CN1650010A - 抑制靶基因表达的方法和治疗肿瘤疾病的药物 - Google Patents
抑制靶基因表达的方法和治疗肿瘤疾病的药物 Download PDFInfo
- Publication number
- CN1650010A CN1650010A CNA028035550A CN02803555A CN1650010A CN 1650010 A CN1650010 A CN 1650010A CN A028035550 A CNA028035550 A CN A028035550A CN 02803555 A CN02803555 A CN 02803555A CN 1650010 A CN1650010 A CN 1650010A
- Authority
- CN
- China
- Prior art keywords
- dsrna
- chain
- medicine
- bcl
- target gene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1131—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against viruses
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/15—Nucleic acids forming more than 2 strands, e.g. TFOs
- C12N2310/152—Nucleic acids forming more than 2 strands, e.g. TFOs on a single-stranded target, e.g. fold-back TFOs
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/315—Phosphorothioates
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/318—Chemical structure of the backbone where the PO2 is completely replaced, e.g. MMI or formacetal
- C12N2310/3183—Diol linkers, e.g. glycols or propanediols
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/33—Chemical structure of the base
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/351—Conjugate
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/351—Conjugate
- C12N2310/3511—Conjugate intercalating or cleaving agent
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/50—Physical structure
- C12N2310/53—Physical structure partially self-complementary or closed
Abstract
本发明涉及抑制至少一种在肿瘤细胞中抑制或阻止细胞凋亡的靶基因表达的方法,其中,向该肿瘤细胞中引入至少一条双链核糖核酸(dsRNA),所述双链核糖核酸的S1链具有由少于25个连续的核苷酸组成、至少部分互补于靶基因的区域。
Description
本发明涉及抑制细胞中至少一种靶基因表达的方法,以及治疗肿瘤疾病的药物。
WO 99/32619中公开了一种通过双链寡核糖核苷酸抑制靶基因表达的方法。这一已知方法目的在于抑制无脊椎动物细胞中的基因表达。为此,所述的双链寡核糖核苷酸必须具有一种由至少25个碱基组成的、与靶基因同一的序列。
WO 00/44895中公开了一种抑制细胞中靶基因表达的方法和一种药物。在该方法中,将具有双链结构的寡核糖核苷酸(dsRNA)引入所述细胞。一条dsRNA链显示由最多49个连续的核苷酸对组成的区域,该区域至少部分互补于靶基因。所述的药物包含至少一个抑制给定靶基因的表达的dsRNA,其中,该dsRNA链至少部分互补于所述的靶基因。
由Gautschi O.et al.(2001),J Natl Cancer Inst 93,463到471页,可知抗凋亡蛋白Bcl-2和Bcl-xL的增量表达与多种肿瘤的发生和进展相关。裸鼠的体内数据表明,抗Bcl-2和Bcl-xL基因表达的单链反义寡核糖核苷酸的联合疗法可使肿瘤的生长量降低约50%到60%。应用这一疗法,每日每kg体重需20mg寡核糖核苷酸。由于需要大量的寡核糖核苷酸,所以这种治疗相对昂贵。除此之外,所用的单链寡核糖核苷酸在血清中很快即被分解。需要大量的寡核糖核苷酸是因为,最终引入到靶细胞中的反义寡核糖核苷酸的量至少要与靶细胞中存在的靶基因mRNA的数量相当。这一方法只能使肿瘤的生长减少,但不能使肿瘤缩小。
本发明的目的在于消除现有技术中的缺陷。具体说来,公开了一种方法和一种药物,由此经济有效地抑制肿瘤细胞的增殖。
这一目的是通过权利要求1和13的技术方案达到的。权利要求2到12和14到26提供了优选的实施方案。
本发明提供试图抑制至少一种在肿瘤细胞中抑制或阻止细胞凋亡的基因表达的方法,其中,向该肿瘤细胞中引入至少一条双链核糖核酸(dsRNA),所述的核糖核酸的S1链包括由少于25个连续的核苷酸组成、至少部分互补于靶基因的区域。术语″靶基因″理解为指双链DNA中与用作转录模板的DNA链相互补的那条DNA链,包括全部的转录区域。因此靶基因通常指有义链。因此,S1链可互补于靶基因表达过程中形成的RNA转录物,或其加工产物,如mRNA。当由一条或两条核糖核酸链组成的核糖核酸呈现双链结构时即出现dsRNA。不是所有的dsRNA核苷酸都必须遵循Watson-Crick碱基配对原则。特别的单一非互补碱基对几乎不影响本发明的方法。最大的可能碱基对数目等于dsRNA中最短的链所包含的核苷酸数。所用的术语″引入″指摄取到细胞中。摄取可由细胞本身进行。但也可以通过辅助试剂或装置进行。
令人惊讶的是,已表明通过这一方法仅用相当少量的寡核糖核酸即可抑制肿瘤细胞增殖,相比之下,要通过传统的反义技术达到类似的抑制效果所需的寡核苷酸要多得多。此外,利用本发明的方法可以诱导肿瘤细胞群中细胞凋亡达到下述的程度,即不仅肿瘤细胞群的生长减少,肿瘤细胞的总数也减少。与应用对照dsRNA的方法相比,利用正常的,即非转化的细胞实施本发明的方法并不引起细胞凋亡率的显著提高。对照dsRNA是其中没有一条链与存在于所述细胞中的基因的某一条链互补的dsRNA。
已表明当所述dsRNA的至少一个末端具有由1到4个,特别是2或3个核苷酸组成的单链突出端时非常有益。与至少一个末端没有单链突出端的dsRNA相比,这种dsRNA在抑制靶基因表达方面表现出优越的效果。此处,一个末端指dsRNA区域,其中存在5′和3′链末端。因此,仅由S1链组成的dsRNA为环状结构并仅有一个末端。由S1链和S2链组成的dsRNA有两个末端。此处,所有的情况下一个末端都是由S1链的一个链末端和S2链的一个链末端形成。
所述的单链突出端优选位于S1链的3′末端。这种单链突出端定位将导致该方法的效率进一步提高。在一个实施例中,dsRNA只有一个末端具有单链突出端,特别是定位于S1链的3′末端。在有两个末端的dsRNA中,另一个末端是平端,即没有突出端。经证明这种dsRNA在血清和多种细胞培养基中都特别稳定。
