the oligos that generated desired target interactions and imposing maximum values to the Tm of undesired interactions to limited cross-hybridizations and secondary structures. Next, a quality factor was calculated based on the lineal combination of the following parameters: distance of the oligo to the 3' end of the mRNA sequence (3' bias of Eberwein labeling), Tm of the oligo, length of the oligo, distance of the Tm of the oligo to the maximum cross-hybridization Tm, distance of the Tm of the oligo to the maximum secondary structure Tm, GC content. The quality factor was used to rank the different possible oligos for a given gene and select the best possible oligos in function of the available spot positions.

For the design of this array, parameters were set as follows: Array type: gene expression (DNA/RNA); Oligo size min 50, max 60, Distance 3' max 1500, Tm range 70-80, max Tm secondary structure 60, max Tm cross-hybridization 60, 1 oligo per target sequence. Salt concentration and nucleic acid concentration: as per Agilent gene expression hybridization protocol.

The final microarrays contain triplicate gene probes for each of the different mouse genes as well as thousands of replicas probes for the spike controls.

Gene probes were designed using the ENSEMBL database. For sequences where we did not find high quality probes, we complemented the design with suboptimal probes (R-probes). DNA microarrays synthesis was outsourced to Agilent. The mouse Whole Genome Gene Expression Array contains:

^• 17386 Oryzon High Quality probes designed based on ENSEMBL Database built 53, may 2009 (based on built NCBI36).

^• 10736 Oryzon Recovery probes designed based on ENSEMBL Database.

The total amount of mouse gene probes is 28122.

In addition, the mouse array design contains probes that recognize the spiked-in plant aRNA; as well as negative controls.

The following probes were examined in detail:

TYPE NAME Microarray Probe Sequence

BIOMARKER S100a8 AAAAGTGGGTGTGGCATCTCACAAAGACAGCCACAAGGAGTAGCAGAG

CTTCTGG

BIOMARKER S100a9 GCCATGTGACAGCTGCCCAACCAAGTCTAAAGGGAATGGCTTACTCAAT

GGC

BIOMARKER Prph GTTCTGATCAGGACAATTGAGACCCGGGATGGGGAGAAGGTGGTGACA

GAGT

BIOMARKER Npw CAGCAAGTCATCTTTGCCGATCCTGTCAGGCCCAAGAACCGATGGCGC

CC

BIOMARKER Baiap3 GCCACGTACAAAGCAACCCATAGCGGGGTCTCCTTGGTTTTATTGAGAG

CACTAAGGCAG

BIOMARKER Avp TGGGACACGGGAGTCCGTGGATTCTGCCAAGCCCCGGGTCTACTGAGC

CAT

HOUSEKEEPI Tubb3 ACTGGGTTGTGTTTATATTCGGGGGGAGGGGTATACTTAATAAAGTTAC NG TGCTGTCTGTC

HOUSEKEEPI Tubb2c GCTGTCCTGTGTCCTGACATCACTTGTACAGATACCACCATTAAAGCAA NG TTCATAGT Example 3: S100A8 and S100A9 are up-regulated in SAMP-8 vs SAMR1 mice and down-regulated in the hippocampus of SAMP-8 mice after treatment with LSD1 inhibitors

This example illustrates that S100A8 and mostly S100A9 are over-expressed in the SAMP-8 mice, a model for accelerated aging and Alzheimer's disease, and that the over-expression of these genes can be modulated by treatment with LSD1 inhibitors in the absence of significant effects on hematology, and with beneficial effects on memory as assessed by the Novel Object Recognition Test (NORT). 3.1 MICE STRAINS AND TREATMENT

The Senescence Accelerated Mouse Prone 8 (SAMP8) strain is a non-transgenic model for neurodegeneration reminiscent of Alzheimer's disease (T Takeda, Neurobiol Aging 1999, 20(2): 105-10). Memory deficits appear around 5 months of age in SAMP8 mice and can be reliably assessed using the Novel Object Recognition Test (NORT). The Senescence Accelerated Mouse Resistant 1 (SAMR1 ) strain shows no memory deficits and is used as a control.

SAMP8 and SAMR1 mice were maintained 5 individuals par cage under standard conditions (temperature 23 ± 1 °C, humidity 50-60%, 12:12-h light-dark cycle, lights on at 7:00 a.m.), with food (A04, Harlan, Spain) and tap water available ad libitum until the treatment started. Body weight (g) was measured weekly. Test compound: Compound 1 , as defined in Example 1 above. Compound 1 is orally available and has been shown to cross the blood-brain barrier.

Males and females were separated in two different cohorts and all treatments started at 5 months of age.

In a first experiment, female mice were randomly distributed in 4 experimental groups (n=16/group): SAMR1 vehicle, SAMP8 vehicle, SAMP8 Compound 1 at 0.96 mg/kg/day and SAMP8 Compound 1 at 3.2 mg/kg/day.

Based on the results obtained in the first experiment, doses were adjusted in a second experiment using male mice. Male mice were randomly distributed in 4 experimental groups (n=16/group): SAMR1 vehicle, SAMP8 vehicle, SAMP8 Compound 1 at 0.32 mg/kg/day and SAMP8 Compound 1 at 0.96 mg/kg/day.

The test compound (Compound 1) was diluted in vehicle (1.8% hyd roxy pro pyl -beta-cyclodext ri n , Sigma- Aldrich) and administered in drinking water. The dose was calculated according to the animal water consumption average par cage and adjusted weekly. The test compound (or vehicle) was available for 5 days followed by a 2 day clearance in a weekly period.

3.2 NOVEL OBJECT RECOGNITION TEST (NORT) 3.2.1 METHOD

NORT is used to assess animal's behavior when it is exposed to a novel and a familiar object (M Antunes and G Biala, Cogn Process. 2012, 13(2): 93-110). Animals explore the novel object as their natural propensity to the novelty, and it is possible to evaluate the index of stimulus recognition (Discrimination Index or Dl, see below for description). After training or habituation, the Dl can be configured to measure working memory (minutes after training), midterm (hours after training) and and long term memory (24 h and beyond) when information can remain indefinitely (Taglialatela et al., 2009, Behav Brain Res 200:95-99).

The NORT test was performed after 2 (n=16/group) and repeated at 4 (n=10/group) months of treatment (between 12:30 am and 6:30 pm). Animals were placed in a 90° two-arm, 25-cm-long, 20-cm-high, 5-cm-wide black maze. The 20-cm-high walls could be lifted off for easy cleaning. The light intensity in the middle of the field was 30 lux. The objects to be discriminated were made of plastic with different shape and color clearly distinguishable. For the first 3 days, the mice were individually habituated to the apparatus for 10 min. On the 4th day, the animals were submitted to a 10-min acquisition trial (first trial) during which they were placed in the maze in the presence of two identical novel objects (A+A or B+B) placed at the end of each arm. A 10-min retention trial was performed 2 h (both in males and females) and 24 h later (males only) in order to evaluate mid- and long-term memory, respectively. During this second trial, objects A and B were placed in the maze, and the time that the animal explored the new object (tn) and the old object (to) were video-recorded. A discrimination index (Dl) was defined as (tn-to)/(tn+to). In order to avoid object preference biases, objects A and B were counterbalanced so that half of the animals in each experimental group were first exposed to object A and then to object B, whereas the other half saw first object B and then object A. The maze and the objects were cleaned with 96° ethanol between different animals, so as to eliminate olfactory cues.

3.2.2 STATISTICAL ANALYSIS

Statistical analysis was performed using the GraphPad Prism 6.0 software package. NORT data from SAMP8 mice was analyzed by one-way ANOVA with treatment as the main factor. Post-hoc comparisons with Bonferroni test were done, if appropriate. Student t-Test was used to compare SAMR1 vehicle and SAMP8 vehicle.

3.2.3 RESULTS

Compound 1 completely prevents memory loss in SAMP8 as assessed by NORT after 2 m and 4m of treatment both in males and females, as discussed in more detail below.

3.2.3.1 Females

Treatment with Compound 1 administered orally in drinking water rescued the memory deficits in mid-term memory (2h trial test) in SAMP8 females. This effect was observed at the two doses tested and both after 2 and 4 months of treatment, as shown in Fig 1A and 1 B. The t-Student test showed differences in the discrimination index Dl between vehicle-treated SAMR1 and vehicle-treated SAMP8 animals after 2 (p < 0.0001) and 4 (p < 0.001) months of treatment. The ANOVA showed differences due to the treatment in the discrimination index (p < 0.0001) after 2 or 4 months of treatment with Compound 1. Post-hoc analysis showed higher discrimination index in the SAMP8 groups treated with Compound 1 compared to SAMP8 vehicle. **** p < 0.0001 ; *** p < 0.001

3.2.3.2 Males

Treatment with Compound 1 administered orally in drinking water rescued the memory deficits of SAMP8 males. This effect was observed with the two doses tested and after a 2- and 4-month treatment, with positive effects both on medium- and long-term memory. The results are shown in Figures 2A (mid-term memory, 2m treatment), 2B (mid-term memory, 4m treatment), 3A (long-term memory, 2m treatment) and 3B (long-term memory, 4m treatment).

Midterm memory (2h trial test):

As shown in Fig 2A and 2B, the t-Student test showed differences in the discrimination index between vehicle- treated SAMR1 and SAMP8 animals after 2 (p < 0.0001) and 4 (p < 0.0001) months of treatment. The ANOVA showed differences due to the treatment in the discrimination index Dl after 2 (p < 0.0001) and 4 (p < 0.0001) months of treatment with Compound 1. Post-hoc analysis showed higher discrimination index in the SAMP8 groups treated with Compound 1 compared to SAMP8 vehicle. **** p < 0.0001 ; *** p < 0.001

Long term memory (24 h trial test):

As shown in Fig 3A and 3B, the t-Student test showed differences in the discrimination index Dl between vehicle-treated SAMR1 and SAMP8 animals after 2 (p < 0.0001) and 4 (p < 0.0001) months of treatment. The ANOVA showed differences due to the treatment in the discrimination index after 2 (p < 0.001) and 4 (p < 0.001) months of treatment with Compound 1. Post-hoc analysis showed higher discrimination index in the SAMP8 groups treated with Compound 1 compared to SAMP8 vehicle. **** p < 0.0001 ; *** p < 0.001 ; * p < 0.05

3.3 SAMPLING METHODS

One day after the NORT test, 7 (n=2-6/group) or 9 (n=2-4/group) month old animals were deeply anesthetized with 80 mg/kg of sodium pentobarbital. Blood samples were obtained by intracardiac puncture, collected in EDTA tubes and stored at 4°C until analyzed. Afterwards, hippocampi were dissected and snap frozen on dry ice for further RNA extraction. 3.4 EFFECTS ON HEMATOPOIESIS

It is known that LSD1 is implicated in normal hematopoiesis (Spriissel et al, Leukemia 2012, 26(9)2039-51). To assess whether treatment with LSD1 inhibitors has an effect in hematopoiesis in SAMP8 mice at the doses administered, the effect on platelet levels in males of the higher dose tested of Compound 1 (0.96 mg/kg/day) was evaluated after 2 or 4 months of treatment. The mice were sacrificed and blood was collected in sodium citrate-containing tubes for hemogram analysis. Platelets levels were determined in a standard hematology analyzer (Abacus Junior Vet, from Diatron) following the manufacturer's instructions.

The results obtained after 16 weeks of treatment are shown in Fig 4. While a tendency towards reduction in platelet levels was observed, no statistically significant effects of Compound 1 treatment compared to vehicle- treated SAMP8 mice were observed.

3.5 GENE EXPRESSION ANALYSIS BY MICROARRAY 3.5.1 SAMPLE PREPARATION

Hippocampi samples from female mice from the above-described experiment obtained as described in section 3.3 were used for microarray GE analysis.

RNA extraction and labeling for gene expression analysis was performed using the general methods described in Example 2, to obtain the following samples:

3.5.1.1 INDIVIDUAL SAMPLE LIST 2 month treatment

Strain Treatment Sample Female

SAMR1 Vehicle 1530 R1 FV7-SAMR1-F-Vehicle

1531 R1 FV10-SAMR1-F-Vehicle

1399 R1 FV11-SAMR1-F-Vehicle

1532 R1 FV12-SAMR1-F-Vehicle

1533 R1 FV15-SAMR1-F-Vehicle

1400 R1 FV16 SAMR1-F-Vehicle

SAMP8 Vehicle 1535 S8FV6-SAMP8-F-Vehicle

1536 S8FV7-SAMP8-F-Vehicle

1537 S8FV8-SAMP8-F-Vehicle

1401 S8FV9 SAMP8-F-Vehicle

1402 S8FV14 SAMP8 Vehicle

1403 S8FV15 SAMP8 Vehicle SAMP8 Compl 1539 S8FH9-SAMP8-F-3,2mg

1540 S8FH11-SAMP8-F-3,2mg

1408 S8FH12 SAMP8 3,2 mg

3,2mg/kg/day 1409 S8FH16 SAMP8 3,2 mg

Strain Treatment Sample Male

SAMR1 Vehicle 1516 R1 MV1-SAMR1-M-Vehicle

1517 R1 MV2-SAMR1-M-Vehicle

SAMP8 Vehicle 1519 S8MV3-SAMP8-M-Vehicle

1520 S8MV4-SAMP8-M-Vehicle

SAMP8 Compl 1524 S8ML8-SAMP8-M-0.32mg

0,32 mg/kg/day 1545 S8ML9-SAMP8-M-0.32mg

1546 S8ML10-SAMP8-M-0,32mg

4 month treatment

Strain Treatment Sample Female

SAMR1 Vehicle 1528 R1 FV1-SAMR1-F-Vehicle

1398 R1 FV4-SAMR1-F-Vehicle

1529 R1 FV5-SAMR1-F-Vehicle

SAMP8 Vehicle 1512 S8FV1-SAMP8-F-Vehicle

1513 S8FV4-SAMP8-F-Vehicle

1534 S8FV5-SAMP8-F-Vehicle

SAMP8 Compl 1404 S8FL1-SAMP8-F-0,96 mg

0,96 mg/kg/day 1405 S8FL4-SAMP8-F-0,96 mg

1406 S8FL5-SAMP8-F-0,96 mg

SAMP8 Compl 1514 S8FH1-SAMP8-F-3,2mg

3,2mg/kg/day 1515 S8FH3-SAMP8-F-3,2mg

1538 S8FH4-SAMP8-F-3,2mg

1407 S8FH5 SAMP8-F-3,2 mg

Strain Treatment Sample Male

SAMR1 Vehicle 1518 R1 MV6-SAMR1-M-Vehicle 1541 R1 MV7-SAMR1-M-Vehicle

1542 R1 MV12-SAMR1-M-Vehicle

SAMP8 Vehicle 1521 S8MV6-SAMP8-M-Vehicle

1543 S8MV7-SAMP8-M-Vehicle

1544 S8MV8-SAMP8-M-Vehicle

SAMP8 Compl 1522 S8ML1-SAMP8-M- 0,32mg

0,32 mg/kg/day 1523 S8ML4-SAMP8-M-0,32mg

SAMP8 Compl 1525 S8MH5-SAMP8-M-0.96mg

0,96 mg/kg/day 1526 S8MH6-SAMP8-M-0.96mg

1527 S8MH8-SAMP8-M-0.96mg

The following RNA samples were pooled for labeling and microarray analysis:

POOL SAMPLES LIST

As used herein, Compl means Compound 1. LD means the low dose of Compound 1 administered to female mice, i.e. 0.96 mg/kg/day, and HD means the high dose of Compound 1 administered to female mice, i.e. 3.2 mg/kg/day. VEH means Vehicle.

3.5.2 HYBRIDIZATION LIST

The following hybridizations were performed as described above

HYB. # CODE CONTROL DESCRIPTION CODE SAMPLE DESCRIPTION

1 1414 Cy3 POOL SAMP8 VEHICLE 1413 Cy5 POOL SAMR1 VEH

2 1414 Cy3 POOL SAMP8 VEHICLE 1414 Cy5 POOL SAMP8 VEH 3 1414 Cy3 POOL SAMP8 VEHICLE 1415 Cy5 POOL SAMP8 Compl (0.96 mg/kg/day) LD

4 1414 Cy3 POOL SAMP8 VEHICLE 1416 Cy5 POOL SAMP8 Compl (3.2 mg/kg/day) HD

3.5.3 REPLICA ANALYSIS

Replica analysis was intra-array.

GROUP CODE

1414 Cy3 vs 1413 Cy5

1414 Cy3 vs 1415 Cy5

1414 Cy3 vs 1416 Cy5

Self-to-Self 1414

3.5.4 GENE EXPRESSION RESULTS

The results obtained are shown in the table below: log2(sample/control) Hybridization signal Statistics

HIPPOCAMPUS log2(1414 Cy5/ 1414 Cy3)

log2(SAMP-8 VEH/SAMP8 VEH) control_Cy3 sample_Cy5 p-value

S100A8 -0.108507 81.4243 75.5249 0.0676827

S100A9 -0.217568 105.749 90.9456 0.0117551

TUBB3 0.0224714 2432.8 2470.99 0.326168

TUBB2C 0.24601 6856.62 8131.42 0.0011662

Low 61 63

log2 (1415 Cy5/1414 Cy3)

log2(SAMP-8 LD/SAMP8 VEH) control_Cy3 sample_Cy5 p-value

S100A8 -0.225482 82.6741 70.7119 0.0276339

S100A9 -0.838056 118.85 66.4843 0.0010589

TUBB3 0.0449797 2910.14 3002.3 0.101615

TUBB2C 0.119916 8643.34 9392.47 0.0063925

Low 66 57

log2 (1416 Cy5/1414 Cy3)

log2(SAMP-8 HD/SAMP8 VEH) control_Cy3 sample_Cy5 p-value S100A8 -0.181268 87.3979 77.0786 3.35E-02

S100A9 -0.764724 124.418 73.2282 1.1 1 E-03

TUBB3 0.0576913 3044.2 3168.4 0.0618207

TUBB2C 0.132662 8367.12 9173 0.0051698

Low 71 64

log2(1413 Cy5/1414 Cy3)

log2(SAMR1 VEH/SAMP8 VEH) control_Cy3 sample_Cy5 p-value

S100A8 -0.42018 92.615 69.2141 0.014109

S100A9 -0.858165 120.373 66.4042 1.33E-03

TUBB3 -0.153249 31 19.47 2805.1 0.0027589

TUBB2C 0.296597 8426.99 10350.4 0.001325

Low 67 43

Low: Lowest above background signal on the array, rounded to the lower unit. Log2 (sample/control) values were calculated without background subtraction as described above. S100A8 and particularly S100A9 were up-regulated in SAMP8 versus reference strain SAMR1 and were down- regulated by treatment with Compound 1. Two housekeeping genes i.e. genes that showed a relatively constant levels of expression across the different experiments, Tubb3 and Tubb2c, were included for comparison.

Down-regulation of S100A9 and S100A8 with Compound 1 was observed at HD, at which a significant reduction of platelet levels was observed, but importantly, also at LD, where no significant reduction of platelet levels was observed. Full rescue of the memory capacity as assessed by the NORT test was also observed in SAMP-8 animals treated at HD and LD.

Example 4: Changes in expression of additional biomarkers in the hippocampus of SAMP-8 mice after treatment with Compound 1

Microarray hybridization results disclosed in Example 3 were extended with additional biomarkers analysis using the same methodology.

4.1 GENE EXPRESSION RESULTS The results obtained are shown in the table below:

log2(sample/control) Hybridiza tion signal Statistics

HIPPOCAMPUS

log2(1414 Cy5/ 1414 Cy3) control_Cy3 sample_Cy5 p-value log2(SAMP-8 VEH/SAMP8 VEH)

Prph -0.025034 82.2 80.8 0.524567

Npw 0.066138 74.8 78.3 0.106716

Baiap3 -0.060528 153.1 146.8 0.037497

Avp -0.057579 117.8 113.2 0.140089

TUBB3 0.0224714 2432.8 2470.99 0.326168

TUBB2C 0.24601 6856.62 8131.42 0.0011662

Low 61 63

log2 (1415 Cy5/1414 Cy3)

log2(SAMP-8 LD/SAMP8 VEH) control_Cy3 sample_Cy5 p-value

Prph 0.8948 95.1 176.9 2.65E-05

Npw 0.5367 87.3 126.6 0.0002037

Baiap3 1.0228 209.6 426.0 2.12E-05

Avp 0.2522 135.6 161.5 0.0010039

TUBB3 0.0449797 2910.14 3002.3 0.101615

TUBB2C 0.119916 8643.34 9392.47 0.0063925

Low 66 57

log2 (1416 Cy5/1414 Cy3)

log2(SAMP-8 HD/SAMP8 VEH) control_Cy3 sample_Cy5 p-value

Prph 0.6317 95.8 148.4 5.38E-05

Npw 0.4750 90.0 125.1 0.0002716

Baiap3 1.4369 214.3 580.2 4.00E-06

Avp 0.6959 139.3 225.7 0.0018829

TUBB3 0.0576913 3044.2 3168.4 0.0618207

TUBB2C 0.132662 8367.12 9173 0.0051698

Low 71 64

log2(1413 Cy5/1414 Cy3)

log2(SAMR1 VEH/SAMP8 VEH) control_Cy3 sample_Cy5 p-value

Prph -0.0741704 88.7 84.3 0.032208

Npw 0.0696582 84.4 88.6 0.030022

Baiap3 0.0605712 191.1 199.2 0.150415

Avp -0.345273 134.9 106.2 0.001935

TUBB3 -0.153249 3119.47 2805.1 0.0027589

TUBB2C 0.296597 8426.99 10350.4 0.001325

Low 67 43

Low: Lowest above background signal on the array, rounded to the lower unit. Log2 (sample/control) values were calculated without background subtraction as described above. No differences in expression between SAMR1 and SAMP8 vehicle groups were observed. But, Prph, Npw, Baiap3 and Avp genes were up-regulated by treatment with Compound 1 at HD and LD.

Example 5: Validation of the effects of LSD1 inhibitors on S100A9 expression by RNA sequencing Microarray hybridization results disclosed in Example 3 were confirmed using lllumina RNA sequencing as an alternative gene expression technology, using samples from female and male mice treated for 4 months with Compound 1 or vehicle in Example 3.

5.1 ILLUMINA RNA-SEQ TECHNOLOGY lllumina dye sequencing begins with the attachment of cDNA molecules to primers on a slide, followed by amplification of that DNA to produce local colonies. The four types (adenine, cytosine, guanine, and thymine) of reversible terminate bases are added, each fluorescently labeled with a different color and attached with a blocking group. The four bases then compete for binding sites on the template cDNA to be sequenced and non- incorporated molecules are washed away. After each synthesis, a laser is used to excite the dyes and a photograph of the incorporated base is taken. A chemical deblocking step is then used in the removal of the 3' terminal blocking group and the dye in a single step. The process is repeated until the full cDNA molecule is sequenced. lllumina RNA-Seq technology records the numerical frequency of sequences in a library population. 50 bp single reads with multiples of 30M single reads are guaranteed using lllumina sequencing technology. The RNA-Seq reads are aligned to the reference genome or reference transcriptome using Bowtie generating genome / transcriptome alignments. TopHat identifies the potential exon-exon splice junctions of the initial alignment. Then Cufflinks identifi es and quantifies the transcripts from the preprocessed RNA-Seq alignment assembly. After this, Cuffmerge merges the identified transcript pieces to full length transcripts and annotates the transcripts based on the given annotations. Finally, merged transcripts from two or more samples / conditions are compared using Cuffdiff to determine the differential expression levels at transcript and gene level including a measure of significance between samples / conditions.

Differential gene expression. Operating on the RNA-Seq alignments and Cuffinks processing, Cuffdiff tracks the mapped reads and determines the fragment per kilo base per million mapped reads (FPKM) for each transcript in all the samples. Primary transcripts and gene FPKMs are then computed by adding up the FPKMs of each primary transcript group or gene group. For each pair of samples (control vs. case), the differential expression values such as fold change and p-value are computed.

5.2 SAMPLE PREPARATION RNA extraction for gene expression analysis was performed as described in Example 2 above to obtain the following pool samples:

SAMPLES LIST

5.3 GENE EXPRESSION RESULTS

The results obtained are shown in the table below:

As used herein, Compl means Compound 1 , VEH means vehicle

Changes in S100A9 expression in the hippocampus of Compound 1-treated relative to vehicle-treated SAMP8 mice were validated by RNA-seq analysis. Treatment with Compound 1 down-regulated S100A9 expression compared to vehicle-treated animals of the same sex. Example 6: Analysis of expression of additional biomarkers by RNA sequencing

RNA sequencing results disclosed in Example 5 were extended with additional biomarkers analysis using the same methodology.

6.1 GENE EXPRESSION RESULTS

The results obtained are shown in the table below:

Male FPKM Female FPKM

Compl 0.32 Fold Compl 0.96 Fold gene refseqjd VEH mg/kg/day Change VEH mg/kg/day Change

Baiap3 NM_001163270 1.95 2.90 0.57 1.62 6.64 2.03 Prph NM_013639 2.21 3.61 0.71 1.73 5.20 1.59

Avp NM_009732 0.94 1.24 0.40 069 1.99 1.53

Npw NM_001099664 0.19 0.41 1.14 0.49 1.13 1.21

As used herein, Compl means Compound 1 , VEH means vehicle

RNA-seq analysis showed that treatment with Compound 1 up-regulated Prph, Npw, Baiap3 and Avp expression compared to vehicle-treated animals of the same sex.

Example 7: Validation of effects of LSD1 inhibitors on S100A9 and S100A8 expression by qRT-PCR

7. 1 QUANTITATIVE RT-PCR qRT-PCR is a variant of the PCR (Polymerase Chain Reaction) method that permits the simultaneous exponential amplification and detection of specific cDNA fragments. The Taqman gene expression assays employ the principle of doubly labeled hydrolysis probes. The probes are marked with a fluorescent moiety at their 5' end and with a quencher moiety at the 3' end, which prevents the generation of fluorescence according to the Forster energy transfer principle. During the amplification process, the hydrolysis probe hybridizes to its complementary sequence in the target amplicon. During each cycle, the Taq polymerase initiates the production of a copy of the target sequence starting from the primer. When the Taq polymerase reaches the hydrolysis probe, its 5'-3' exonuclease activity fragments the hydrolysis probe, and liberates the fluorescent group from the quencher moiety, resulting in the emission of a fluorescent signal.

In the exponential phase of the amplification reaction, the intensity of the fluorescence is directly proportional to the quantity of PCR product formed. The LightCycler® 480 Software determines the "crossing point" (Cp), i.e. the point where the reaction's fluorescence reaches the maximum of the second derivative of the amplification curve, which corresponds to the point where the acceleration of the fluorescence signal is at its maximum. Hence, this crossing point should always be located in the middle of the log-linear portion of the PCR amplification plot. The 2-Cp values are proportional to the target mRNA concentration in the original RNA sample. qRT-PCR analysis of gene expression levels of S100A8 was performed using Taqman assay Mm00496696_g1 , Life Technologies; amplicon length 131 bp, targeting exon 2-3 boundary, RefSeq NM_013650.2, assay location 191) and of S100A9 using Taqman assay Mm00656925_m1 , Life Technologies; amplicon length 162 bp, targeting exon 2-3 boundary, RefSeq NM_001281852.1 , assay location 212) on total RNA extracted from the hippocampus of SAMR1 mice and of SAMP8 mice treated for 2 or 4 months with vehicle or with Compound 1 obtained as described in Example 3. Samples from animals receiving treatment for 2 months and 4 months were processed and statistically analyzed together. After extraction (RNeasy Mini KIT; QIAGEN), total RNA was reverse transcribed to obtain 1st strand cDNA (High Capacity RNA-to-cDNA Master Mix; Applied Biosystems). A serial dilution of 1st strand product from hippocampus was used to perform triplicate qRT-PCR (Taqman gene expression assay, Life technologies) reactions to analyze the Cp values of S100A8 and S100A9. Cp increase was normalized relative to the expression level of an endogenous reference gene (GADPH). 7.2 RESULTS

Changes in S100A9 expression in the hippocampus of Compound 1 -treated relative to vehicle-treated SAMP8 mice were validated by qRT-PCR. The results obtained are shown in Figures 5A and 5B. S100A9 was up- regulated in SAMP8 vs SAMR1 mice and treatment with Compound 1 down-regulated S100A9 expression in a dose-dependent fashion in females at 0.96 mg/kg/day (p < 0.001) and 3.2mg/kg/day (p < 0.001 ); and also in males at 0.96 mg/kg (p < 0.001). Similarly, S100A8 was up-regulated in SAMP8 vs SAMR1 female mice and treatment with Compound 1 resulted in a down-regulated S100A8 expression tendency. *** p < 0.001

Example 8: S100A9 and S100A8 are down-regulated in brain upon treatment with Compound 1 or Compound 2 This example illustrates that the degree of S100A9 and S100A8 down-regulation in the brain is dependent on the degree of LSD1 inhibition.

As part of Maximum Tolerated Dose (MTD) studies, LSD1 inhibitors were administered to mice at various doses and brain samples were collected and subjected to GE analysis.

8.1 TEST COMPOUNDS Compound 1 , Compound 2.

These compounds are enantiomers with very similar pharmacokinetic profile and biochemical potency for MAO- B and MAO-A inhibitions, but highly distinct biochemical potency for LSD1 inhibition, as shown by the data provided in Example 1.

8.2 PREPARATION OF TEST COMPOUND FOR ADMINISTRATION

Appropriate quantities of powered Compound 1 or Compound 2 were dissolved in vehicle (20% 2- hydroxypropyl- -cyclodextrin; 80 % H2O), vortexed and placed in an ultrasonic bath for 10 minutes. 8.3 MICE STRAIN AND TREATMENT

Male Hsd:ICR (CD1®) mice were maintained in air- and temperature-controlled cages with regular supply of water and food. A maximum of 3 mice were raised per cage. Three mice were assigned to each group. Before the first administration, each mouse was labeled and weighed. Test compounds were administered orally using 1 ml syringes using animal feeding needles proper for mice at 10 ml/kg as follows.

(Binary code; 1 = dose and 0 = no dose)

G1 : Compound 2, 3 mg/kg, (1111100), oral (n=3) one week

G2: Compound 2, 10 mg/kg, (1111100), oral (n=3) one week

G3: Compound 2, 30 mg/kg, (1111100), oral (n=3) one week

G4: Compound 2, 100 mg/kg, (1111100), oral (n=3) one week

G5: Compound 1 , 3 mg/kg, (1111100), oral (n=3) one week

G6: Compound 1 , 10 mg/kg, (1111100), oral (n=3) one week

G7: Compound 1 , 30 mg/kg, (1111100), oral (n=3) one week

G8: Compound 1 , 100 mg/kg, (1111100), oral (n=3) one week

G9: Vehicle, (1), oral (n=3) one week

As used herein, Compl means Compound 1 and Comp2 means Compound 2.

8.4 SAMPLES

After killing the animals, tissue samples of brain (left hemisphere) were extracted and placed immediately on liquid nitrogen and stored at -80°C. The left brain hemisphere samples were pre-processed for RNA extraction with 0.5 ml of RLT lysis buffer from Qiagen using an Ultraturrax.

8.5 GENE EXPRESSION ANALYSIS 8.5.1 SAMPLE PREPARATION

RNA extraction and labeling for gene expression analysis was performed as described above to obtain the following pool samples:

SAMPLES LIST SAMPLE CODE SAMPLE DESCRIPTION

Pool Comp2 B5 G1 Cy5 Comp2, 5d Brain 3mg/kg

Pool Comp2 B5 G2 Cy5 Comp2, 5d Brain 10mg/kg

Pool Comp2 B5 G3 Cy5 Comp2, 5d Brain 30mg/kg

Pool Comp2 B5 G4 Cy5 Comp2, 5d Brain 100mg/kg

Pool Compl B5 G5 Cy5 Compl , 5d Brain 3mg/kg

Pool Compl B5 G6 Cy5 Compl , 5d Brain 10mg/kg

Pool Compl B5 G7 Cy5 Compl , 5d Brain 30mg/kg

Pool Compl B5 G8 Cy5 Compl , 5d Brain 100mg/kg

Pool V B5 G9 Cy5 5d Brain vehicle

Pool V B5 G9 Cy3 5d Brain vehicle

8.5.2 HYBRIDIZATION LIST

The following hybridizations were performed as described above

8.5.3 REPLICA ANALYSIS

Three replica hybridizations were included for the vehicle vs vehicle comparison (SELF TO SELF); which were grouped for replica analysis. No biological replicas or repeat hybridizations were included for the other comparisons, therefore replica analysis was intra-array. GROUP CODE

3x Pool V B5 G9 Cy3 vs Pool V B5 G9 Cy5

Pool V B5 G9 Cy3 vs Pool Comp2 B5 G1 Cy5

Pool V B5 G9 Cy3 vs Pool Comp2 B5 G2 Cy5

Pool V B5 G9 Cy3 vs Pool Comp2 B5 G3 Cy5

Pool V B5 G9 Cy3 vs Pool Comp2 B5 G4 Cy5

Pool V B5 G9 Cy3 vs Pool Compl B5 G5 Cy5

Pool V B5 G9 Cy3 vs Pool Compl B5 G6 Cy5

Pool V B5 G9 Cy3 vs Pool Compl B5 G7 Cy5

Pool V B5 G9 Cy3 vs Pool Compl B5 G8 Cy5

8.5.4 GENE EXPRESSION RESULTS

BRAIN DAY 5

Comp2- 3mg/kg/vehicle control_Cy3 sample_Cy5 p-value

S100A8 -0.101464 135.57 126.363 0.0655865

S100A9 -0.251184 347.361 291.855 0.0140746

TUBB3 0.094582 3419.03 3650.69 0.0120556

TUBB2C 0.190822 5034.64 5746.61 0.0014985

Low 38 38

Comp2-1 Omg/kg/vehicle control_Cy3 sample_Cy5 p-value

S100A8 -1.15568 155.933 69.9912 0.0000057

S100A9 -1.51472 334.82 117.175 0.0004347

TUBB3 -0.123943 4039.16 3706.64 0.0079356

TUBB2C 0.117903 5291.46 5742.06 0.0111321

Low 37 37

Comp2-30mg/kg/vehicle control_Cy3 sample_Cy5 p-value

S100A8 -1.02864 163.592 80.188 2.34E-05

S100A9 -1.285 364.406 149.542 5.95E-05

TUBB3 -0.00203348 4415.82 4409.6 0.899688

TUBB2C 0.179776 5584.88 6326.04 0.0018191

Low 36 36

Comp2-1 OOmg/kg/vehicle control_Cy3 sample_Cy5 p-value S100A8 -1.92058 149.004 39.3591 0.0000023

S100A9 -2.87556 332.776 45.3442 3.58E-05

TUBB3 -0.433804 3044.33 2253.74 0.0001474

TUBB2C -0.398341 4908.57 3724.28 0.0012381

Low 37 35

Comp1-3mg/kg/vehicle control_Cy3 sample_Cy5 p-value

S100A8 -1.45228 151.321 55.2994 2.32E-04

S100A9 -1.93493 374.416 97.9225 2.06E-05

TUBB3 -0.185238 4039.96 3553.16 0.0011209

TUBB2C -0.0321599 5120.92 5008.03 0.162332

Low 35 35

Comp1-10mg/kg/vehicle control_Cy3 sample_Cy5 p-value

S100A8 -1.80982 138.972 39.6385 3.44E-05

S100A9 -2.96162 360.46 46.2723 9.00E-06

TUBB3 -0.596407 3665.88 2424.61 0.0000767

TUBB2C -0.308977 4912.07 3965.09 0.0013168

Low 36 36

Comp1-30mg/kg/vehicle control_Cy3 sample_Cy5 p-value

S100A8 -1.85879 147.249 40.5977 4.00E-06

S100A9 -2.9408 348.843 45.4319 9.50E-06

TUBB3 -0.11023 3142.63 2911.46 0.0066891

TUBB2C 0.035435 4937.3 5060.07 0.158613

Low 38 39

Comp1-100mg/kg/vehicle control_Cy3 sample_Cy5 p-value

S100A8 -1.78625 139.552 40.4596 2.52E-04

S100A9 -2.79213 392.777 56.7063 8.00E-07

TUBB3 -0.0257939 3733.62 3667.46 0.211211

TUBB2C 0.0423985 5417.68 5579.26 0.0819403

Low 35 35

vehicle/vehicle control_Cy3 sample_Cy5 p-value

S100A8 0.0608739 145.671 158.755 6.90E-03

S100A9 0.0608739 344.235 342.735 0.772812

TUBB3 -0.0512777 3170.5 3059.79 0.121021

TUBB2C 0.0289686 4789.85 4887 0.398542

Low 36 36 Low: Lowest above background signal on the array, rounded to the lower unit. Log2 (sample/control) values were calculated without background subtraction as described above.