互补的dsRNA区域可以有19到24个,优选21到23个,并且特别22个核苷酸。带有这种结构的dsRNA对抑制靶基因特别有效。dsRNA的S1链可以有少于30个,优选少于25个,特别是21到24个核苷酸。这些核苷酸的数目与dsRNA中的最多可能碱基对数目一致。
至少可对dsRNA的一个末端进行修饰以抵抗肿瘤细胞中的破坏作用或双链结构的解离。此外,可通过至少一个,优选两个附加的化学键增强由互补核苷酸对实现的双链结构的键合。所述的化学键可由共价或离子键,氢键,疏水性相互作用,优选或范德华力,堆积相互作用,或者金属离子配位作用形成。也可以利用嘌呤类似物代替双链结构中的嘌呤而形成。
在该方法的优选的实施方案中,靶基因是至少一个属于Bcl-2家族的基因,特别是Bcl-2,Bcl-w,或Bcl-xL。所述的靶基因也可能是几个基因。所以,Bcl-2和Bcl-xL都可能是靶基因。抑制Bcl-2家族的基因特别有益,这是因为这些基因的增量表达与许多肿瘤细胞的发生和生长相关。由于存在表达多个抗凋亡基因的肿瘤细胞,所以能抑制多个靶基因是有益的。
dsRNA优选地由具有SEQ ID NO:1所示序列的S2链和具有SEQ IDNO:2所示序列的S1链组成,或由具有SEQ ID NO:3所示序列的S2链和具有SEQ ID NO:4所示序列的S1链组成,所述序列如后附的序列表所示。这样的dsRNA对抑制Bcl-2靶基因表达特别有效。所述的肿瘤细胞可以是胰腺癌细胞。为将dsRNA引入肿瘤细胞,可利用围绕dsRNA的胶束(micellar)结构,优选脂质体,或利用围绕dsRNA的衣壳。具体说来,所述的衣壳可能是天然的病毒衣壳,或通过化学或酶学方法产生的合成衣壳,或由其衍生的结构。
另外,本发明涉及治疗肿瘤疾病的药物,其包含至少一种抑制至少一个靶基因表达的双链核糖核酸(dsRNA),其中,该dsRNA链的S1链具有由少于25个连续的核苷酸组成的、至少部分互补于所述靶基因的区域。此处,所述的靶基因是其表达抑制或阻止肿瘤细胞中细胞凋亡的基因。所述药物的剂量为使至少一个靶基因的表达受到抑制。令人惊讶的是,已表明这种药物的使用剂量非常低。每天每kg体重5mgdsRNA即足以抑制或完全禁止肿瘤细胞中靶基因的表达。这种低剂量大大地消除了副作用。
优选地,所述dsRNA的至少一个末端具有由1到4个,特别是2或3个核苷酸组成的单链突出端。该单链突出端可定位于S1链的3′末端。若dsRNA只有一端具有单链突出端,特别是定位于S1链的3′末端特别有益。已表明这种dsRNA在体内特别稳定。其在血液中被破坏或排泄掉要比两端都是单链突出端的dsRNA慢得多。因此可施用低剂量。
互补区可以有19到24个,优选21到23个,特别是22个核苷酸。S1链可以有少于30个,优选少于25个,特别是21到24个核苷酸。在一种实施形式中,可对dsRNA的至少一个末端进行修饰以抵抗肿瘤细胞中的破坏作用或解离作用。可通过至少一个,优选两个附加的化学键增强由互补核苷酸对实现的双链结构的键合。
靶基因优选是至少一个属于Bcl-2家族的基因,特别是Bcl-2,Bcl-w,或Bcl-xL。带有对靶基因Bcl-2和Bcl-xL具有特异性的dsRNA的药物特别有效。
dsRNA可以由具有SEQ ID NO:1所示序列的S2链和具有SEQ ID NO:2所示序列的S1链组成,或由具有SEQ ID NO:3所示序列的S2链和具有SEQ ID NO:4所示序列的S1链组成,所述序列如后附的序列表所示。用这种药物治疗的肿瘤疾病可以是胰腺癌。目前还没有对胰腺癌足够有效的治疗。约3%的5年存活率是所有癌症中最低的。所述的dsRNA可以溶液或经胶束结构,优选脂质体或衣壳围绕的形式存在于药物中。胶束结构或衣壳可使dsRNA易于被摄入到肿瘤细胞中。所述的药物可制备成制剂以适合于吸入、口服摄取或注射,特别是静脉内或腹膜内注射,或者直接注射到瘤组织内。适合于吸入或注射的制剂,最简单的可由本发明的dsRNA和生理上可耐受的缓冲液,特别磷酸缓冲盐溶液组成。令人惊讶的是,已表明简单溶于这种缓冲液的dsRNA即可被肿瘤细胞摄取并抑制靶基因的表达,而无需使所述dsRNA包装到特定的载体中。
下面,结合附图描述本发明的实施例。附图显示:
图1用互补于人Bcl-2基因第一序列的dsRNA1转染120小时后,人胰腺癌细胞YAP的凋亡率(百分比);
图2用互补于人Bcl-2基因第二序列的dsRNA转染120小时后,YAPC细胞的凋亡率(百分比);
图3用互补于新霉素抗性基因序列的dsRNA转染120小时后,YAP C细胞的凋亡率(百分比)。
将可从德国微生物和细胞培养物保藏中心,Braunschweig(No.ACC 382)得到的人胰腺癌细胞系YAP C细胞,在添加在10%胎牛血清(FCS)和1%青霉素/链霉素的RPMI 1640培养基中,在37℃,5%CO2的恒定条件下进行培养。在相同的条件下,于添加了10%FCS和1%青霉素/链霉素的Dulbecco′s MEM中培养人皮肤成纤维细胞。
用于转染的双链寡核糖核苷酸具有下述序列,即序列表中的SEQ IDNo:1到SEQ ID No:6:
与人Bcl-2基因第一序列互补的dsRNA:
S2:5′- cag gac cuc gcc gcu gca gac c-3′(SEQ ID NO:1)
S1:3′-cg guc cug gag cgg cga cgu cug g-5′(SEQ ID NO:2)
与人Bcl-2基因第二序列互补的dsRNA2:
S2:5′- g ccu uug ugg aac ugu acg gcc-3′(SEQ ID NO:3)
S1:3′-uac gga aac acc uug aca ugc cgg-5′(SEQ ID NO:4)
与新霉素抗性基因的序列互补的dsRNA 3:
S2:5′- c aag gau gag gau cgu uuc gca-3′(SEQ ID NO:5)
S1:3′-ucu guc cua cuc cua gca aag cg-5′(SEQ ID NO:6)
在6-孔板中用oligofectamine(Invitrogen Corp.,Karlsruhe)进行转染。每孔250,000个细胞。双链寡核糖核苷酸的转染按照Invitrogen推荐的oligofectamine相关方法进行(与6-孔板的中的1孔相关的数据):用175μl无添加剂的细胞培养基稀释10μl双链寡核糖核苷酸(0.1-10μM)。用12μl无添加剂的细胞培养基稀释3μloligofectamine,在室温下温育10分钟。将稀释过的oligofectamine添加到经稀释的双链寡核糖核苷酸中,混合,再在室温下温育20分钟。这期间,将待转染的细胞用无添加剂的细胞培养基洗一次,再添加800μl新鲜的细胞培养基。然后,在每孔中添加200μl上述的oligofectamine-dsRNA-混合物,使进行转染的终体积达1000μl。由此产生的双链寡核糖核苷酸的终浓度为1-100μm。转染试验是在37℃下温育4小时。然后,每孔添加500μl含30%FCS的细胞培养基,使FCS的终浓度为10%。将所述试验在37℃下温育120小时。
温育后,收集上清,用磷酸缓冲盐溶液洗细胞,用胰蛋白酶分离,100g离心10分钟。弃上清,将所得沉淀于4℃在黑暗中与低渗碘化丙啶(propidium iodide)溶液一起处理30分钟。接下来在FACSCalibur荧光-活化细胞分类器(BD GmbH,Heidelberg)中通过流式细胞光度术分析。