S100A8 and S100A9 were down-regulated by treatment with LSD1 inhibitors, Compound 1 and Compound 2. Two HOUSEKEEPING genes, Tubb3 and Tubb2c, were included for comparison. The potency of the effect was correlated to the biochemical LSD1 inhibitory potency in vitro, i.e Compound 2 « Compound 1.

These data further confirm that the down-regulation of S100A8 and S100A9 observed by treatment with Compound 1 in Example 3 is due to the LSD1 -inhibitory component of Compound 1. Example 9: Effect on Prph, Npw, Baiap3 and Avp expression in brain upon treatment with Compound 1 or Compound 2

Microarray hybridization results disclosed in Example 8 were extended with additional biomarkers analysis using the same methodology.

9.1 GENE EXPRESSION RESULTS

The results obtained for Prph, Npw, Baiap3 and Avp gene expression in brain are shown in the following tables:

log2(sample/control) Hybridization signal Statistics

BRAIN DAY 5

Comp2- 3mg/kg/vehicle control_Cy3 sample_Cy5 p-value

Prph 0.36 52.54 67.32 0.001061

Npw 0.11 45.56 49.02 0.078424

Baiap3 1.29 359.76 877.67 0.000005

Avp 1.63 329.10 1020.77 0.000251

TUBB3 0.094582 3419.03 3650.69 0.0120556

TUBB2C 0.190822 5034.64 5746.61 0.0014985

Low 38 38

Comp2-1 Omg/kg/vehicle control_Cy3 sample_Cy5 p-value

Prph 0.27 50.25 60.60 0.010956

Npw 0.10 46.92 50.14 0.076979

Baiap3 0.66 349.12 550.56 0.000068

Avp 0.39 303.84 397.88 0.008057

TUBB3 -0.123943 4039.16 3706.64 0.0079356

TUBB2C 0.117903 5291.46 5742.06 0.0111321

Low 37 37

Comp2-30mg/kg/vehicle control_Cy3 sample_Cy5 p-value Prph 0.49 50.77 71.25 0.000135

Npw 0.31 48.40 60.00 0.002150

Baiap3 0.34 361.56 456.96 0.000619

Avp -0.68 332.21 207.89 0.000145

TUBB3 -0.00203348 4415.82 4409.6 0.899688

TUBB2C 0.179776 5584.88 6326.04 0.0018191

Low 36 36

Comp2-1 OOmg/kg/vehicle control_Cy3 sample_Cy5 p-value

Prph 0.44 49.50 67.20 0.000315

Npw 0.23 46.76 54.70 0.014571

Baiap3 0.49 338.34 474.91 0.000199

Avp 0.66 321.55 507.44 0.000091

TUBB3 -0.433804 3044.33 2253.74 0.0001474

TUBB2C -0.398341 4908.57 3724.28 0.0012381

Low 37 35

Comp1-3mg/kg/vehicle control_Cy3 sample_Cy5 p-value

Prph 0.47 54.46 75.53 0.005622

Npw 0.43 50.47 68.17 0.000582

Baiap3 0.74 360.45 604.05 0.000023

Avp 0.41 322.62 428.63 0.000884

TUBB3 -0.185238 4039.96 3553.16 0.001 1209

TUBB2C -0.0321599 5120.92 5008.03 0.162332

Low 35 35

Comp1-10mg/kg/vehicle control_Cy3 sample_Cy5 p-value

Prph 0.69 52.63 85.19 0.000409

Npw 0.24 46.36 54.91 0.000882

Baiap3 0.83 350.10 624.06 0.000023

Avp 0.77 309.80 526.81 0.000048

TUBB3 -0.596407 3665.88 2424.61 0.0000767

TUBB2C -0.308977 4912.07 3965.09 0.0013168

Low 36 36

Comp1-30mg/kg/vehicle control_Cy3 sample_Cy5 p-value

Prph 0.62 54.42 83.74 0.000166

Npw 0.36 47.78 61.37 0.002883

Baiap3 1.05 351.67 726.36 0.000016 Avp 1.43 354.17 952.46 0.000005

TUBB3 -0.11023 3142.63 2911.46 0.0066891

TUBB2C 0.035435 4937.3 5060.07 0.158613

Low 38 39

Comp1-100mg/kg/vehicle control_Cy3 sample_Cy5 p-value

Prph 0.58 52.108 78.042 0.0000427

Npw 0.52 48.6495 69.5446 0.0000835

Baiap3 0.66 369.533 584.28 0.0000571

Avp -0.21 329.475 284.275 0.0021654

TUBB3 -0.0257939 3733.62 3667.46 0.211211

TUBB2C 0.0423985 5417.68 5579.26 0.0819403

Low 35 35

vehicle/vehicle control_Cy3 sample_Cy5 p-value

Prph 0.01 48.30 48.64 0.688232

Npw -0.08 45.59 43.10 0.040023

Baiap3 0.09 296.34 315.93 0.028449

Avp -0.02 302.99 297.81 0.648860

TUBB3 -0.0512777 3170.5 3059.79 0.121021

TUBB2C 0.0289686 4789.85 4887 0.398542

Low 36 36

The biomarkers Prph, Npw, Baiap3 and Avp, were evaluated in the left hemisphere of the brain. Prph, Baiap3, Npw and Avp were up-regulated by both treatments (Compound 1 and 2). Example 10: S100A8 and S100A9 are down-regulated upon treatment with LSD1 inhibitors in spleen, liver and brain tissue

This example further illustrates that LSD1 inhibitors downregulate S100A8 and S100A9 gene expression in a variety of tissues and that the degree of downregulation is related to the degree of LSD1 inhibition. Tissue samples of animals treated with LSD1 inhibitors obtained from MTD studies were analyzed for gene expression of S100A9 and S100A8.

10.1 TEST COMPOUNDS

Compounds 3, 4 and 5, as described in Example 1. Compound 3 is a LSD1/MA0-B inhibitor, whereas Compounds 2 and 3 are more selective LSD1 inhibitors with biochemical potency for LSD1 , MAO-B and MAO-A as disclosed in Example 1.

10.2 PREPARATION OF TEST COMPOUNDS FOR ADMINISTRATION Powered Compound 3, 4 or 5 was dissolved in a 20% solution of 2-hydroxypropyl- -cyclodextrin in water at the appropriate concentrations, vortexed and placed in an ultrasonic bath for 5 minutes.

10.3 MICE STRAIN AND TREATMENT

Hsd:Athymic Nude-Foxn1 nu mice were maintained in air- and temperature-controlled cages with regular supply of water and food. A maximum of 6 mice/cage were raised. Before the first administration, the mice were labeled and weighed.

Intraperitoneal injection was done with 1 ml syringes using 27G needles at 15 ml/kg.

Animals were administered compound by i.p. injection on 5 consecutive days. Treatment schemes were as follows (1 : administration; 0: no administration)

OG 044/23:

G1 : Comp3, 5 mg/kg, (1111100), i.p. (n=6) one week

G2: Comp3, 10 mg/kg, (1111100)), i.p. (n=6), one week

G3: Comp3, 20 mg/kg, (1111100), i.p. (n=6), one week

G4: Comp3, 40 mg/kg, (1111100), i.p. (n=6), one week

G8: Vehicle, (1111100), i.p. (n=6) one week

OG 044/24

G1 : Comp4, 1 mg/kg, (1111100), i.p. (n=6) one week

G2: Comp4, 3 mg/kg, (1111100)), i.p. (n=6), one week

G3: Comp4, 10 mg/kg, (1111100), i.p. (n=6), one week

G4: Comp5, 3.3 mg/kg, (1111100), i.p. (n=6), one week

G5: Comp5, 11 mg/kg, (1111100), i.p. (n=6), one week

G6: Comp5, 33 mg/kg, (1111100), i.p. (n=6), one week

G7: Vehicle, (1111100), i.p. (n=6) one week

OG 044/25

G5: Vehicle, (1111100), i.p. (n=6) one week 10.4 SAMPLING PROCEDURES:

Immediately after killing each animal, samples of spleen, liver (caudate lobule) and brain were extracted. These tissues were rinsed in physiological solution and frozen on liquid nitrogen. The samples were thereafter homogenized with 10X RLT buffer (1 ml/sample) (Qiagen #79216) with Ultraturrax and stored at -80°C for further processing and RNA extraction.

10.5 GENE EXPRESSION ANALYSIS 10.5.1 SAMPLE PREPARATION

Pool 23-B5-G1 Cy5 means Cy5 Labeled aRNA derived from Pool from RNA from brain from mice from treatment group G1 of OG 044/23 sacrificed on day 5 of treatment

"OG 044/23 G1 -1 ,2,3- Brain- day 5th" means RNA derived from the brain of mouse n° 1 , 2, 3 from treatment group G1 of OG 044/23 sacrificed on day 5 of treatment

SAMPLE CODE SAMPLE DESCRIPTION MOUSE TREATMENT

Pool 23-B5-G1 Cy5 OG 044/23 cr (G1-1 ,2,3) - Brain - day 5th Comp3 5 mg/kg

Pool 23-B5-G2 Cy5 OG 044/23 cr (G2-1 ,2,3) - Brain - day 5th Comp3 10 mg/kg

Pool 23-B5-G3 Cy5 OG 044/23 cr (G3-1 ,2,3) - Brain - day 5th Comp3 20 mg/kg

Pool 23-B5-G4 Cy5 OG 044/23 cr (G4-1 ,2,3) - Brain - day 5th Comp3 40 mg/kg

Pool 23-S5-G1 Cy5 OG 044/23 cr (G1-1 ,2,3) - Spleen - day 5th Comp3 5 mg/kg

Pool 23-S5-G2 Cy5 OG 044/23 cr (G2-1 ,2,3) - Spleen - day 5th Comp3 10 mg/kg

Pool 23-S5-G3 Cy5 OG 044/23 cr (G3-1 ,2,3) - Spleen - day 5th Comp3 20 mg/kg

Pool 23-S5-G4 Cy5 OG 044/23 cr (G4-1 ,2,3) - Spleen - day 5th Comp3 40 mg/kg

Pool 23-L5-G1 Cy5 OG 044/23 cr (G1-1 ,2,3) - Liver - day 5th Comp3 5 mg/kg

Pool 23-L5-G2 Cy5 OG 044/23 cr (G2-1 ,2,3) - Liver - day 5th Comp3 10 mg/kg

Pool 23-L5-G3 Cy5 OG 044/23 cr (G3-1 ,2,3) - Liver - day 5th Comp3 20 mg/kg

Pool 23-L5-G4 Cy5 OG 044/23 cr (G4-1 ,2,3) - Liver - day 5th Comp3 40 mg/kg

Pool 24-B5-G1 Cy5 OG 044/24 cr (G1-1 ,2,3) - Brain - day 5th Comp4 1 mg/kg

Pool 24-B5-G2 Cy5 OG 044/24 cr (G2-1 ,2,3) - Brain - day 5th Comp4 3 mg/kg

Pool 24-B5-G3 Cy5 OG 044/24 cr (G3-1 ,2,3) - Brain - day 5th Comp4 10 mg/kg

Pool 24-B5-G4 Cy5 OG 044/24 cr (G4-1 ,2,3) - Brain - day 5th Comp5 3.3 mg/kg

Pool 24-B5-G5 Cy5 OG 044/24 cr (G5-1 ,2,3) - Brain - day 5th Comp5 11 mg/kg Pool 24-B5-G6 Cy5 OG 044/24 cr (G6-1 ,2,3) - Brain - day 5th Comp5 33 mg/kg

Pool 24-S5-G1 Cy5 OG 044/24 cr (G1 -1 ,2,3) - Spleen - day 5th Comp4 1 mg/kg

Pool 24-S5-G2 Cy5 OG 044/24 cr (G2-1 ,2,3) - Spleen - day 5th Comp4 3 mg/kg

Pool 24-S5-G3 Cy5 OG 044/24 cr (G3-1 ,2,3) - Spleen - day 5th Comp4 10 mg/kg

Pool 24-S5-G4 Cy5 OG 044/24 cr (G4-1 ,2,3) - Spleen - day 5th Comp5 3.3 mg/kg

Pool 24-S5-G5 Cy5 OG 044/24 cr (G5-1 ,2,3) - Spleen - day 5th Comp5 11 mg/kg

Pool 24-S5-G6 Cy5 OG 044/24 cr (G6-1 ,2,3) - Spleen - day 5th Comp5 33 mg/kg

Pool 24-L5-G1 Cy5 OG 044/24 cr (G1-1 ,2,3) - Liver - day 5th Comp4 1 mg/kg

Pool 24-L5-G2 Cy5 OG 044/24 cr (G2-1 ,2,3) - Liver - day 5th Comp4 3 mg/kg

Pool 24-L5-G3 Cy5 OG 044/24 cr (G3-1 ,2,3) - Liver - day 5th Comp4 10 mg/kg

Pool 24-L5-G4 Cy5 OG 044/24 cr (G4-1 ,2,3) - Liver - day 5th Comp5 3.3 mg/kg

Pool 24-L5-G5 Cy5 OG 044/24 cr (G5-1 ,2,3) - Liver - day 5th Comp5 11 mg/kg

Pool 24-L5-G6 Cy5 OG 044/24 cr (G6-1 ,2,3) - Liver - day 5th Comp5 33 mg/kg

Pool 25-B5-G5 Cy5 OG 044/25 cr (G5-1 ,2,3) - Brain - day 5th VEH

Pool 25-S5-G5 Cy5 OG 044/25 cr (G5-1 ,2,3) - Spleen - day 5th VEH

Pool 25-L5-G5 Cy5 OG 044/25 cr (G5-1 ,2,3) - Liver - day 5th VEH

Pool 25-B5-G5 Cy3 OG 044/25 cr (G5-1 ,2,3) - Brain - day 5th VEH

Pool 25-S5-G5 Cy3 OG 044/25 cr (G5-1 ,2,3) - Spleen - day 5th VEH

Pool 25-L5-G5 Cy3 OG 044/25 cr (G5-1 ,2,3) - Liver - day 5th VEH

Pool 23-B5-G8 Cy3 OG 044/23 cr (G8-1 ,2,3) - Brain - day 5th VEH

Pool 23-S5-G8 Cy3 OG 044/23 cr (G8-1 ,2,3) - Spleen - day 5th VEH

Pool 23-L5-G8 Cy3 OG 044/23 cr (G8-1 ,2,3) - Liver - day 5th VEH

10.5.2 HYBRIDIZATIONS

The following labeled samples were co-hybridized on applicant's mouse WGA arrays and analyzed described above in Example 2:

HYB. # CODE CONTROL DESCRIPTION CODE SAMPLE DESCRIPTION

Pool 23-B5-G8 Cy3 OG 044/23 cr (G8-1.2.3) - Pool 23-B5-G1 OG 044/23 cr (G1 -1 ,2,3) -

1 Brain - day 5th Cy5 Brain - day 5th

Pool 23-B5-G8 Cy3 OG 044/23 cr (G8-1.2.3) - Pool 23-B5-G2 OG 044/23 cr (G2-1.2.3) -

2 Brain - day 5th Cy5 Brain - day 5th

Pool 23-B5-G8 Cy3 OG 044/23 cr (G8-1.2.3) - Pool 23-B5-G3 OG 044/23 cr (G3-1.2.3) -

3 Brain - day 5th Cy5 Brain - day 5th Pool 23-B5-G8 Cy3 OG 044/23 cr (G8-1.2.3) - Pool 23-B5-G4 OG 044/23 cr (G4-1.2.3) - Brain - day 5th Cy5 Brain - day 5th

Pool 23-S5-G8 Cy3 OG 044/23 cr (G8-1.2.3) - Pool 23-S5-G1 OG 044/23 cr (G1 -1 ,2,3) - Spleen - day 5th Cy5 Spleen - day 5th

Pool 23-S5-G8 Cy3 OG 044/23 cr (G8-1.2.3) - Pool 23-S5-G2 OG 044/23 cr (G2-1.2.3) - Spleen - day 5th Cy5 Spleen - day 5th

Pool 23-S5-G8 Cy3 OG 044/23 cr (G8-1.2.3) - Pool 23-S5-G3 OG 044/23 cr (G3-1.2.3) - Spleen - day 5th Cy5 Spleen - day 5th

Pool 23-S5-G8 Cy3 OG 044/23 cr (G8-1.2.3) - Pool 23-S5-G4 OG 044/23 cr (G4-1.2.3) - Spleen - day 5th Cy5 Spleen - day 5th

Pool 23-L5-G8 Cy3 OG 044/23 cr (G8-1.2.3) - Pool 23-L5-G1 OG 044/23 cr (G1 -1 ,2,3) - Liver - day 5th Cy5 Liver - day 5th

Pool 23-L5-G8 Cy3 OG 044/23 cr (G8-1.2.3) - Pool 23-L5-G2 OG 044/23 cr (G2-1.2.3) - Liver - day 5th Cy5 Liver - day 5th

Pool 23-L5-G8 Cy3 OG 044/23 cr (G8-1.2.3) - Pool 23-L5-G3 OG 044/23 cr (G3-1.2.3) - Liver - day 5th Cy5 Liver - day 5th

Pool 23-L5-G8 Cy3 OG 044/23 cr (G8-1.2.3) - Pool 23-L5-G4 OG 044/23 cr (G4-1.2.3) - Liver - day 5th Cy5 Liver - day 5th

Pool 25-B5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-B5-G1 OG 044/24 cr (G1 -1 ,2,3) - Brain - day 5th Cy5 Brain - day 5th

Pool 25-B5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-B5-G2 OG 044/24 cr (G2-1.2.3) - Brain - day 5th Cy5 Brain - day 5th

Pool 25-B5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-B5-G3 OG 044/24 cr (G3-1.2.3) - Brain - day 5th Cy5 Brain - day 5th

Pool 25-B5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-B5-G4 OG 044/24 cr (G4-1.2.3) - Brain - day 5th Cy5 Brain - day 5th

Pool 25-B5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-B5-G5 OG 044/24 cr (G5-1.2.3) - Brain - day 5th Cy5 Brain - day 5th

Pool 25-B5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-B5-G6 OG 044/24 cr (G6-1.2.3) - Brain - day 5th Cy5 Brain - day 5th

Pool 25-S5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-S5-G1 OG 044/24 cr (G1 -1 ,2,3) - Spleen - day 5th Cy5 Spleen - day 5th

Pool 25-S5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-S5-G2 OG 044/24 cr (G2-1.2.3) - Spleen - day 5th Cy5 Spleen - day 5th

Pool 25-S5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-S5-G3 OG 044/24 cr (G3-1.2.3) - Spleen - day 5th Cy5 Spleen - day 5th

Pool 25-S5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-S5-G4 OG 044/24 cr (G4-1.2.3) -

28 Spleen - day 5th Cy5 Spleen - day 5th

Pool 25-S5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-S5-G5 OG 044/24 cr (G5-1.2.3) -

29 Spleen - day 5th Cy5 Spleen - day 5th

Pool 25-S5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-S5-G6 OG 044/24 cr (G6-1.2.3) -

30 Spleen - day 5th Cy5 Spleen - day 5th

Pool 25-L5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-L5-G1 OG 044/24 cr (G1 -1 ,2,3) -

31 Liver - day 5th Cy5 Liver - day 5th

Pool 25-L5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-L5-G2 OG 044/24 cr (G2-1.2.3) -

32 Liver - day 5th Cy5 Liver - day 5th

Pool 25-L5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-L5-G3 OG 044/24 cr (G3-1.2.3) -

33 Liver - day 5th Cy5 Liver - day 5th

Pool 25-L5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-L5-G4 OG 044/24 cr (G4-1.2.3) -

34 Liver - day 5th Cy5 Liver - day 5th

Pool 25-L5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-L5-G5 OG 044/24 cr (G5-1.2.3) -

35 Liver - day 5th Cy5 Liver - day 5th

Pool 25-L5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 24-L5-G6 OG 044/24 cr (G6-1.2.3) -

36 Liver - day 5th Cy5 Liver - day 5th

Pool 25-B5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 25-B5-G5 OG 044/25 cr (G5-1.2.3) -

40 Brain - day 5th Cy5 Brain - day 5th

Pool 25-S5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 25-S5-G5 OG 044/25 cr (G5-1.2.3) -

41 Spleen - day 5th Cy5 Spleen - day 5th

Pool 25-L5-G5 Cy3 OG 044/25 cr (G5-1.2.3) - Pool 25-L5-G5 OG 044/25 cr (G5-1.2.3) -

42 Liver - day 5th Cy5 Liver - day 5th

10.5.3 REPLICA ANALYSIS Replica analysis was intra-array.

GROUP CODE COMPARISON (CONTROL-sample)

Pool 23-B5-G8 Cy3 vs Pool 23-B5-G1 Cy5 Brain VEH-Comp3 5 mg/kg

Pool 23-B5-G8 Cy3 vs Pool 23-B5-G2 Cy5 Brain VEH-Comp3 10 mg/kg

Pool 23-B5-G8 Cy3 vs Pool 23-B5-G3 Cy5 Brain VEH-Comp3 20 mg/kg

Pool 23-B5-G8 Cy3 vs Pool 23-B5-G4 Cy5 Brain VEH-Comp3 40 mg/kg

Pool 23-L5-G8 Cy3 vs Pool 23-L5-G1 Cy5 Liver VEH-Comp3 5 mg/kg Pool 23-L5-G8 Cy3 vs Pool 23-L5-G2 Cy5 Liver VEH-Comp3 10 mg/kg

Pool 23-L5-G8 Cy3 vs Pool 23-L5-G3 Cy5 Liver VEH-Comp3 20 mg/kg

Pool 23-L5-G8 Cy3 vs Pool 23-L5-G4 Cy5 Liver VEH-Comp3 40 mg/kg

Pool 23-S5-G8 Cy3 vs Pool 23-S5-G1 Cy5 Spleen VEH-Comp3 5 mg/kg

Pool 23-S5-G8 Cy3 vs Pool 23-S5-G2 Cy5 Spleen VEH-Comp3 10 mg/kg

Pool 23-S5-G8 Cy3 vs Pool 23-S5-G3 Cy5 Spleen VEH-Comp3 20 mg/kg

Pool 23-S5-G8 Cy3 vs Pool 23-S5-G4 Cy5 Spleen VEH-Comp3 40 mg/kg

Pool 25-B5-G5 Cy3 vs Pool 24-B5-G1 Cy5 Brain VEH-Comp4 1 mg/kg

Pool 25-B5-G5 Cy3 vs Pool 24-B5-G2 Cy5 Brain VEH-Comp4 3 mg/kg

Pool 25-B5-G5 Cy3 vs Pool 24-B5-G3 Cy5 Brain VEH-Comp4 10 mg/kg

Pool 25-B5-G5 Cy3 vs Pool 24-B5-G4 Cy5 Brain VEH-Comp5 3.3 mg/kg

Pool 25-B5-G5 Cy3 vs Pool 24-B5-G5 Cy5 Brain VEH-Comp5 11 mg/kg

Pool 25-B5-G5 Cy3 vs Pool 24-B5-G6 Cy5 Brain VEH-Comp5 33 mg/kg

Pool 25-B5-G5 Cy3 vs Pool 25-B5-G5 Cy5 Brain VEH-veh

Pool 25-L5-G5 Cy3 vs Pool 24-L5-G1 Cy5 Liver VEH-Comp4 1 mg/kg

Pool 25-L5-G5 Cy3 vs Pool 24-L5-G2 Cy5 Liver VEH-Comp4 3 mg/kg

Pool 25-L5-G5 Cy3 vs Pool 24-L5-G3 Cy5 Liver VEH-Comp4 10 mg/kg

Pool 25-L5-G5 Cy3 vs Pool 24-L5-G4 Cy5 Liver VEH-Comp5 3.3 mg/kg

Pool 25-L5-G5 Cy3 vs Pool 24-L5-G5 Cy5 Liver VEH-Comp5 11 mg/kg

Pool 25-L5-G5 Cy3 vs Pool 24-L5-G6 Cy5 Liver VEH-Comp5 33 mg/kg

Pool 25-L5-G5 Cy3 vs Pool 25-L5-G5 Cy5 Liver VEH-veh

Pool 25-S5-G5 Cy3 vs Pool 24-S5-G1 Cy5 Spleen VEH-Comp4 1 mg/kg

Pool 25-S5-G5 Cy3 vs Pool 24-S5-G2 Cy5 Spleen VEH-Comp4 3 mg/kg

Pool 25-S5-G5 Cy3 vs Pool 24-S5-G3 Cy5 Spleen VEH-Comp4 10 mg/kg

Pool 25-S5-G5 Cy3 vs Pool 24-S5-G4 Cy5 Spleen VEH-Comp5 3.3 mg/kg

Pool 25-S5-G5 Cy3 vs Pool 24-S5-G5 Cy5 Spleen VEH-Comp5 11 mg/kg

Pool 25-S5-G5 Cy3 vs Pool 24-S5-G6 Cy5 Spleen VEH-Comp5 33 mg/kg

Pool 25-S5-G5 Cy3 vs Pool 25-S5-G5 Cy5 Spleen VEH-Veh

10.5.4 GENE EXPRESSION RESULTS

The results obtained for S100A9 and S100A8 gene expression in brain, liver and spleen are shown in the following tables:

BRAIN log2(sample/control) Hybridization signal Statistics Comp3- 5mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -0.116017 248.95 229.714 0.0528036

S100A9 0.110561 701.012 756.846 0.0067591

TUBB3 -0.223014 3004.34 2574.04 0.0006934

TUBB2C 0.091149 5541.7 5903.12 0.019801

Comp3 - 10mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -0.330416 232.91 185.235 0.0006585

S100A9 -0.55889 685.045 465.025 0.0001163

TUBB3 -0.0628319 3393.48 3248.86 0.0342762

TUBB2C -0.00895453 6267.43 6228.65 0.704312

Comp3-20mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -1.21795 253.211 108.854 1.17E-05

S100A9 -1.38783 703.749 268.93 5.90E-06

TUBB3 -0.0238012 3129.74 3078.53 0.202855

TUBB2C 0.0728923 6593.57 6935.27 0.0201539

Comp3-40mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -1.59783 271.032 89.5415 0.0004946

S100A9 -1.79791 724.946 208.488 5.20E-06

TUBB3 0.0205359 3523.25 3573.76 0.316423

TUBB2C 0.063281 7087.54 7405.34 0.0378478

Comp5-3.3mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -0.646209 419.687 268.162 3.46E-05

S100A9 -0.963497 1455.77 746.537 2.11 E-05

TUBB3 -0.0512589 4912.3 4740.83 0.0376315

TUBB2C -0.0139633 10745.5 10642 0.636057

Comp5-11 mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -3.26296 369.474 38.4889 5.91 E-05

S100A9 -4.54044 1408.99 60.5479 2.00E-07

TUBB3 -0.0283428 6340.6 6217.25 0.151714

TUBB2C -0.0612686 11645.3 11161.1 0.0314123

Comp5-33mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -3.56994 435.767 36.6941 3.59E-05

S100A9 -4.69667 1514.28 58.3941 2.88E-05

TUBB3 0.107328 5311.82 5722.06 0.0077311

TUBB2C -0.0514525 13041 12584.1 0.105786 Comp4-1 mg/kgA EH control_Cy3 sample_Cy5 p-value

S100A8 -1.76098 361.771 106.74 2.30E-06

S100A9 -2.14315 1352.76 306.245 3.20E-06

TUBB3 -0.038249 5126.16 4992.04 0.0853952

TUBB2C -0.0491179 10363.6 10016.7 0.0518424

Comp4-3mg/kgA EH control_Cy3 sample_Cy5 p-value

S100A8 -2.35046 335.347 65.756 4.00E-06

S100A9 -3.28645 1294.92 132.716 0.0001198

TUBB3 0.0785165 4857.36 5129.04 0.0113096

TUBB2C -0.0658487 10338.7 9877.42 0.0465475

Comp4-10mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -3.04151 385.173 46.781 4.53E-05

S100A9 -4.22221 1469.58 78.7372 2.75E-05

TUBB3 -0.177847 6721.42 5941.88 0.0009661

TUBB2C -0.042907 12353.7 11991.7 0.0850895

VehicleA EH control_Cy3 sample_Cy5 p-value

S100A8 -0.418623 427.068 319.506 0.0056197

S100A9 -0.425301 1399.83 1042.43 0.0002849

TUBB3 0.12973 5781.97 6325.99 0.0035088

TUBB2C 0.0473502 12132.4 12537.2 0.058029 log2(sample/control) Hybridization signal Statistics

LIVER

Comp3-5mg/kgA EH control_Cy3 sample_Cy5 p-value

S100A8 -1.37141 647.329 250.202 0.0000055

S100A9 -1.469 2270.08 820.026 0.0000061

TUBB3 -0.0974207 69.2938 64.7691 0.0591413

TUBB2C -0.119352 2906.83 2676.03 0.0188672

Comp3-10mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -1.1185 608.779 280.387 0.0000137

S100A9 -1.41023 2235.37 841.06 0.0000077

TUBB3 0.0234532 67.5989 68.7068 0.428766

TUBB2C -0.268688 2772.56 2301.43 0.002107

Comp3-20mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -1.31838 663.39 266.01 3.50E-04

S100A9 -1.44015 2341.46 862.896 2.90E-06

TUBB3 -0.0422453 49.8966 48.4567 0.166853 TUBB2C -0.577977 3073.85 2059.18 0.0000399

Comp3-40mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -2.17684 729.021 161.23 0.0001201

S100A9 -2.57138 2450.08 412.209 7.00E-07

TUBB3 0.0192666 46.2878 46.9101 0.277263

TUBB2C -0.972821 3044.5 1551.2 0.0000148

Comp5-3.3mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -0.47611 438.772 315.439 2.34E-03

S100A9 -0.572778 1468.58 987.357 6.64E-05

TUBB3 -0.448273 66.9185 49.0459 0.0002499

TUBB2C 0.369152 2841.97 3670.67 0.000257

Comp5-11 mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -2.35673 375.405 73.2915 9.81 E-05

S100A9 -3.05631 1421.86 170.929 1.04E-04

TUBB3 -0.641122 67.3675 43.197 0.0035129

TUBB2C 0.457003 2903.16 3985.13 0.000075

Comp5-33mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -2.90929 432.068 57.5133 2.20E-06

S100A9 -3.81082 1599.43 113.971 1.60E-06

TUBB3 -0.421099 69.6654 52.03 0.0005435

TUBB2C 0.320464 3471.85 4335.41 0.0006955

Comp4-1 mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -0.871751 404.016 220.788 8.02E-05

S100A9 -1.19204 1522.62 666.426 1.10E-05

TUBB3 -0.40896 121.463 91.4818 0.0029989

TUBB2C 0.297059 3521.82 4327.04 0.0010995

Comp4-3mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -1.18111 478.702 211.114 6.78E-04

S100A9 -1.63169 1519.07 490.218 0.0000036

TUBB3 -0.243158 78.9793 66.7291 0.0010767

TUBB2C 0.106902 2972.69 3201.33 0.0064836

Comp4-10mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -1.33533 435.176 172.461 4.02E-04

S100A9 -1.92803 1471.75 386.758 3.25E-04

TUBB3 0.681142 64.8556 103.99 0.0000383 TUBB2C 0.329165 2502.36 3143.68 0.0006093

Vehicle/VEH control_Cy3 sample_Cy5 p-value

S100A8 0.762602 303.336 514.624 0.0000682

S100A9 0.387227 1092.61 1429 0.0008392

TUBB3 0.299751 87.1803 107.313 0.0068201

TUBB2C 0.523662 2346.8 3373.76 0.0000781 log2(sample/control) Hybridization signal Statistics

SPLEEN

Comp3-5mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -1.18074 10277.2 4533.52 0.0004379

S100A9 -1.21321 25045.6 10802.4 0.0000119

TUBB3 -0.0294416 59.8944 58.6845 0.21592

TUBB2C -0.0527213 6478.39 6245.92 0.0762385

Comp3-10mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -0.470554 8788.86 6342.81 0.0001133

S100A9 -0.581246 22715.6 15182.8 0.000045

TUBB3 -0.0225851 53.4995 52.6685 0.586351

TUBB2C -0.486263 5631.11 4019.89 0.0001504

Comp3-20mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -0.529633 10126.5 7014.94 8.21 E-05

S100A9 -0.517902 22505.3 15717.4 1.45E-04

TUBB3 -0.118253 67.8779 62.5361 0.0281949

TUBB2C -0.409736 6107.86 4597.76 0.0000958

Comp3-40mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -1.65026 15074 4802.3 0.0000088

S100A9 -1.71866 44306.9 13461.8 1.30E-06

TUBB3 0.168976 78.5777 88.3418 0.0016755

TUBB2C -0.947642 17333 8986.8 0.0001762

Comp5-3.3mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -1.65026 15074 4802.3 8.80E-06

S100A9 -1.71866 44306.9 13461.8 1.30E-06

TUBB3 0.168976 78.5777 88.3418 0.0016755

TUBB2C -0.947642 17333 8986.8 0.0001762

Comp5-11 mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -5.38002 15948.8 382.984 2.00E-06

S100A9 -5.62508 47530.9 963.073 1.20E-06 TUBB3 1.52085 80.0591 229.738 0.0000132

TUBB2C -0.873906 16901.7 9222.71 0.0019696

Comp5-33mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -5.24323 15486.8 408.877 3.00E-07

S100A9 -5.68502 48567.9 944.034 9.00E-07

TUBB3 1.39838 63.6658 167.826 0.0000182

TUBB2C -1.41024 17370.5 6535.64 0.0000229

Comp4-1 mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -1.31235 14941 6016.2 2.81 E-05

S100A9 -1.57948 41089.3 13748.6 4.40E-06

TUBB3 0.23143 64.757 76.0246 0.0097577

TUBB2C -0.312444 16522.9 13305.5 0.0004177

Comp4-3mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -3.14813 16439.6 1854.43 8.00E-07

S100A9 -3.54115 44522.6 3824.62 0.0000002

TUBB3 0.335203 90.5137 114.188 0.0002296

TUBB2C -0.433932 15791.6 11689.6 0.000515

Comp4-10mg/kg/VEH control_Cy3 sample_Cy5 p-value

S100A8 -3.58663 14588.6 1214.31 8.77E-05

S100A9 -4.16055 44755.7 2502.64 1.70E-06

TUBB3 0.916853 81.7996 154.437 0.0000333

TUBB2C -1.31564 16281.9 6541.2 0.0000418

Vehicle/VEH control_Cy3 sample_Cy5 p-value

S100A8 -0.230196 16016.3 13654.2 0.0027948

S100A9 -0.249258 41150.6 34621.2 0.0005574

TUBB3 -0.141257 64.3274 58.3275 0.0393814

TUBB2C 0.0808866 16317.6 17258.6 0.0759403

As shown in the three tables above, S100A8 and S100A9 were down-regulated by treatment with different LSD1 inhibitors in brain, spleen and liver. Two HOUSEKEEPING genes, Tubb3 and Tubb2c, were included for comparison. The potency of the effect on S100A9 and S100A8 expression was correlated to the biochemical LSD1 inhibitory potency in vitro, i.e Compound 3 < Compound 4, Compound 5.