在研究的人胰腺癌细胞中双链寡核糖核苷酸dsRNA1和dsRNA2降低由Bcl-2介导的对细胞凋亡的抑制。不需要额外的细胞凋亡刺激以诱导或引发细胞凋亡。细胞凋亡率升高依赖于温育时间。图1显示dsRNA1所得结果,图2显示dsRNA2所得结果。未经处理的YAP C对照细胞和在无双链寡核糖核苷酸的情况下用所述方法实施转染的细胞(模拟传染细胞)在温育120小时后,仅显示出3.8%和7.1%的细胞凋亡,该120小时后的细胞凋亡率可通过100nM dsRNA的转染提高,用dsRNA1可提高到37.2%、利用dsRNA2可提高到28.9%。用dsRNA3进行的对照转染得到的最大细胞凋亡率为13.5%。与模拟转染细胞相比并没有明显的提高,由此证实了dsRNA1和dsRNA2作用的序列特异性。
作为对照,也用dsRNA1和dsRNA2转染了作为非转化细胞的皮肤成纤维细胞。120小时后这些细胞没有显示出明显的细胞凋亡率提高。
序列表
<110>里伯药品公司
<120>抑制靶基因表达的方法和治疗肿瘤疾病的药物
<130>412012GA
<140>
<141>
<160>6
<170>PatentIn Ver.2.1
<210>1
<211>22
<212>RNA
<213>合成序列
<220>合成序列说明:与人Bcl-2基因序列互补的dsRNA的有义链
<223>
<400>1
caggaccucg ccgcugcaga cc 22
<210>2
<211>24
<212>RNA
<213>合成序列
<220>
<223>合成序列说明:与人Bcl-2基因序列互补的dsRNA的反义链
<400>2
ggucugcagc ggcgaggucc uggc 24
<210>3
<211>22
<212>RNA
<213>合成序列
<220>
<223>合成序列说明:与人Bcl-2基因序列互补的dsRNA的有义链
<400>3
gccuuugugg aacuguacgg cc 22
<210>4
<211>24
<212>RNA
<213>合成序列
<220>
<223>合成序列说明:与人Bcl-2基因序列互补的dsRNA的反义链
<400>4
ggccguacag uuccacaaag gcau 24
<210>5
<211>22
<212>RNA
<213>合成序列
<220>
<223>合成序列说明:与新霉素抗性基因序列互补的dsRNA的有义链
<400>5
caaggaugag gaucguuucg ca 22
<210>6
<211>23
<212>RNA
<213>合成序列
<220>
<223>合成序列说明:与新霉素抗性基因序列互补的dsRNA的反义链
<400>gcgaaacgau ccucauccug ucu 23
Claims (26)
1.抑制至少一种在肿瘤细胞中抑制或阻止细胞凋亡的靶基因表达的方法,其中,向该肿瘤细胞中引入至少一条双链核糖核酸(dsRNA),所述的双链核糖核酸的S1链具有由少于25个连续的核苷酸组成、至少部分互补于靶基因的区域。
2.如权利要求1所述的方法,其中,所述dsRNA的至少一个末端具有由1到4个,特别是2或3个核苷酸组成的单链突出端。
3.如前述任意一项权利要求所述的方法,其中,所述的单链突出端定位于S1链的3′-末端。
4.如前述任意一项权利要求所述的方法,其中,所述的dsRNA仅在一端具有单链突出端,特别是定位于S1链的3′-末端。
5.如前述任意一项权利要求所述的方法,其中,所述的互补dsRNA区具有19到24,优选21到23,特别是22个核苷酸。
6.如前述任意一项权利要求所述的方法,其中,所述的S1链具有少于30个,优选少于25个,特别是21到24个核苷酸。
7.如前述任意一项权利要求所述的方法,其中,所述的dsRNA的至少一个末端经修饰以抵抗肿瘤细胞中的破坏作用或解离作用。
8.如前述任意一项权利要求所述的方法,其中,通过至少一个,优选两个附加的化学键增强由互补核苷酸对实现的所述的dsRNA的键合。
9.如前述任意一项权利要求所述的方法,其中,所述的靶基因是至少一个属于Bcl-2家族的基因,特别是Bcl-2,Bcl-w,或Bcl-xL,或者靶基因是Bcl-2和Bcl-xL。
10.如前述任意一项权利要求所述的方法,其中,所述的dsRNA由具有如后附的序列表的SEQ ID NO:1所示序列的S2链和具有SEQID NO:2所示序列的S1链组成,或由具有SEQ ID NO:3所示序列的S2链和具有SEQ ID NO:4所示序列的S1链组成。
11.如前述任意一项权利要求所述的方法,其中,所述的肿瘤细胞是胰腺癌细胞。
12.如前述任意一项权利要求所述的方法,其中,所述的dsRNA利用围绕dsRNA的胶束结构,优选脂质体,或利用围绕dsRNA的衣壳引入肿瘤细胞。
13.一种治疗肿瘤疾病的药物,其包含至少一种抑制至少一个抑制或阻止肿瘤细胞中细胞凋亡的靶基因表达的双链核糖核酸(dsRNA),其中,该dsRNA的S1链具有一个由少于25个连续的核苷酸组成的、至少部分互补于所述靶基因的区域。
14.如权利要求13所述的药物,其中,所述dsRNA的至少一个末端具有由1到4个,特别是2或3个核苷酸组成的单链突出端。
15.如权利要求13或14所述的药物,其中,所述的单链突出端定位于S1链的3′-末端。
16.如权利要求13到15的任意一项所述的药物,其中,所述的dsRNA仅在一个末端具有单链突出端,特别是定位于S1链的3′-末端。
17.如权利要求13到16的任意一项所述的药物,其中,所述的互补区具有19到24,优选21到23,特别是22个核苷酸。
18.如权利要求13到17的任意一项所述的药物,其中,所述的S1具有少于30个,优选少于25个,特别是21到24个核苷酸。
19.如权利要求13到18的任意一项所述的药物,其中,所述的dsRNA的至少一个末端经修饰以抵抗肿瘤细胞中的破坏作用或解离作用。
20.如权利要求13到19的任意一项所述的药物,其中,通过至少一个,优选两个附加的化学键增强由互补核苷酸对实现的dsRNA的键合。
21.如权利要求13到20的任意一项所述的药物,其中,所述的靶基因是至少一个属于Bcl-2家族的基因,特别是Bcl-2,Bcl-w,或Bcl-xL,或者靶基因是Bcl-2和Bcl-xL。
22.如权利要求13到21的任意一项所述的药物,其中,所述的dsRNA由具有如后附的序列表的SEQ ID NO:1所示序列的S2链和具有SEQ ID NO:2所示序列的S1链组成,或由具有SEQ ID NO:3所示序列的S2链和具有SEQ ID NO:4所示序列的S1链组成。
23.如权利要求13到22的任意一项所述的药物,其中,所述的肿瘤细胞是胰腺癌细胞。
24.如权利要求13到23的任意一项所述的药物,其中,所述的dsRNA在溶液中或利用胶束结构,优选脂质体,或衣壳围绕而存在于药物中。
25.如权利要求13到24的任意一项所述的药物,其中,所述的药物制备成适合于吸入、口服摄取或注射,特别是静脉内或腹膜内注射,或者直接注射到瘤组织内的制剂。
26.如权利要求25所述的药物,其中,所述的制剂由dsRNA和生理上可耐受的缓冲液,特别是磷酸缓冲盐溶液组成。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10100586A DE10100586C1 (de) | 2001-01-09 | 2001-01-09 | Verfahren zur Hemmung der Expression eines Ziegens |
DE10100586.5 | 2001-01-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1650010A true CN1650010A (zh) | 2005-08-03 |
Family
ID=7669989
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA028035550A Pending CN1650010A (zh) | 2001-01-09 | 2002-01-09 | 抑制靶基因表达的方法和治疗肿瘤疾病的药物 |