Example 11 : Effect on Prph, Npw, Baiap3 and Avp expression in brain upon treatment with further LSD1 inhibitors Microarray hybridization results disclosed in Example 10 were extended with additional biomarkers analysis using the same methodology.

11.1 GENE EXPRESSION RESULTS

The results obtained for Prph, Npw, Baiap3 and Avp gene expression in brain are shown in the following tables: log2(sample/control) Hybridization signal Statistics

BRAIN

Comp3- 5mg/kg/VEH control_Cy3 sample_Cy5 p-value

Prph 0.00855496 73.3427 73.7789 0.766806

Npw 0.237991 48.6816 57.4126 0.0089677

Baiap3 0.299455 524.945 646.039 0.0004747

Avp 0.207379 735.675 849.402 0.0011114

TUBB3 -0.223014 3004.34 2574.04 0.0006934

TUBB2C 0.091149 5541.7 5903.12 0.019801

Comp3 - 10mg/kg/VEH control_Cy3 sample_Cy5 p-value

Prph 0.203487 73.6615 84.8196 0.0038388

Npw 0.179045 52.1379 59.0271 0.0174853

Baiap3 0.118617 565.666 614.14 0.0097028

Avp -0.0139449 733.942 726.882 0.606915

TUBB3 -0.0628319 3393.48 3248.86 0.0342762

TUBB2C -0.00895453 6267.43 6228.65 0.704312

Comp3-20mg/kg/VEH control_Cy3 sample_Cy5 p-value

Prph 0.346248 70.5655 89.7064 0.0102187

Npw 0.416903 48.4829 64.7275 0.0001398

Baiap3 0.244865 557.428 660.542 0.000823

Avp 0.453885 766.089 1049.33 9.86E-05

TUBB3 -0.0238012 3129.74 3078.53 0.202855

TUBB2C 0.0728923 6593.57 6935.27 0.0201539

Comp3-40mg/kg/VEH control_Cy3 sample_Cy5 p-value

Prph 0.694523 79.2734 128.292 3.00E-05

Npw 0.230432 51.0232 59.8597 0.0154809

Baiap3 0.509617 608.733 866.636 0.0001542

Avp 0.734427 922.688 1535.11 0.0015198

TUBB3 0.0205359 3523.25 3573.76 0.316423

TUBB2C 0.063281 7087.54 7405.34 0.0378478 Comp5-3.3mg/kg/VEH control_Cy3 sample_Cy5 p-value

Prph 0.147802 79.867 88.4831 0.013465

Npw 0.0580573 57.6432 60.0102 0.107805

Baiap3 -0.134907 897.598 817.468 0.0073379

Avp -0.615147 1823.69 1190.62 0.0011743

TUBB3 -0.0512589 4912.3 4740.83 0.0376315

TUBB2C -0.0139633 10745.5 10642 0.636057

Comp5-11 mg/kg/VEH control_Cy3 sample_Cy5 p-value

Prph 0.679414 80.6974 129.236 0.0001799

Npw 0.310622 57.4545 71.2575 0.0066851

Baiap3 0.215022 908.952 1055.04 0.0014303

Avp -0.373522 1607.51 1240.83 0.0001593

TUBB3 -0.0283428 6340.6 6217.25 0.151714

TUBB2C -0.0612686 11645.3 11161.1 0.0314123

Comp5-33mg/kg/VEH control_Cy3 sample_Cy5 p-value

Prph 0.860147 79.5599 144.419 0.00011

Npw 0.356691 58.8426 75.3471 0.0111479

Baiap3 0.261052 972.761 1165.71 0.0005619

Avp -0.268972 1992.6 1653.68 0.0004663

TUBB3 0.107328 5311.82 5722.06 0.0077311

TUBB2C -0.0514525 13041 12584.1 0.105786

Comp4-1 mg/kg/VEH control_Cy3 sample_Cy5 p-value

Prph 0.733474 80.7157 134.201 3.83E-05

Npw 0.457788 61.4873 84.4488 8.99E-05

Baiap3 0.265519 885.307 1064.2 0.0005386

Avp -0.645561 1683.16 1075.95 4.35E-05

TUBB3 -0.038249 5126.16 4992.04 0.0853952

TUBB2C -0.0491179 10363.6 10016.7 0.0518424

Comp4-3mg/kg/VEH control_Cy3 sample_Cy5 p-value

Prph 1.01147 76.4254 154.071 5.75E-05

Npw 0.582942 59.3022 88.8288 0.000377

Baiap3 0.378771 845.963 1099.95 0.0002028

Avp -0.565726 1617.0 1092.49 6.16E-05

TUBB3 0.0785165 4857.36 5129.04 0.0113096

TUBB2C -0.0658487 10338.7 9877.42 0.0465475 Comp4-10mg/kg/VEH control_Cy3 sample_Cy5 p-value

Prph 1.20319 85.2395 196.263 0.0002877

Npw 0.475615 62.3299 86.6704 0.0018473

Baiap3 0.282938 978.318 1190.29 0.0009438

Avp -0.281287 1801.14 1482.08 0.0003779

TUBB3 -0.177847 6721.42 5941.88 0.0009661

TUBB2C -0.042907 12353.7 11991.7 0.0850895

Vehicle/VEH control_Cy3 sample_Cy5 p-value

Prph -0.0218243 82.3252 81.0892 0.423608

Npw -0.149761 62.6053 56.4324 0.007187

Baiap3 -0.113376 926.423 856.406 0.0042339

Avp -0.261064 1915.69 1598.59 0.0003579

TUBB3 0.12973 5781.97 6325.99 0.0035088

TUBB2C 0.0473502 12132.4 12537.2 0.058029

11.2 DISCUSSION OF GENE EXPRESSION DATA FROM EXAMPLES 9 AND 11 Prph: Compound 1 at all doses tested produced a higher upregulation of this biomarker compared to equivalent doses of Compound 2, indicating that the effect is mediated by the LSD1 -inhibitory component from Compound 1. Data obtained with potent selective LSD1 i Compounds 4 and 5 and dual LSD1/MAOB Compound 3 also show upregulation of Prph, further supporting the role of LSD1 inhibition in the upregulation of this biomarker .

Npw: Compound 1 produced higher upregulation of Npw compared to equivalent doses of Compound 2, indicating that the effect is mediated by the LSD1 -inhibitory component from Compound 1. Compound 3, which is a dual LSD1/MAOB inhibitor, and Compounds 4 and 5, which are selective LSD1 inhibitors, all produced upregulation of this biomarker, further supporting the role of LSD1 inhibition in the upregulation of this biomarker.

Baiap3: Compounds 1 and 2 produced a similar upregulation of this biomarker at the lowest dose tested, 3 mg/kg, illustrating that the MAO-B inhibitory component contributes to the regulation of this biomarker. Avp: Compound 1 and 2 produced a similar upregulation of this biomarker at the two lower doses, indicating that the effect is mediated by the MAO-B-inhibitory component from these compounds. Further supporting the role of MAOB inhibition on the upregulation of this biomarker, Compound 3, a dual LSD1/MAOB inhibitor, also produced upregulation of Avp, an effect not observed with selective LSD1 i Compounds 4 and 5. Furthermore, both selective LSD1 i compounds produced a down-regulation of Avp at all doses tested.

Example 12: Validation of effects of LSD1 inhibitors on Baiap3, Npw and Prph expression by qRT-PCR

12. 1 QUANTITATIVE RT-PCR qRT-PCR analysis of gene expression levels of Baiap3 was performed using Taqman assay Mm_01301 145_m1 (Life Technologies, amplicon length 1 17 bp, targeting exon 1 -2 boundary, RefSeq NM_001 163270.1 , assay location 206), of Npw using Taqman assay Mm_01299908_g1 (Life Technologies, amplicon length 63 bp, targeting exon 1 -2 boundary, RefSeq NM_001099664.1 , assay location 429) and of Prph using Taqman assay Mm_00449704_m1 (Life Technologies, amplicon length 83 bp, targeting exon 8-9 boundary, RefSeq NM_001 163589.1 , assay location 1388) on total RNA extracted from the hippocampus of SAMR1 mice and of SAMP8 mice treated for 2 or 4 months with vehicle or with Compound 1 obtained as described in Example 3. Samples from animals receiving treatment for 2 months and 4 months were processed and statistically analyzed together. After extraction (RNeasy Mini KIT; QIAGEN), total RNA was reverse transcribed to obtain 1 st strand cDNA (High Capacity RNA-to-cDNA Master Mix; Applied Biosystems). A serial dilution of 1 st strand product from hippocampus was used to perform triplicate qRT-PCR (Taqman gene expression assay, Life technologies) reactions to analyze the Cp values of Baiap3, Npw and Prph. High Cp values characterize rare mRNAs, low Cp values characterize abundant mRNAs. The Cp values of these genes were normalized relative to the Cp values of an endogenous reference gene (Gapdh), and calculated as ACp=Cpgene-CpGapdh. Therefore, a drop in ACp values reflects induction of gene expression.

12.2 RESULTS

Changes in Baiap3 expression in the hippocampus of Compound 1-treated relative to vehicle-treated SAMP8 mice detected by microarray analysis were validated by qRT-PCR on individual samples. The results obtained are shown in Figure 6A (Females: SAMR1 -Vehicle, n=8; SAMP8-vehicle, n=7; SAMP8-Comp1 0.96 mg/kg, n=3; SAMP8-Comp1 3.2 mg/kg, n=6) and Figure 6B (Males: SAMR1 -Vehicle, n=5; SAMP8-vehicle, n=5; SAMP8-Comp1 0.32 mg/kg, n=5; SAMP8-Comp1 0.96 mg/kg, n=3). Baseline Cp values for Baiap3 in vehicle- treated SAMR1 and SAMP8 animals were 37.38 and 37.65, respectively, reflecting a very low level of expression. In females, Baiap3 was significantly up-regulated by treatment with Compound 1 at 0.96 and 3.2 mg/kg/day. In males, treatment with Compound 1 lowered mean Baiap3 ACp values although the change did not reach significance. These data confirm what was observed in the RNA sequencing experiment (Example 6) and illustrate that Baiap3 up-regulation is more prominent in females than in males. Changes in Npw expression in the hippocampus of Compound 1 -treated relative to vehicle-treated SAMP8 mice were validated by qRT-PCR. The results obtained are shown in Figure 7A (Females: SAMR1 -Vehicle, n=8; SAMP8-vehicle, n=7; SAMP8-Comp1 0.96 mg/kg, n=3; SAMP8-Comp1 3.2 mg/kg, n=6) and Figure 7B (Males: SAMR1 -Vehicle, n=5; SAMP8-vehicle, n=5; SAMP8-Comp1 0.32 mg/kg, n=5; SAMP8-Comp1 0.96 mg/kg, n=3). Baseline Cp values for Npw in vehicle-treated SAMR1 and SAMP8 animals were 33.42 and 34.09, respectively, reflecting low levels of expression. In females, treatment with Compound 1 significantly up- regulated Npw expression at 0.96 and 3.2 mg/kg/day. Npw was also significantly up-regulated in males treated with 0.32 mg/kg Compl and, in spite of the small group size, showed a tendency for up-regulation at 0.96 mg/kg/day.

Changes in Prph expression in the hippocampus of Compound 1 -treated relative to vehicle-treated SAMP8 mice were validated by qRT-PCR. The results obtained are shown in Figure 8A (Females: SAMR1 -Vehicle, n=8; SAMP8-vehicle, n=7; SAMP8-Comp1 0.96 mg/kg, n=3; SAMP8-Comp1 3.2 mg/kg, n=6) and Figure 8B (Males: SAMR1 -Vehicle, n=5; SAMP8-vehicle, n=5; SAMP8-Comp1 0.32 mg/kg, n=5; SAMP8-Comp1 0.96 mg/kg, n=3). Baseline Cp values for Prph in vehicle treated SAMR1 and SAMP8 animals were 32.2 and 32.69, respectively, reflecting low levels of expression. In SAMP-8 females, Prph was significantly up-regulated by treatment with Compound 1 at 0.96 mg/kg/day and 3.2mg/kg/day. In males, Prph was significantly up-regulated by treatment with Compound 1 at 0.32 mg/kg/day and, in spite of the small group size, up-regulation was near significant at 0.96 mg/kg/day.

ANOVA values are represented as *** p < 001 , ** p < 0.01 , * p < 0.05; t-Test values of Vehicle vs Compl treated animals are represented as numerical values in Figures 6A, 6B, 7B and 8B.

These data confirm significant up-regulation of Baiap3 in the hippocampus of female mice from very low basal levels and of Npw and Prph in male and female SAMP-8 mice from low basal levels after treatment with Compl , and represent an ideal situation for the analysis of the effects of Compl on these biomarkers in CNS samples.

Example 13: Quantification of S100A9 expression by qRT-PCR in cerebrospinal fluid from human Alzheimer's Disease donors

13. 1 QUANTITATIVE RT-PCR

Human S100A9 gene expression levels were analyzed by qRT-PCR using Taqman assay probe Hs00610058_m1 , (Life Technologies; amplicon length 83 bp, targeting exon 2-3 boundary, RefSeq NM_002965.2, assay location 188) on total RNA extracted from the cell pellet obtained after centrifugation of 10 mL of human cerebrospinal fluid (CSF) from five different Alzheimer's Disease (AD) patient donors obtained from a biobank (PrecisionMed). After extraction (RNeasy Mini KIT; QIAGEN), all the RNA obtained was reverse transcribed to obtain 1st strand cDNA (using the kit iScript Reverse Transcription Supermix, Bio-Rad Ref. 170- 8841)) in 20 μΐ of final volume. 1 μΙοί 1st strand product was used to perform in triplicate qRT-PCR reactions to analyze the Cp values of S100A9 as described in example 5 with an additional previous 10 cycle pre- amplification. Cp was normalized relative to the expression level of an endogenous reference gene (GADPH, Glyceraldehyde 3-phosphate dehydrogenase, also known as GAPDH) using Taqman assay probe Hs02758991_g1 (Life Technologies; amplicon length 93 bp, targeting exon 7-8 boundary, RefSeq NM_002046.4, assay location 704) and the results are expressed as Δ Cp (S100A9-GADPH).

13.2 RESULTS

S100A9 expression in the CSF of human AD patient donors was quantified by qRT-PCR. The results obtained are shown in Figure 9 as a mean +SEM value of the five different donors. These data show that S100A9 mRNA levels were detectable and quantifiable in human CSF samples.

Quantification of S100A9 expression in CSF from human healthy donors can be performed by qRT-PCR following an analogous method to the one described in Example 13.1.

SEQUENCE LISTING

SEQ ID No. 1 : Nucleotide sequence encoding Homo sapiens S100 calcium binding protein A9 (S100A9), mRNA

NCBI Reference Sequence: NM_002965.3 The coding region ranges from nucleotide 44 to nucleotide 385

(highlighted in bold). It is understood that the mRNA corresponds to the sequence below (i.e. is identical to that sequence) with the exception that the "t" (thymidine) residue is replaced by a "uracil" (u) residue.

ORIGIN

1 aaacactctg tgtggctcct cggctttgac agagtgcaag acgatgactt gcaaaatgtc

61 gcagctggaa cgcaacatag agaccatcat caacaccttc caccaatact ctgtgaagct

121 ggggcaccca gacaccctga accaggggga attcaaagag ctggtgcgaa aagatctgca

181 aaattttctc aagaaggaga ataagaatga aaaggtcata gaacacatca tggaggacct

241 ggacacaaat gcagacaagc agctgagctt cgaggagttc atcatgctga tggcgaggct

301 aacctgggcc tcccacgaga agatgcacga gggtgacgag ggccctggcc accaccataa 361 gccaggcctc ggggagggca ccccctaaga ccacagtggc caagatcaca gtggccacgg

421 ccacggccac agtcatggtg gccacggcca cagccactaa tcaggaggcc aggccaccct

481 gcctctaccc aaccagggcc ccggggcctg ttatgtcaaa ctgtcttggc tgtggggcta

541 ggggctgggg ccaaataaag tctcttcctc caagtcaaaa aaaaaa

//

SEQ ID No. 2: Amino acid sequence of Homo sapiens S100 calcium binding protein A9 (S100A9), protein

UniProtKB/Swiss-Prot: S10A9_HUMAN, P06702

MTCKMSQLER NIETIINTFH QYSVKLGHPD TLNQGEFKEL VRKDLQNFLK KENKNEKVIE HIMEDLDTNA DKQLSFEEFI MLMARLTWAS HEKMHEGDEG

PGHHHKPGLG EGTP

SEQ ID No. 3: Nucleotide sequence encoding Mus musculus S100 calcium binding protein A9 (calgranulin B) (S100a9), transcript variant 1 , mRNA

NCBI Reference Sequence: NM_001281852.1 The coding region ranges from nucleotide 67 to nucleotide 405 (highlighted in bold). It is understood that the mRNA corresponds to the sequence below (i.e. is identical to that sequence) with the exception that the "t" (thymidine) residue is replaced by a "uracil" (u) residue.

ORIGIN

1 tataaatact gggcttacac tgctcttacc aacatctgtg actctttagc cttgaagagc

61 aagaagatgg ccaacaaagc accttctcag atggagcgca gcataaccac catcatcgac

121 accttccatc aatactctag gaaggaagga caccctgaca ccctgagcaa gaaggaattc

181 agacaaatgg tggaagcaca gttggcaacc tttatgaaga aagagaagag aaatgaagcc

241 ctcataaatg acatcatgga ggacctggac acaaaccagg acaatcagct gagctttgag

301 gagtgtatga tgctgatggc aaagttgatc tttgcctgtc atgagaagct gcatgagaac

361 aacccacgtg ggcatggcca cagtcatggc aaaggctgtg ggaagtaatt aagaggtcag

421 ccatgtgaca gctgcccaac caagtctaaa gggaatggct tactcaatgg cctttgttct

481 gggaaatgat aagataaata ataaataagt ctttatccat tccaaaaaaa aaaaaaa

// SEQ ID No. 4: Amino acid sequence of Mus musculus S100 calcium binding protein A9 (calgranulin B) (S100a9), protein

UniProtKB/Swiss-Prot: P31725 - S10A9_MOUSE

MANKAPSQME RSITTIIDTF HQYSRKEGHP DTLSKKEFRQ MVEAQLATFM

KKEKRNEALI NDIMEDLDTN QDNQLSFEEC MMLMAKLIFA CHEKLHENNP RGHGHSHGKG CGK SEQ ID No. 5: Nucleotide sequence encoding Homo sapiens S100 calcium binding protein A8 (S100A8), mRNA

NCBI Reference Sequence: NM_002964.4 The coding region ranges from nucleotide 71 to nucleotide 449 (highlighted in bold). It is understood that the mRNA corresponds to the sequence below (i.e. is identical to that sequence) with the exception that the "t" (thymidine) residue is replaced by a "uracil" (u) residue.

ORIGIN

1 gagaaaccag agactgtagc aactctggca gggagaagct gtctctgatg gcctgaagct

61 gtgggcagct ggccaagcct aaccgctata aaaaggagct gcctctcagc cctgcatgtc

121 tcttgtcagc tgtctttcag aagacctggt ggggcaagtc cgtgggcatc atgttgaccg

181 agctggagaa agccttgaac tctatcatcg acgtctacca caagtactcc ctgataaagg

241 ggaatttcca tgccgtctac agggatgacc tgaagaaatt gctagagacc gagtgtcctc

301 agtatatcag gaaaaagggt gcagacgtct ggttcaaaga gttggatatc aacactgatg

361 gtgcagttaa cttccaggag ttcctcattc tggtgataaa gatgggcgtg gcagcccaca

421 aaaaaagcca tgaagaaagc cacaaagagt agctgagtta ctgggcccag aggctgggcc

481 cctggacatg tacctgcaga ataataaagt catcaatacc tcaaaaaaaa aa

//

SEQ ID No. 6: Amino acid sequence of Homo sapiens S100 calcium binding protein A8 (S100A8), protein

UniProtKB/Swiss-Prot: S10A8_HUMAN, P05109

MLTELEKALN SIIDVYHKYS LIKGNFHAVY RDDLKKLLET ECPQYIRKKG

ADVWFKELDI NTDGAVNFQE FLILVIKMGV AAHKKSHEES HKE

SEQ ID No. 7: Nucleotide sequence encoding Mus musculus S100 calcium binding protein A8 (calgranulin A) (S100a8), mRNA

NCBI Reference Sequence: NM_013650.2 The coding region ranges from nucleotide 56 to nucleotide 322 (highlighted in bold). It is understood that the mRNA corresponds to the sequence below (i.e. is identical to that sequence) with the exception that the "t" (thymidine) residue is replaced by a "uracil" (u) residue.

ORIGIN

1 atcctttgtc agctccgtct tcaagacatc gtttgaaagg aaatctttcg tgacaatgcc

61 gtctgaactg gagaaggcct tgagcaacct cattgatgtc taccacaatt attccaatat

121 acaaggaaat caccatgccc tctacaagaa tgacttcaag aaaatggtca ctactgagtg

181 tcctcagttt gtgcagaata taaatatcga aaacttgttc agagaattgg acatcaatag

241 tgacaatgca attaacttcg aggagttcct tgcgatggtg ataaaagtgg gtgtggcatc

301 tcacaaagac agccacaagg agtagcagag cttctggcct agggctgggt ccctggatat

361 gtctacagaa taaagtcatc atatctcagg tc SEQ ID No. 8: Amino acid sequence of Mus musculus S100 calcium binding protein A8 (calgranulin A) (S100a8), protein

UniProtKB/Swiss-Prot: P27005 - S10A8_MOUSE

MPSELEKALS NLIDVYHNYS NIQGNHHALY KNDFKKMVTT ECPQFVQNIN

IENLFRELDI NSDNAINFEE FLAMVIKVGV ASHKDSHKE

SEQ ID No. 9: Nucleotide sequence encoding Homo sapiens BAI1 -associated protein 3 (BAIAP3), transcript variant 1 , mRNA

NCBI Reference Sequence: NM_003933.4 The coding region ranges from nucleotide 159 to nucleotide 3709 (highlighted in bold). It is understood that the mRNA corresponds to the sequence below (i.e. is identical to that sequence) with the exception that the "t" (thymidine) residue is replaced by a "uracil" (u) residue.

ORIGIN

1 agacacgggc gaggggagga agaaggcgcc tcgggctccg gtctcctgcg ctcctgctgg

61 gcgccagcgg ctggaccttg gcagccgtct gaggcttcgg ggagcccaag gccaccggca

121 gcgcttgtta gaatgcagat tcccggggtt cgactggaat gagaccccgg ggagcagcgt

181 ttgcagcggg cccgccaggt gacctgcacc tgggcaccgc catcggcttc gcaggggcca

241 tctggaggag tcggtcaccc gccatgtcga ccttgctgga cattaagagc agcgtgctca

301 ggcaggtgca ggtgtgcccg tccttccgcc gcaggactga gcaggaccca gggagtgcca

361 gcgccgaccc gcaggagcct gccacggggg cctggaaacc cggggatggc gtggagttct

421 ttgcccacat gcgcctcatg ctgaagaagg gggaaggcag acagggcttg ccgtgcctcg

481 aggtccccct gcgcagtggc tcgccagcac ccccggagcc tgtggatccc agcctcggcc

541 tgagagccct ggccccagag gaggtggaga tgctctacga ggaggccctg tacacggtgc

601 tttaccgcgc gggtaccatg ggccctgacc aggtggacga cgaggaggcc ctgctcagct

661 atctccagca ggtgtttggc accagccttg aggagcacac tgaggccatc gagcgagtga

721 ggaaggccaa ggcccccacg tatgccctga aagtctctgt catgcgtgcc aagaaccttc

781 tggccaagga ccccaacggc ttcagcgacc catactgcat gctgggcatc ctgcctgcct

841 cggacgccac gcgggagccc cgtgcacaga aggagcagcg cttcggcttc cgcaagggca

901 gcaagcgcgg tggacccctg cctgccaagt gcatccaggt caccgaggtg aagagcagca

961 ccctgaaccc cgtctggaag gagcacttcc tcttcgagat tgaggatgtg agcacggacc

1021 agctgcacct ggacatctgg gatcatgacg acgatgtatc cctggtagaa gcgtgcagga

1081 agctgaatga agtcatcggc ctgaagggca tgggcaggta cttcaaacag atcgtcaagt

1141 cagcccgcgc aaacgggaca gcaggaccca ccgaggacca caccgatgac ttcctggggt

1201 gcctcaacat acctgtccgg gaggtgcctg tggctggcgt cgaccgctgg ttcaagctgg 1261 agccacgctc cagtgcctcg cgtgtgcagg gacactgcca cctggttctc aagctgatca 1321 ctacgcagag ggatacggcc atgagccagc gcgggcgatc cggcttcctg tcccacctgc 1381 tgctgctcag ccatctgctg cggttggagc actcagcaga ggagcccaac tccagcagct 1441 ggcgaggaga gctcagcaca ccagccgcca ccatcctctg cctgcacgga gcccagagca 1501 acctgtcacc cttgcagctg gccgtgctgc actggcaggt cagcagccgc caccatcaaa 1561 cctgcacgct ggactacagc tacctgctgg ggctgctgga ggacatgcag gcacactggg 1621 aagaggctcc ttcactgccc caggagcagg aggagagcct ggctgatagc ctttccgcct 1681 tctctgagtt cgggctgcag ctgctgcgcc agctccgaga ctacttccct gccaccaaca 1741 gcaccgctgt ccaccgcctg gagctgctgc tgaagtgtct gggcaagctg cagctcttcc 1801 aaccctcctt tgagatctgc cccttcgagt cggagctgaa catggacatt gctgcggccc 1861 tgaagagagg caaccgtgag tggtacgaca ggatcctgaa tgacaagagt ccccgagagc 1921 agccaggacc acagcgcctg cctgggctgg ttgtgctggc tgacgccgtc tatgatgacc 1981 ttcagttctg ctacagtgtg tacgccagcc tcttccacag catcctcaat gtggacgtct 2041 tcaccctgac cttccggcag ctggagcgtc tggtggctga ggaggcgtgg gtgctgacgg 2101 aggagctgag ccccaagatg accctggagg tggcctcggg gctctttgag ctctacctga 2161 ccctggctga cctccagcgc ttctgggata gcatccctgg ccgggacagc cgctctctgg 2221 ccctggctgg catccacgcc cccttcctgc ctgctgtgaa gctctggttc caagtgctga 2281 gggaccaggc caagtggagg cttcagggag ccgtggacat ggacacgctg gagcccgtgg 2341 acgcctcctc caggcacagc agctccgcag ccactgctgg tctctgcctc agccacatcc 2401 aggagttgtg ggtgcgcctg gcgtggcctg accctgccca ggctcagggg ctgggcaccc 2461 agcttggcca ggacgtgtgt gaggccaccc tcttctatac ggagctgctt cggaagaagg 2521 tggacactca gccaggggcg gccggtgaag cagtgagcga ggcgctctgc gtggtcctca 2581 acaatgtgga gctcgtgcgc aaggctgctg ggcaggcctt gaagggcctg gcatggccag 2641 agggggccac ggggcccgag ggggtgctcc cccgccctct gctcagctgc acacaggccc 2701 tggacgatga tctgcaacgg gaggcccaca cggtgacagc gcacctgacc tctaagatgg 2761 tgggcgacat ccgcaagtat gtacagcaca tcagtctctc gcctgactcc atccagaacg 2821 atgaggccgt ggccccgctc atgaagtacc tggatgagaa gctggccctg ctgaacgcct 2881 cgctggtgaa ggggaacctg agcagggtgc tggaggccct gtgggagcta ctcctccagg 2941 ccattctgca ggcgctgggt gcaaaccgtg acgtctctgc tgatttctac agccgcttcc 3001 atttcacgct ggaggccctg gtcagttttt tccacgcaga gggtcagggt ttgcccctgg 3061 agagcctgag ggatggaagc tacaagaggc tgaaggagga gctgcggctg cacaaatgtt 3121 ccacccgcga gtgcatcgag cagttctacc tggacaagct caaacagagg accctggagc 3181 agaaccggtt tggacgcctg agcgtccgtt gccattacga ggcggctgag cagcggctgg 3241 ccgtggaggt gctgcacgcc gcggacctgc tccccctgga cgccaacggc ttaagtgacc 3301 cctttgtgat cgtggagctg ggcccaccgc atctctttcc actggtccgc agccagagga 3361 cccaggtgaa gacccggacg ctgcaccctg tatacgacga actcttctac ttttccgtgc 3421 ctgccgaggc gtgccgccgc cgcgcggcct gtgtgttgtt caccgtcatg gaccacgact

3481 ggctgtccac caacgacttc gctggggagg cggccctcgg cctaggtggc gtcactggtg

3541 tcgcccggcc ccaggtgggc gggggtgcaa gggctgggca gcctgtcacc ctgcacctgt

3601 gccggcccag agcccaggtg agatctgcgc tgaggaggct ggaaggccgc accagcaagg

3661 aggcgcagga gttcgtgaag aaactcaagg agctggagaa gtgcatggag gcggacccct

3721 gagtccatca gctgccagcc ccggccctgg cccccacccc aagttccctg aagcatcctc

3781 cagctcactg tggccagctt tgtgcaacca gggcccacgg cgcccctcct gtgctgtgac

3841 gtgtgtgtcg tggctggccc cgcggcgcct accgccctgg ccgtgtctgt ctggtgtgtg

3901 ctgtgaaccc ctgcacccaa ccccacatct gggtggccaa cttggcagga cttggccagc

3961 agctgcccag gacacagtgc aggccagagc gggcttgacc acctggtggg cctccctgcc

4021 cgcttccttg ggctccccgg ccctgggtgg gcggtgggca gctggtctcc agggactcag

4081 tgagtggctg tgctctctgc acaacgggca atgtgcagac gcatttttgg taatcacagc

4141 tggggagtga aaagggtgcc actggcacca ctgggtggat ggtccagagc ctccacccac

4201 agaggggatg caaagggcag gtgagtcaag aaccgcatag gtctccagtc cccacggggc

4261 tcccaggccg gggaaaggtt cccctgaggt cactctgagg ccagggacgt cacccaaggc

4321 tggtggtcag tgtgaagggc tccgtgccaa ctggtcagct gtccttcacg cacatatccg

4381 tggccacctg agacctgctc cacgaccctt ccaggcagag ccgagagttc gccccaaccc

4441 ttccccaggc ccagtgtgaa aaacagactc acaaggggct tcttggcctg cagcttcatt

4501 tgcgagagcg ccgaggcagg acacagagca cagctgtgct ggaagtgtgg ggagaacccg

4561 gacagctcag tcctgccagc agccgcaaag agccgaggct gccaggccca tttatgtccc

4621 tcatgtctct agattttctc gtcacccagc ctcaaaaata tatgtgtctg caaccctcag

4681 taaaaaaaaa a

SEQ ID No. 10: Amino acid sequence of Homo sapiens BAI1 -associated protein 3 (BAIAP3), transcript variant 1 , protein

UniProtKB/Swiss-Prot: 094812 - BAIP3JHUMAN

MRPRGAAFAA GPPGDLHLGT AIGFAGAIWR SRSPAMSTLL DIKSSVLRQV

QVCPSFRRRT EQDPGSASAD PQEPATGAWK PGDGVEFFAH MRLMLKKGEG

RQGLPCLEVP LRSGSPAPPE PVDPSLGLRA LAPEEVEMLY EEALYTVLYR

AGTMGPDQVD DEEALLSYLQ QVFGTSLEEH TEAIERVRKA KAPTYALKVS

VMRAKNLLAK DPNGFSDPYC MLGILPASDA TREPRAQKEQ RFGFRKGSKR

GGPLPAKCIQ VTEVKSSTLN PVWKEHFLFE IEDVSTDQLH LDIWDHDDDV

SLVEACRKLN EVIGLKGMGR YFKQIVKSAR ANGTAGPTED HTDDFLGCLN

IPVREVPVAG VDRWFKLEPR SSASRVQGHC HLVLKLITTQ RDTAMSQRGR

SGFLSHLLLL SHLLRLEHSA EEPNSSSWRG ELSTPAATIL CLHGAQSNLS PLQLAVLHWQ VSSRHHQTCT LDYSYLLGLL EDMQAHWEEA PSLPQEQEES

LADSLSAFSE FGLQLLRQLR DYFPATNSTA VHRLELLLKC LGKLQLFQPS

FEICPFESEL NMDIAAALKR GNREWYDRIL NDKSPREQPG PQRLPGLWL

ADAVYDDLQF CYSVYASLFH SILNVDVFTL TFRQLERLVA EEAWVLTEEL

SPKMTLEVAS GLFELYLTLA DLQRFWDSIP GRDSRSLALA GIHAPFLPAV

KLWFQVLRDQ AKWRLQGAVD MDTLEPVDAS SRHSSSAATA GLCLSHIQEL

WVRLAWPDPA QAQGLGTQLG QDVCEATLFY TELLRKKVDT QPGAAGEAVS

EALCWLNNV ELVRKAAGQA LKGLAWPEGA TGPEGVLPRP LLSCTQALDD

DLQREAHTVT AHLTSKMVGD IRKYVQHISL SPDSIQNDEA VAPLMKYLDE

KLALLNASLV KGNLSRVLEA LWELLLQAIL QALGANRDVS ADFYSRFHFT

LEALVSFFHA EGQGLPLESL RDGSYKRLKE ELRLHKCSTR ECIEQFYLDK

LKQRTLEQNR FGRLSVRCHY EAAEQRLAVE VLHAADLLPL DANGLSDPFV

IVELGPPHLF PLVRSQRTQV KTRTLHPVYD ELFYFSVPAE ACRRRAACVL

FTVMDHDWLS TNDFAGEAAL GLGGVTGVAR PQVGGGARAG QPVTLHLCRP RAQVRSALRR LEGRTSKEAQ EFVKKLKELE KCMEADP

SEQ ID No. 11 : Nucleotide sequence encoding Mus musculus B AM -associated protein 3 (Baiap3), mRNA

NCBI Reference Sequence: NM_001163270.1 The coding region ranges from nucleotide 214 to nucleotide 3663 (highlighted in bold). It is understood that the mRNA corresponds to the sequence below (i.e. is identical to that sequence) with the exception that the "t" (thymidine) residue is replaced by a "uracil" (u) residue.