Country Status (10)
Country | Link |
---|---|
US (1) | US7473525B2 (zh) |
EP (3) | EP2213736B1 (zh) |
JP (1) | JP4209678B2 (zh) |
CN (1) | CN1650010A (zh) |
AT (1) | ATE460481T1 (zh) |
CA (1) | CA2432341A1 (zh) |
DE (2) | DE10100586C1 (zh) |
ES (1) | ES2204360T3 (zh) |
WO (1) | WO2002055692A2 (zh) |
ZA (2) | ZA200304127B (zh) |
Families Citing this family (187)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040171031A1 (en) * | 1996-06-06 | 2004-09-02 | Baker Brenda F. | Sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation |
US7812149B2 (en) * | 1996-06-06 | 2010-10-12 | Isis Pharmaceuticals, Inc. | 2′-Fluoro substituted oligomeric compounds and compositions for use in gene modulations |
US5898031A (en) * | 1996-06-06 | 1999-04-27 | Isis Pharmaceuticals, Inc. | Oligoribonucleotides for cleaving RNA |
US20050119470A1 (en) * | 1996-06-06 | 2005-06-02 | Muthiah Manoharan | Conjugated oligomeric compounds and their use in gene modulation |
US20040147022A1 (en) * | 1996-06-06 | 2004-07-29 | Baker Brenda F. | 2'-methoxy substituted oligomeric compounds and compositions for use in gene modulations |
US20050042647A1 (en) * | 1996-06-06 | 2005-02-24 | Baker Brenda F. | Phosphorous-linked oligomeric compounds and their use in gene modulation |
US20050053976A1 (en) * | 1996-06-06 | 2005-03-10 | Baker Brenda F. | Chimeric oligomeric compounds and their use in gene modulation |
US9096636B2 (en) | 1996-06-06 | 2015-08-04 | Isis Pharmaceuticals, Inc. | Chimeric oligomeric compounds and their use in gene modulation |
US20040203024A1 (en) * | 1996-06-06 | 2004-10-14 | Baker Brenda F. | Modified oligonucleotides for use in RNA interference |
AU776150B2 (en) | 1999-01-28 | 2004-08-26 | Medical College Of Georgia Research Institute, Inc. | Composition and method for (in vivo) and (in vitro) attenuation of gene expression using double stranded RNA |
DE19956568A1 (de) | 1999-01-30 | 2000-08-17 | Roland Kreutzer | Verfahren und Medikament zur Hemmung der Expression eines vorgegebenen Gens |
US7601494B2 (en) | 1999-03-17 | 2009-10-13 | The University Of North Carolina At Chapel Hill | Method of screening candidate compounds for susceptibility to biliary excretion |
US7829693B2 (en) | 1999-11-24 | 2010-11-09 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of a target gene |
DE10100586C1 (de) | 2001-01-09 | 2002-04-11 | Ribopharma Ag | Verfahren zur Hemmung der Expression eines Ziegens |
US8202979B2 (en) | 2002-02-20 | 2012-06-19 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid |
WO2003070918A2 (en) | 2002-02-20 | 2003-08-28 | Ribozyme Pharmaceuticals, Incorporated | Rna interference by modified short interfering nucleic acid |
WO2001068836A2 (en) * | 2000-03-16 | 2001-09-20 | Genetica, Inc. | Methods and compositions for rna interference |
US8202846B2 (en) * | 2000-03-16 | 2012-06-19 | Cold Spring Harbor Laboratory | Methods and compositions for RNA interference |
DE60140676D1 (de) | 2000-03-30 | 2010-01-14 | Massachusetts Inst Technology | Mediatoren von rns-interferenz, die rns-sequenzspezifisch sind |
DE60130583T3 (de) | 2000-12-01 | 2018-03-22 | Europäisches Laboratorium für Molekularbiologie | Kleine rns moleküle, die rns-interferenz vermitteln |
WO2003035869A1 (de) * | 2001-10-26 | 2003-05-01 | Ribopharma Ag | Verwendung einer doppelsträngigen ribonukleinsäure zur gezielten hemmung der expression eines vorgegebenen zielgens |
EP1438405A1 (de) | 2001-01-09 | 2004-07-21 | Ribopharma AG | Verwendung einer doppelsträngigen ribonukleinsäure zur gezielten hemmung der expression eines vorgegebenen zielgens |
US8546143B2 (en) | 2001-01-09 | 2013-10-01 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of a target gene |
US7423142B2 (en) | 2001-01-09 | 2008-09-09 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of anti-apoptotic genes |
US7767802B2 (en) | 2001-01-09 | 2010-08-03 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of anti-apoptotic genes |
US20050159381A1 (en) * | 2001-05-18 | 2005-07-21 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of chromosome translocation gene expression using short interfering nucleic acid (siNA) |
US20050182007A1 (en) * | 2001-05-18 | 2005-08-18 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA) |
US20050203040A1 (en) * | 2001-05-18 | 2005-09-15 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of vascular cell adhesion molecule (VCAM) gene expression using short interfering nucleic acid (siNA) |
US20040019001A1 (en) * | 2002-02-20 | 2004-01-29 | Mcswiggen James A. | RNA interference mediated inhibition of protein typrosine phosphatase-1B (PTP-1B) gene expression using short interfering RNA |
US20050176025A1 (en) * | 2001-05-18 | 2005-08-11 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of B-cell CLL/Lymphoma-2 (BCL-2) gene expression using short interfering nucleic acid (siNA) |
US20050143333A1 (en) * | 2001-05-18 | 2005-06-30 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA) |
US20050196767A1 (en) * | 2001-05-18 | 2005-09-08 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of GRB2 associated binding protein (GAB2) gene expression using short interfering nucleic acis (siNA) |
US20050158735A1 (en) * | 2001-05-18 | 2005-07-21 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of proliferating cell nuclear antigen (PCNA) gene expression using short interfering nucleic acid (siNA) |
US9994853B2 (en) | 2001-05-18 | 2018-06-12 | Sirna Therapeutics, Inc. | Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference |
US20050124566A1 (en) * | 2001-05-18 | 2005-06-09 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of myostatin gene expression using short interfering nucleic acid (siNA) |
US20050159382A1 (en) * | 2001-05-18 | 2005-07-21 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of polycomb group protein EZH2 gene expression using short interfering nucleic acid (siNA) |
US20050288242A1 (en) * | 2001-05-18 | 2005-12-29 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of RAS gene expression using short interfering nucleic acid (siNA) |
US20050233997A1 (en) * | 2001-05-18 | 2005-10-20 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of matrix metalloproteinase 13 (MMP13) gene expression using short interfering nucleic acid (siNA) |
US20050196765A1 (en) * | 2001-05-18 | 2005-09-08 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of checkpoint Kinase-1 (CHK-1) gene expression using short interfering nucleic acid (siNA) |
US20050148530A1 (en) | 2002-02-20 | 2005-07-07 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