ORIGIN

1 ggaacctctg accagcaaac caggccaggc cccgcctccg cccgcccgcg ccccccgccc

61 gcggcgcccg ctctgcagtg ctcagtctcc agcgcgcgcg gctgctagcg gtcgctgtgc

121 ctcggtgtcc ccagctagtg cgacagcaac gccagcgcca gcagggaccc ccccgaccct

181 gtggcccccg aagccctgtc cacggtggct gccatgtcaa ccttgctgga catcaagagc

241 agcgtgctca ggcaggtgca ggtgtgcccg tccttccgcc gcaagacaga gcaggaacct

301 gaggtcacaa actcacagga gccccccaca ggggcctgga aacctgggga tggtgtggag

361 ttctttgccc acatgcgcct catcctgaaa aagggggatg gcagacaggg cctgccatgt

421 cctgaggttc ttcttcgaag tggttcccca gcccctgctg agcctgtgga tcccaatcgt

481 ggcctgagaa ccctgaccca agaggaggtg gagatgctct atgaggaggc tttatacaca

541 gtcctccacc gggctggcac catgggccct gaccaggtag atgacgagga ggtcttgcta

601 agctaccttc agcaggtgtt tggcaccagt tctgaggaac acatggaggc catcatgcgt

661 gtgaagaagg ccaaggcccc cacatacgcc ctgaaagtct ctgtcatgcg tgccaagaac

721 cttctggcta aagaccccaa tggcttcagt gacccgtact gtatgctggg catcctgcct 781 gcctcaagtg ccccccagga gcccagtggg cagaaggagc agcgctttgg cttccgaaag 841 ggcagcaagc gtagcagccc actgcctgcc aagtgtatcc aggtcacgga ggtcaaaaac 901 agcaccctga atcctgtctg gaaagagcac ttcctgtttg aaattgacga tgtcaacaca 961 gaccagctgc acctggacat atgggaccat gatgatgatg tatccctggc agaggcatgc 1021 aggaagctaa atgaagttat tggcctgaag ggcatgacca gatacttcaa acagattgtc 1081 aagtcggccc gtgcaaatgg gacagcagga cccactgagg accacactga tgacttcctg 1 141 ggatgcctca acatccctat ccgggaggtg cctgtggcag gtgctgaccg ctggtttaag 1201 ctggaaccac gatccagtgc ctcccgtgtg cagggagact gccacctggt cctgaagctg 1261 atcaccaccc agagggacac tgttatgagt cagcgtggac gctcgggctt cctgtcctac 1321 ctgttgctcc tcagccgtgt gctgcggttt gagcatcgag tggaagagcc caattccagc 1381 agttggcgtg gcgagcttag cgggcctggg accacagtcc tctgtctgca tggagcccaa 1441 agcaatcttt cccctttgca gctggcggtg ctgcactggc aagtcagtag ccgtcaccat 1501 cagacacgga ccctggacta tgggtacctg ctggggctgc tggaagacgt gcaggcccac 1561 tgggaggagg cagcttcact gccccaggag caggaggaga gcctggctga cagcttttct 1621 gccttctcgg agttcgggct gaggctgctg cgccagctcc gagattactt ccccgccacc 1681 aacagcacgg ctgtgtatcg cctggagctg ctgctgaagt gcctggagaa gctacagctc 1741 ttccagccgg cctttgaaat ctgccccttt gagacagagc tcagcatgga cattgctgct 1801 gccctgaagc ggggcaaccg tgagtggtat gaccagctcc tgaacaccaa gagtccccga 1861 gagcagccag ggccgcagcg cctcgcgggg cttgttgagc ttgcagacat catctatgag 1921 gacttgcagt tgtgctatgg ggtctatgcc agcctcttcc atggtatcct taaggtggac 1981 ttcttcaccc ttaccttccg gcagctggaa cgtctggtgg ctgaggaggc atgggtgctg 2041 acagaggagc tgagccccaa gatgaactta gaggtggcct cggggctctt tgagctctac 2101 ctgaccctgg cagacaccca gcgcttctgg agctgcatcc ctggacggga aagccgctcc 2161 ctagctctgg ctggcatcca caccccattc ctgccagctg tgaagctctg gctgcaggtg 2221 ctgcgggacc aggccaagtg gcgccttcag ggagctgtgg atgtagacac gctggagcct 2281 gtggatgcgg cttccaaaca cagtagttct gcagctaccg ccagcctctg ccttagtcac 2341 attcaggagc tctgggtccg cctggcttgg cctgaccctt cccaggccca ggggctaggc 2401 actcaactca gccaggacat gtgtgaggcc tccctcttct acacggaact gctgaggaag 2461 aaggtggaca cccagccagg ggctgctggt gaggcagtga gtgagcagct ctgtgtggtg 2521 ctcaacaacg tggagttggt gcgcagagct tcggggcagg cactaagagg actggcgtgg 2581 tctgaagggg ccagtgggct ggagggagtg ctcccccgcc ctctactcag ctgcatacag 2641 gccctggacg aagacctcca ccgggaggcc cacactgtga cagcacacct gacttccaag 2701 atggtggccg acatcaggaa gtacatacag cacatcagcc tgtcccctga ctcgattcag 2761 aacgatgagg ctgtagcccc actcctgaag tacctagatg agaagctggc cttgctgaat 2821 gacgcgctgg tgaaggagaa cctgaacagg gtgctggagg ccctctggga gctgcttctt 2881 caggccattc tgcaggcgct gagtgcaaac agggatgtct ctgctgattt ctacgggcgc 2941 ttccatttca cactggaggc cctggtcagt ttcttccatg ccgagggaca ggggctgccc

3001 ctggagaacc tgagggatgg aagctacaag aggctgcagg aggagctccg gctacacaaa

3061 tgctccaccc gggagtgcat cgagcagttt tacctggaca agctcaagca gaggtctctg

3121 gagcagaacc ggtttgggcg cctgactgtc cggtgtcatt atgaagcagc ggagcagcgg

3181 ctagctgtgg aggtgctgca tgcggcggac ttactgcctc tggatgccaa cggcctaagt

3241 gacccgttcg tgattgtgga gcttggtcca ccacacctct tcccactggt ccgcagccag

3301 aggacccaag tcaaagctcg cacgctgcac cccgtgtacg atgaactctt ccacttctct

3361 gtgcctgctg aggcgtgccg ccgccgcggg gcctgcgtgc tgttcacggt tatggaccac

3421 gactggctgt ccaccaatga ctttgctggg gaagcagccc ttggtctggg tggcatcagt

3481 ggcatcgcaa ggccgcatgt gggagggggc atgaggccag gtcagcctat cactctccac

3541 ctgcgcaggc ccagagctca ggtgaggtct gcactgcgga tgctagaagg ccgcaccagc

3601 agagaagcac aggagtttgt caagaaactc aaggagctgg agaagtgcat ggaggcggac

3661 ctctgagcgc cttgatggtc atagtgccgc cctccccatc tccctgaggg acccactttg

3721 tgcagcaagg gcttctgggg gcccctccct caccatgtga cctgcctgct ctggttggac

3781 cctgtggctt ctgtctgccc ttgctgtgtc ttttggtgtg tgctgtgaac cctttgtgcc

3841 ccagcatgcc ccacccagaa tatgggcagc cagctctgtg gaattggcca gcatccgccc

3901 tggacacagc aggatggatg ggacttgacc ctagtgggcg cccccacccc accccagagc

3961 agtggtcata tgctctcagg actctgcccc ctagaggcta ctgggttgta cttggggaga

4021 aacatttatg gtcataacta gggagtagaa gccactacta caagggtgga ggccaacttt

4081 gctgttcaca cctttgtagc catcattcgg cttgatgaga aataatctgt gccccatgac

4141 agcagtgtca cggggaagcc tctcctagag aaggccctgc ccgcagaggg tgagggcaga

4201 gtttccactg cttgcggctt ctctctcctg gacccggaca ctccccaccg caggtgagca

4261 aggggccagc ggagggttac ttgtg ctctg gtccgggcct ggctcctggt cccaggagag

4321 tttctcccac agtcacggtt aggaacagga attgcccaca ggtggagacc aggctgaagg

4381 gctcgatggc tagctgctca gacatccctt gacgcatctt tatatgccca taccagactt

4441 acctcacagg ccagatctgc ccgggtagac ttccccagcg cttagccacg tacaaagcaa

4501 cccatagcgg ggtctccttg gttttattga gagcactaag gcaggacact aaacaaggtt

4561 gtcccagcag gcccgtccat ccccaggtcc tactgccact tctgaataat gcacaccagc

4621 ttcaataata tgtttgtgac cttca

SEQ ID No. 12: Amino acid sequence of Mus musculus BAI1 -associated protein 3 (Baiap3), protein

UniProtKB/Swiss-Prot: Q80TT2 - BAIP3_MOUSE

MSTLLDIKSS VLRQVQVCPS FRRKTEQEPE VTNSQEPPTG AWKPGDGVEF

FAHMRLILKK GDGRQGLPCP EVLLRSGSPA PAEPVDPNRG LRTLTQEEVE MLYEEALYTV LHRAGTMGPD QVDDEEVLLS YLQQVFGTSS EEHMEAIMRV

KKAKAPTYAL KVSVMRAKNL LAKDPNGFSD PYCMLGILPA SSAPQEPSGQ

KEQRFGFRKG SKRSSPLPAK CIQVTEVKNS TLNPVWKEHF LFEIDDVNTD

QLHLDIWDHD DDVSLAEACR KLNEVIGLKG MTRYFKQIVK SARANGTAGP

TEDHTDDFLG CLNIPIREVP VAGADRWFKL EPRSSASRVQ GDCHLVLKLI

TTQRDTVMSQ RGRSGFLSYL LLLSRVLRFE HRVEEPNSSS WRGELSGPGT

TVLCLHGAQS NLSPLQLAVL HWQVSSRHHQ TRTLDYGYLL GLLEDVQAHW

EEAASLPQEQ EESLADSFSA FSEFGLRLLR QLRDYFPATN STAVYRLELL

LKCLEKLQLF QPAFEICPFE TELSMDIAAA LKRGNREWYD QLLNTKSPRE

QPGPQRLAGL VELADIIYED LQLCYGVYAS LFHGQVAEEA WVLTEELSPK

MNLEVASGLF ELYLTLADTQ RFWSCIPGRE SRSLALAGIH TPFLPAVKLW

LQVLRDQAKW RLQGAVDVDT LEPVDAASKH SSSAATASLC LSHIQELWVR

LAWPDPSQAQ GLGTQLSQDM CEASLFYTEL LRKKVDTQPG AAGEAVSEQL

CWLNNVELV RRASGQALRG LAWSEGASGL EGVLPRPLLS CIQALDEDLH

REAHTVTAHL TSKMVADIRK YIQHISLSPD SIQNDEAVAP LLKYLDEKLA

LLNDALVKEN LNRVLEALWE LLLQAILQAL SANRDVSADF YGRFHFTLEA

LVSFFHAEGQ GLPLENLRDG SYKRLQEELR LHKCSTRECI EQFYLDKLKQ

RSLEQNRFGR LTVRCHYEAA EQRLAVEVLH AADLLPLDAN GLSDPFVIVE

LGPPHLFPLV RSQRTQVKAR TLHPVYDELF HFSVPAEACR RRGACVLFTV

MDHDWLSTND FAGEAALGLG GISGIARPHV GGGMRPGQPI TLHLRRPRAQ

VRSALRMLEG RTSREAQEFV KKLKELEKCM EADL

SEQ ID No. 13: Nucleotide sequence encoding Homo sapiens peripherin (PRPH), mRNA

NCBI Reference Sequence: NM_006262.3 The coding region ranges from nucleotide 76 to nucleotide 1485 (highlighted in bold). It is understood that the mRNA corresponds to the sequence below (i.e. is identical to that sequence) with the exception that the "t" (thymidine) residue is replaced by a "uracil" (u) residue.

ORIGIN

1 cctcgcagcg gtctgcggct ccttcccagc ccccggccta gctctgcgaa cggtgactgc

61 ccatccttgg ccgcaatgag ccaccacccg tcgggcctcc gggccggctt cagctccacc

121 tcataccgcc gtaccttcgg tccaccgccc tcactatccc ccggggcctt ctcctactcg

181 tccagctccc gcttctccag cagccgcctg ctgggctccg cgtccccgag ctcctcggtg

241 cgcctgggca gcttccgtag cccccgagcg ggagcgggcg ccctcctgcg cctgccctcg

301 gagcgcctcg acttctccat ggccgaggcc ctcaaccagg agttcctggc cacgcgcagc

361 aacgagaagc aggagctgca ggagctcaac gaccgcttcg ccaacttcat cgagaaggta 421 cgctttctgg agcagcagaa cgcggccctg cgcggggagc tgagccaagc ccggggccag

481 gagccggcgc gcgccgacca gctgtgccag caggagctgc gcgagctgcg gcgagagctg

541 gagctgttgg gccgcgagcg tgaccgggtg caggtggagc gcgacgggct ggcggaggac

601 ctggcggcgc tcaagcagag gttggaggag gagacgcgca agcgggagga cgcggagcac

661 aacctcgtgc tcttccgcaa ggacgtggac gatgccactc tgtcccgcct ggaactagag

721 cgcaagattg agtctctgat ggatgagatt gagttcctca agaagctgca cgaggaggag

781 ctgcgagacc tgcaggtgag tgtggagagc cagcaggtgc agcaggtgga ggtggaagcc

841 acggtgaagc ccgagctgac ggcagcgctg agggacatcc gcgcgcagta cgagagcatc

901 gccgcgaaga acctgcagga ggcggaggag tggtacaagt ccaagtacgc ggacctgtcc

961 gacgctgcca accggaacca cgaggccctg cgccaggcca agcaggagat gaacgagtcc

1021 cgacgccaga tccagagtct aacgtgcgag gtggacgggc tgcgcggcac gaacgaggcg

1081 ctgctcaggc agttgagaga gctggaggag cagttcgccc tggaggcggg gggctaccag

1 141 gcgggcgctg cgcggctcga ggaggagctg cgacagctaa aagaggagat ggcgcggcac

1201 ctgagggagt accaggagct cctcaacgtc aagatggccc tggacatcga gatcgccacc

1261 taccgcaagc tgctggaggg cgaggagagc cggatctccg tgcccgtcca ttcttttgcc

1321 tccttaaata taaagacgac tgtgcctgag gtggagcctc cccaggacag ccacagccgg

1381 aagacggttc tgatcaagac cattgagacc cggaatgggg aggtggtgac agagtcccag

1441 aaggagcagc gcagtgagct ggacaagtct tctgcccaca gttactgaac cccttggtcc

1501 ggagccttga ctctgcccta ggcctgctca aagcccaaac cctaagacca ctcctgaatt

1561 gtctcctctc cctctgcatg tgtctaaaag gtggtaccag gcatcccttt cctggcttat

1621 ggccaagccc tacccggcca gcagtcgctg ggcctctccc tgccctgaca cttgatgtga

1681 cctatgtgct tcccttttca tgtcccgata agaagccaat gatcccccct caggacaaat

1741 ctactccagc cacgatgaga agtgggtgag ccagggtctg agtttcacat ttgaaccaaa

1801 taaaatgctg tcaagagaaa actctccagt gca

SEQ ID No. 14: Amino acid sequence of Homo sapiens peripherin (PRPH), protein

UniProtKB/Swiss-Prot: P41219 - PERIJHUMAN

MSHHPSGLRA GFSSTSYRRT FGPPPSLSPG AFSYSSSSRF SSSRLLGSAS

PSSSVRLGSF RSPRAGAGAL LRLPSERLDF SMAEALNQEF LATRSNEKQE

LQELNDRFAN FIEKVRFLEQ QNAALRGELS QARGQEPARA DQLCQQELRE

LRRELELLGR ERDRVQVERD GLAEDLAALK QRLEEETRKR EDAEHNLVLF

RKDVDDATLS RLELERKIES LMDEIEFLKK LHEEELRDLQ VSVESQQVQQ

VEVEATVKPE LTAALRDIRA QYESIAAKNL QEAEEWYKSK YADLSDAANR

NHEALRQAKQ EMNESRRQIQ SLTCEVDGLR GTNEALLRQL RELEEQFALE

AGGYQAGAAR LEEELRQLKE EMARHLREYQ ELLNVKMALD IEIATYRKLL EGEESRISVP VHSFASLNIK TTVPEVEPPQ DSHSRKTVLI KTIETRNGEV

VTESQKEQRS ELDKSSAHSY

SEQ ID No. 15: Nucleotide sequence encoding Mus musculus peripherin (Prph), transcript variant 1 , mRNA