JP4210737B2 (ja) | 2001-07-12 | 2009-01-21 | ユニバーシティー オブ マサチューセッツ | 遺伝子サイレンシングを仲介する低分子干渉リボ核酸のインビボにおける製造方法 |
US10590418B2 (en) | 2001-07-23 | 2020-03-17 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions for RNAi mediated inhibition of gene expression in mammals |
US20030153519A1 (en) * | 2001-07-23 | 2003-08-14 | Kay Mark A. | Methods and compositions for RNAi mediated inhibition of gene expression in mammals |
DE10163098B4 (de) | 2001-10-12 | 2005-06-02 | Alnylam Europe Ag | Verfahren zur Hemmung der Replikation von Viren |
US7745418B2 (en) | 2001-10-12 | 2010-06-29 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting viral replication |
FR2832154B1 (fr) | 2001-11-09 | 2007-03-16 | Centre Nat Rech Scient | Oligonucleotides inhibiteurs et leur utilisation pour reprimer specifiquement un gene |
JP4242590B2 (ja) | 2002-01-11 | 2009-03-25 | 俊一 塩澤 | 慢性関節リウマチの疾患感受性遺伝子、及びその利用 |
DE10202419A1 (de) | 2002-01-22 | 2003-08-07 | Ribopharma Ag | Verfahren zur Hemmung der Expression eines durch eine Chromosomen-Aberration entstandenen Zielgens |
EP2128248B2 (en) | 2002-02-01 | 2017-01-11 | Life Technologies Corporation | Oligonucleotide compositions with enhanced efficiency |
US9181551B2 (en) | 2002-02-20 | 2015-11-10 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US9657294B2 (en) | 2002-02-20 | 2017-05-23 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
AU2003213119A1 (en) * | 2002-02-20 | 2003-09-09 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF BCL2 GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
AU2003207708A1 (en) | 2002-02-20 | 2003-09-09 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of map kinase genes |
US7399586B2 (en) | 2002-05-23 | 2008-07-15 | Ceptyr, Inc. | Modulation of biological signal transduction by RNA interference |
US7148342B2 (en) | 2002-07-24 | 2006-12-12 | The Trustees Of The University Of Pennyslvania | Compositions and methods for sirna inhibition of angiogenesis |
EP1572956A2 (en) * | 2002-08-01 | 2005-09-14 | City of Hope | Methods and kits for synthesis of sirna expression cassettes |
US20040241854A1 (en) | 2002-08-05 | 2004-12-02 | Davidson Beverly L. | siRNA-mediated gene silencing |
US20080274989A1 (en) | 2002-08-05 | 2008-11-06 | University Of Iowa Research Foundation | Rna Interference Suppression of Neurodegenerative Diseases and Methods of Use Thereof |
US20050042646A1 (en) | 2002-08-05 | 2005-02-24 | Davidson Beverly L. | RNA interference suppresion of neurodegenerative diseases and methods of use thereof |
WO2004014933A1 (en) | 2002-08-07 | 2004-02-19 | University Of Massachusetts | Compositions for rna interference and methods of use thereof |
US7892793B2 (en) | 2002-11-04 | 2011-02-22 | University Of Massachusetts | Allele-specific RNA interference |
CA2504929C (en) * | 2002-11-05 | 2014-07-22 | Charles Allerson | Compositions comprising alternating 2'-modified nucleosides for use in gene modulation |
JP4526228B2 (ja) * | 2002-11-22 | 2010-08-18 | 隆 森田 | RNAiによる新規治療法および治療剤 |
US20040248299A1 (en) * | 2002-12-27 | 2004-12-09 | Sumedha Jayasena | RNA interference |
GB0306148D0 (en) * | 2003-03-18 | 2003-04-23 | Milner Jo | Regulation of gene expression |
AU2004225480A1 (en) * | 2003-03-26 | 2004-10-14 | Multicell Immunotherapeutics, Inc. | Selected RNA motifs to include cell death and/or apoptosis |
KR20060063788A (ko) * | 2003-05-30 | 2006-06-12 | 니뽄 신야쿠 가부시키가이샤 | 올리고 핵산 담지 복합체, 이 복합체를 함유하는 의약조성물 |
EP2251039A3 (en) | 2003-05-30 | 2010-12-08 | Nippon Shinyaku Co., Ltd. | Oligo double-stranded rna inhibiting the expression of bcl-2 and pharmaceutical composition containing the same |
EP1633767B1 (en) | 2003-06-02 | 2018-11-21 | University of Massachusetts | Methods and compositions for controlling efficacy of rna silencing |
ATE485394T1 (de) | 2003-06-02 | 2010-11-15 | Univ Massachusetts | Verfahren und zusammensetzungen zur verbesserung der wirksamkeit und spezifität von fnai |
US7750144B2 (en) | 2003-06-02 | 2010-07-06 | University Of Massachusetts | Methods and compositions for enhancing the efficacy and specificity of RNA silencing |
EP1486564A1 (de) * | 2003-06-13 | 2004-12-15 | Ribopharma AG | SiRNA mit erhöhter Stabilität in Serum |
GB2417727B (en) * | 2003-06-13 | 2008-01-16 | Alnylam Europe Ag | Double-stranded ribonucleic acid with increased effectiveness in an organism |
US20060241072A1 (en) * | 2003-06-20 | 2006-10-26 | Isis Pharmaceuticals, Inc. | Oligomeric compounds for use in gene modulation |
ITRM20030335A1 (it) * | 2003-07-09 | 2005-01-10 | Univ Roma | Sistema di espressione di sirna. |
ES2485848T3 (es) | 2003-09-12 | 2014-08-14 | University Of Massachusetts | ARN de interferencia para el tratamiento de trastornos relacionados con la ganancia de función |
US8680063B2 (en) | 2003-09-12 | 2014-03-25 | University Of Massachusetts | RNA interference for the treatment of gain-of-function disorders |
US20060134787A1 (en) | 2004-12-22 | 2006-06-22 | University Of Massachusetts | Methods and compositions for enhancing the efficacy and specificity of single and double blunt-ended siRNA |
EP1713915B1 (en) | 2004-02-10 | 2009-12-16 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING MULTIFUNCTIONAL SHORT INTERFERING NUCLEIC ACID (MULTIFUNCTIONAL siNA) |
US20060019914A1 (en) | 2004-02-11 | 2006-01-26 | University Of Tennessee Research Foundation | Inhibition of tumor growth and invasion by anti-matrix metalloproteinase DNAzymes |
US8569474B2 (en) * | 2004-03-09 | 2013-10-29 | Isis Pharmaceuticals, Inc. | Double stranded constructs comprising one or more short strands hybridized to a longer strand |
EP2365077B1 (en) | 2004-03-12 | 2013-05-08 | Alnylam Pharmaceuticals, Inc. | iRNA agents targeting VEGF |
AU2005238034A1 (en) | 2004-04-23 | 2005-11-10 | The Trustees Of Columbia University In The City Of New York | Inhibition of hairless protein mRNA |
JP5220406B2 (ja) | 2004-04-28 | 2013-06-26 | ブリガム・ヤング・ユニバーシティ | 皮膚疾患を処置するためのエクオールの使用 |
US10508277B2 (en) | 2004-05-24 | 2019-12-17 | Sirna Therapeutics, Inc. | Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference |
EP2290071B1 (en) * | 2004-05-28 | 2014-12-31 | Asuragen, Inc. | Methods and compositions involving microRNA |
AU2005252663B2 (en) * | 2004-06-03 | 2011-07-07 | Isis Pharmaceuticals, Inc. | Double strand compositions comprising differentially modified strands for use in gene modulation |
US8394947B2 (en) * | 2004-06-03 | 2013-03-12 | Isis Pharmaceuticals, Inc. | Positionally modified siRNA constructs |
EP1782321A4 (en) | 2004-07-23 | 2009-11-04 | Univ North Carolina | METHOD AND MATERIALS FOR DETERMINING PAIN SENSITIVITY AND PREDICTING AND TREATING SUFFERING INTERFERENCE |