NCBI Reference Sequence: NM_013639.2 The coding region ranges from nucleotide 34 to nucleotide 1564 (highlighted in bold). It is understood that the mRNA corresponds to the sequence below (i.e. is identical to that sequence) with the exception that the "t" (thymidine) residue is replaced by a "uracil" (u) residue. ORIGIN

1 cttgccaccc ggcctagttc tgccaagcgc tgaatgccat cttccgccag catgagccat

61 catcactcgt cgggcctgcg gtccagcatc agctccacct cgtaccgccg gacctttggg

121 ccgccgccct cactgtcccc cggggctttc tcctactcgt ccagctctcg cttctccagc

181 agccgcctgc tgggctcggg gtccccgagc tcctcggcgc ggctgggcag cttccgtgcc

241 cctcgagcgg gggcactgcg cttgccctcg gagcgcctcg atttctccat ggccgaggcc

301 ctcaaccaag agttcctggc cactcggagc aacgagaagc aagagttaca ggagctcaac

361 gaccgcttcg ccaacttcat cgagaaggtg cgcttcttgg agcagcagaa cgcagccctg

421 cgcggggagc tgagccaggc gcggggccag gagccggcgc gcgccgacca gctttgccag

481 caggagctgc gcgagctgcg gcgcgaactg gagctgctgg gccgggagcg cgaccgggtg

541 caggtggagc gggacgggct ggcggaggac ctagcggcgc tcaagcagag gttagaagaa

601 gaaacccgca agcgggagga tgcggagcac aacctggtgc tcttccgtaa ggacgtggac

661 gacgccactc tgtcccgcct agaactggag cgcaagattg agtctctgat ggatgaaatt

721 gagttcctca agaagctaca cgaagaggaa cttcgagacc tgcaggtgag cgtagagagc

781 cagcaggtgc agcaggtgga ggtagaggca acagtgaagc cagagctgac ggcggcgctg

841 agggacatcc gtgcacagta cgagaacatc gcggcaaaga atctgcagga ggcagaggag

901 tggtataagt cgaaagtgcg agagcattgg gggaaccctg ggggaccaag ggtggggagg

961 cactgggaat ggcggtgcgc atcccagccg ggcttgtctg ctaccgcgca gtatgctgac

1021 ctgtcggacg ccgccaaccg caaccatgag gccctacgcc aggccaagca agagatgaac

1081 gagtctcgac gtcagatcca gagtctgatg tgcgaggtgg atgggctgcg aggcacgaat

1141 gaggcgctgc tcagacagct gcgggagctg gaagagcagt tcgccctgga ggctggaggg

1201 taccaagcag gcgcagcacg gctggaggaa gagcttcgac agctgaagga agagatggcg

1261 aggcacctgc gagagtacca ggagctcctt aacgtcaaga tggccctgga catcgagata

1321 gccacctaca ggaagctact ggaaggggag gagagccgga tctcagtgcc ggttcattcc

1381 tttgcctctc taagtttaaa gacgactgtg cctgagatgg agcctctcca ggatagccac

1441 agcaagaaga tggttctgat caggacaatt gagacccggg atggggagaa ggtggtgaca

1501 gagtcccaga aggaacagca cagtgacctg gacaagtctt ctatccacag ctactgaggc 1561 ctcagccaga gctctgaccc tgatctcagc ctattcctaa gcttggccct ccccagcacc

1621 agtctgtatc cagtcctgct ctgcatgcca cagcccctgc ctgccaagca agcgccagcc

1681 tgatccagag gctgggcctc ttcccgatgc ataggtgtga cccatagctt tcttgtcctt

1741 gtaagaggtg gataaagata cccaggacag caaatctact caagaatgac cccatggtct

1801 gtggggtggg ccagagtgtg ggactcactc tgagtcaaat aaaactgcta ctgagagaaa

1861 ctcct

//

SEQ ID No. 16: Amino acid sequence of Mus musculus peripherin (Prph), transcript variant 1 , protein UniProtKB/Swiss-Prot: P15331 - PERI_MOUSE

MPSSASMSHH HSSGLRSSIS STSYRRTFGP PPSLSPGAFS YSSSSRFSSS

RLLGSGSPSS SARLGSFRAP RAGALRLPSE RLDFSMAEAL NQEFLATRSN

EKQELQELND RFANFIEKVR FLEQQNAALR GELSQARGQE PARADQLCQQ

ELRELRRELE LLGRERDRVQ VERDGLAEDL AALKQRLEEE TRKREDAEHN

LVLFRKDVDD ATLSRLELER KIESLMDEIE FLKKLHEEEL RDLQVSVESQ

QVQQVEVEAT VKPELTAALR DIRAQYENIA AKNLQEAEEW YKSKYADLSD

AANRNHEALR QAKQEMNESR RQIQSLTCEV DGLRGTNEAL LRQLRELEEQ

FALEAGGYQA GAARLEEELR QLKEEMARHL REYQELLNVK MALDIEIATY

RKLLEGEESR ISVPVHSFAS LSLKTTVPEM EPLQDSHSKK MVLIRTIETR DGEKWTESQ KEQHSDLDKS SIHSY

SEQ ID No. 17: Nucleotide sequence encoding Homo sapiens neuropeptide W (NPW), mRNA

NCBI Reference Sequence: NM_001099456.2 The coding region ranges from nucleotide 383 to nucleotide 877 (highlighted in bold). It is understood that the mRNA corresponds to the sequence below (i.e. is identical to that sequence) with the exception that the "t" (thymidine) residue is replaced by a "uracil" (u) residue.

ORIGIN

1 gtacccactc cctggcactt ccactcctag agggaggagg ctgagcaggc agagaatggg

61 acgtgtcccc tcagaggagc ctcgagccca gttccagcca gcggcccact cagtgaggtg

121 ctcaagtacc cacgtccccc gccagctgcc agggttccct ctcctccctc cgtccctccc

181 cccatctggg gagcccagcg gtactgaggg ggcggaacga ggcggggcca ccgagcggtt

241 atagctgggc ctgcagggga cccacggctc gcctccagcc tcctgcgctc cggtacctgg

301 gcgtcccaac tccactgcgc gcccaaaccc agccgagccg gttcgtggcc cgccccgccg

361 ggcggccgtc gacgcgagcg ccctggcgtg gcgcccaggg gagcgggggg ctcccgcgag

421 ccggccgcgg ctggcactgc tgctgcttct gctcctgctg ccgctgccct ccggcgcgtg 481 gtacaagcac gtggcgagtc cccgctacca cacggtgggc cgcgccgctg gcctgctcat

541 ggggctgcgt cgctcaccct atctgtggcg ccgcgcgctg cgcgcggccg ccgggcccct

601 ggccagggac accctctccc ccgaacccgc agcccgcgag gctcctctcc tgctgccctc

661 gtgggttcag gagctgtggg agacgcgacg caggagctcc caggcaggga tccccgtccg

721 tgcgccccgg agcccgcgcg ccccagagcc tgcgctggaa ccggagtccc tggacttcag

781 cggagctggc cagagacttc ggagagacgt ctcccgccca gcggtggacc ccgcagcaaa

841 ccgccttggc ctgccctgcc tggcccccgg accgttctga cagcgtcccc cgcccgcccg

901 tggcgcctcc gcgcctgacc caggaggagt ggccgcgcgc ttccaggagc cgctcataga

961 ccccgcctgc cgtccggtca ataaaatccg cctgactcct gcgcccccgc atgcgaaaaa

1021 aaaaaaaaaa aaa

//

SEQ ID No. 18: Amino acid sequence of Homo sapiens neuropeptide W (NPW), protein

UniProtKB/Swiss-Prot: Q8N729 - NPWJHUMAN

MAWRPGERGA PASRPRLALL LLLLLLPLPS GAWYKHVASP RYHTVGRAAG

LLMGLRRSPY LWRRALRAAA GPLARDTLSP EPAAREAPLL LPSWVQELWE

TRRRSSQAGI PVRAPRSPRA PEPALEPESL DFSGAGQRLR RDVSRPAVDP

AANRLGLPCL APGPF SEQ ID No. 19: Nucleotide sequence encoding Mus musculus neuropeptide W (Npw), mRNA

NCBI Reference Sequence: NM_001099664.1 The coding region ranges from nucleotide 1 to nucleotide 528 (highlighted in bold). It is understood that the mRNA corresponds to the sequence below (i.e. is identical to that sequence) with the exception that the "t" (thymidine) residue is replaced by a "uracil" (u) residue. ORIGIN

1 ctggcgtcta acagagaagt gcggggccct gggcccggga ctcccaggaa ccggcccctg

61 ctgcccctgc tgctgcttct gctcttgcta ccgctgcccg ccagcgcctg gtataagcac

121 gtggcgagtc cccgctatca cacagtgggt cgtgcctccg ggctgctcat ggggctgcgc

181 cgctcgccct accagtggcg ccgtgccctg ggcggggctg ctggacccct ctcccggctc

241 ccaggaccgg tcgcccgcgg cgctctcctg cttccttcct cagggcagga gctgtgggag

301 gtacgaagca ggagctcacc tgcagggctt cccgtccatg caccctggag tccgcgggac

361 ctggagggag tccgccaacc ggagcagtcg ctaagccttc actcctggat ctcagaggag

421 cccgctgcta gagccttcgg agagacgctt cgtgcccagc catggttcct gcagcaagtc

481 atctttgccg atcctgtcag gcccaagaac cgatggcgcc cccatgcttg acctaggcag

541 gagcacagct tgaagctcca gtcaggcctc gtggtctggt caataaaacc aacctgattc

601 ctgcgc //

SEQ ID No. 20: Amino acid sequence of Mus musculus neuropeptide W (Npw), protein

UniProtKB/Swiss-Prot: F7B5D6 - F7B5D6_MOUSE

LASNREVRGP GPGTPRNRPL LPLLLLLLLL PLPASAWYKH VASPRYHTVG

RASGLLMGLR RSPYQWRRAL GGAAGPLSRL PGPVARGALL LPSSGQELWE VRSRSSPAGL PVHAPWSPRD LEGVRQPEQS LSLHSWISEE PAARAFGETL

RAQPWFLQQV IFADPVRPKN RWRPHA SEQ ID No. 21 : Nucleotide sequence encoding Homo sapiens arginine vasopressin (AVP), mRNA

NCBI Reference Sequence: NM_000490.4 The coding region ranges from nucleotide 39 to nucleotide 542 (highlighted in bold). It is understood that the mRNA corresponds to the sequence below (i.e. is identical to that sequence) with the exception that the "t" (thymidine) residue is replaced by a "uracil" (u) residue. ORIGIN

1 acagagccac caagcagtgc tgcatacggg gtccacctgt gtgcaccagg atgcctgaca

61 ccatgctgcc cgcctgcttc ctcggcctac tggccttctc ctccgcgtgc tacttccaga

121 actgcccgag gggcggcaag agggccatgt ccgacctgga gctgagacag tgcctcccct

181 gcggccccgg gggcaaaggc cgctgcttcg ggcccagcat ctgctgcgcg gacgagctgg

241 gctgcttcgt gggcacggct gaggcgctgc gctgccagga ggagaactac ctgccgtcgc

301 cctgccagtc cggccagaag gcgtgcggga gcgggggccg ctgcgccgcc ttcggcgttt

361 gctgcaacga cgagagctgc gtgaccgagc ccgagtgccg cgagggcttt caccgccgcg

421 cccgcgccag cgaccggagc aacgccacgc agctggacgg gccggccggg gccttgctgc

481 tgcggctggt gcagctggcc ggggcgcccg agcccttcga gcccgcccag cccgacgcct

541 actgagcccc gcgctcgccc caccggcgcg ctcttcgcgc ccgcccctgc agcacggaca

601 ataaacctcc gccaatgcaa a

//

SEQ ID No. 22: Amino acid sequence of Homo sapiens arginine vasopressin (AVP), protein

UniProtKB/Swiss-Prot: X5DQP6 - X5DQP6_HUMAN

MLARMLNTTL SACFLSLLAF SSACYFQNCP RGGKRAISDM ELRQCLPCGP

GGKGRCFGPS ICCADELGCF VGTAEALRCQ EENYLPSPCQ SGQKPCGSGG RCAAVGICCS DESCVAEPEC HDGFFRLTRA REPSNATQLD GPARALLLRL

VQLAGTRESV DSAKPRVY

SEQ ID No. 23: Nucleotide sequence encoding Mus musculus arginine vasopressin (Avp), mRNA NCBI Reference Sequence: NM_009732.1 The coding region ranges from nucleotide 1 to nucleotide 504 (highlighted in bold). It is understood that the mRNA corresponds to the sequence below (i.e. is identical to that sequence) with the exception that the "t" (thymidine) residue is replaced by a "uracil" (u) residue. ORIGIN

1 atgctcgcca ggatgctcaa cactacgctc tccgcttgtt tcctgagcct gctggccttc

61 tcctccgcct gctacttcca gaactgccca agaggcggca agagggccat ctctgacatg

121 gagctgagac agtgtctccc ctgcggcccg ggcggcaaag gacgctgctt cggaccaagc

181 atctgctgcg cggacgagct gggctgcttc gtgggcaccg ccgaggcgct gcgctgccag

241 gaggagaact acctgccctc gccctgccag tccggccaga agccctgcgg gagcgggggc

301 cgctgcgccg ccgtgggcat ctgctgcagc gacgagagct gcgtggccga gcccgagtgc

361 cacgacggtt ttttccgcct cacccgcgct cgggagccaa gcaacgccac acagctggac

421 ggccctgctc gggcgctgct gctaaggctg gtacagctgg ctgggacacg ggagtccgtg

481 gattctgcca agccccgggt ctactga

//

SEQ ID No. 24: Amino acid sequence of Mus musculus arginine vasopressin (Avp), protein

UniProtKB/Swiss-Prot: Q3UUQ5 - Q3UUQ5_MOUSE

MLARMLNTTL SACFLSLLAF SSACYFQNCP RGGKRAISDM ELRQCLPCGP GGKGRCFGPS ICCADELGCF VGTAEALRCQ EENYLPSPCQ SGQKPCGSGG RCAAVGICCS DESCVAEPEC HDGFFRLTRA REPSNATQLD GPARALLLRL

VQLAGTRESV DSAKPRVY

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

All publications, patents and patent applications cited herein are hereby incorporated herein by reference in their entireties.

The publications, patents and patent applications mentioned in the specification are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that they are prior art to the instant application.

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the appended claims.

Claims

1. A method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of Npw, Prph, and Baiap3 in a sample obtained from the subject, wherein an increase in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the LSD1 inhibitor.

2. A method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of Npw, Prph, and Baiap3 in a sample obtained from the subject, wherein an increase in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative that LSD1 is being inhibited in the subject.

3. A method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising determining the level of one or more biomarkers selected from the group consisting of Npw, Prph and Baiap3 in a sample obtained from the subject, wherein the degree of increase in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative of the degree of LSD1 inhibition in the subject.

4. A method for monitoring LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of Npw, Prph, and Baiap3 in the sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein an increase in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative that LSD1 is being inhibited in the subject.

5. A method for monitoring the degree of LSD1 inhibition in a subject receiving treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of Npw, Prph, and Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein the degree of increase in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control is indicative of the degree of LSD1 inhibition in the subject.

6. A method for monitoring the response of a subject to treatment with an LSD1 inhibitor, comprising (i) administering an LSD1 inhibitor to the subject, (ii) obtaining a sample from the subject, (iii) determining the level of one or more biomarkers selected from the group consisting of Npw, Prph, and Baiap3 in a sample obtained from the subject, and (iv) comparing the level of the biomarker(s) in the sample with the level of the biomarker(s) in a control, wherein an increase in the level of the biomarker(s) in the sample as compared to the level of the biomarker(s) in a control indicates response to the treatment with the LSD1 inhibitor.

7. The method of any of claims 1 to 6, wherein the biomarker is Npw.

8. The method of any of claims 1 to 6, wherein the biomarker is Prph.

9. The method of any of claims 1 to 6, wherein the biomarker is Baiap3.

10. The method of any of claims 1 to 9, wherein the LSD1 inhibitor is an irreversible LSD1 inhibitor.

11. The method of any of claims 1 to 10, wherein the LSD1 inhibitor is a 2-(hetero)arylcyclopropylamino compound.

12. The method of any of claims 1 to 11 , wherein the LSD1 inhibitor is a compound disclosed in WO2010/043721 , WO2010/084160, WO2011/035941 , WO2011/042217, WO2011/131697, WO2012/013727, WO2012/013728, WO2012/045883, WO2013/057320, WO2013/057322, WO2012/135113, WO2013/022047, WO2014/058071 , WO2010/143582, US2010-0324147, WO2011/131576, WO2014/084298, WO2014/086790, WO2014/164867, or WO2015/021128.

13. The method of any of claims 1 to 9, wherein the LSD1 inhibitor is (-) 5-((((trans)-2-(4- (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof.

14. The method of any of claims 1 to 9, wherein the LSD1 inhibitor is (trans)-N1-((1 R,2S)-2- phenylcyclopropyl)cyclohexane-1 ,4-diamine or a pharmaceutically acceptable salt or solvate thereof.

15. The method of any of claims 1 to 9, wherein the LSD1 inhibitor is 4-((4-((((1R,2S)-2- phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid or a pharmaceutically acceptable salt or solvate thereof.

16. The method of any of claims 1 to 15, wherein the subject is a human.

17. The method of any of claims 1 to 16, wherein the subject has a CNS disease.

18. The method of any of claims 1 to 16, wherein the subject has Alzheimer's disease.