US20060040391A1 (en) * | 2004-08-20 | 2006-02-23 | Promega Corporation | RNA interference vectors |
JP5087924B2 (ja) | 2004-08-26 | 2012-12-05 | 日本新薬株式会社 | ガラクトース誘導体、薬物担体及び医薬組成物 |
US7884086B2 (en) * | 2004-09-08 | 2011-02-08 | Isis Pharmaceuticals, Inc. | Conjugates for use in hepatocyte free uptake assays |
WO2006035432A2 (en) * | 2004-09-27 | 2006-04-06 | Tel Hashomer Medical Research Infrastructure And Services Ltd. | Gene silencing for use in dermatology |
EP2281887A1 (en) * | 2004-11-12 | 2011-02-09 | Asuragen, Inc. | Methods and compositions involving miRNA and miRNA inhibitor molecules |
WO2007011702A2 (en) | 2005-07-15 | 2007-01-25 | The University Of North Carolina At Chapel Hill | Use of egfr inhibitors to prevent or treat obesity |
WO2007022470A2 (en) | 2005-08-18 | 2007-02-22 | Alnylam Pharmaceuticals, Inc. | Methods and compositions for treating neurological disease |
CN101268194A (zh) | 2005-09-20 | 2008-09-17 | 巴斯福植物科学有限公司 | 使用ta-siRNA调控基因表达的方法 |
EP1934348B1 (en) | 2005-10-11 | 2018-05-02 | Ben-Gurion University Of The Negev Research And Development Authority | Compositions for silencing the expression of vdac1 and uses thereof |
CA2627025A1 (en) | 2005-10-28 | 2007-05-03 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of huntingtin gene |
WO2007056326A2 (en) | 2005-11-04 | 2007-05-18 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of nav1.8 gene |
WO2007056331A2 (en) | 2005-11-09 | 2007-05-18 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of factor v leiden mutant gene |
CA2638797A1 (en) | 2006-03-01 | 2007-09-07 | Nippon Shinyaku Co., Ltd. | Galactose derivative, drug carrier and medicinal composition |
FR2898908A1 (fr) | 2006-03-24 | 2007-09-28 | Agronomique Inst Nat Rech | Procede de preparation de cellules aviaires differenciees et genes impliques dans le maintien de la pluripotence |
AU2007233109B2 (en) | 2006-03-31 | 2010-10-14 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of Eg5 gene |
PL2194128T3 (pl) | 2006-05-11 | 2012-12-31 | Alnylam Pharmaceuticals Inc | Kompozycje i sposoby inhibicji ekspresji genu PCSK9 |
BRPI0712034A2 (pt) | 2006-05-19 | 2012-01-10 | Alnylam Pharmaceuticals Inc | modulação de rnai de aha e usos terapêuticos do mesmo |
EP2192200B1 (en) | 2006-05-22 | 2012-10-24 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of IKK-B gene |
US8598333B2 (en) | 2006-05-26 | 2013-12-03 | Alnylam Pharmaceuticals, Inc. | SiRNA silencing of genes expressed in cancer |
WO2008036638A2 (en) | 2006-09-18 | 2008-03-27 | Alnylam Pharmaceuticals, Inc. | Rnai modulation of scap and therapeutic uses thereof |
WO2008036741A2 (en) * | 2006-09-19 | 2008-03-27 | Asuragen, Inc. | Mir-200 regulated genes and pathways as targets for therapeutic intervention |
JP2010510964A (ja) * | 2006-09-19 | 2010-04-08 | アシュラジェン インコーポレイテッド | 治療的介入の標的としての、miR−15、miR−26、miR−31、miR−145、miR−147、miR−188、miR−215、miR−216、miR−331、mmu−miR−292−3pによって調節される遺伝子および経路 |
WO2008036933A2 (en) | 2006-09-21 | 2008-03-27 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of the hamp gene |
CA2671294A1 (en) * | 2006-12-08 | 2008-06-19 | Asuragen, Inc. | Mir-21 regulated genes and pathways as targets for therapeutic intervention |
AU2007333109A1 (en) * | 2006-12-08 | 2008-06-19 | Asuragen, Inc. | Functions and targets of let-7 micro RNAs |
CN101622349A (zh) * | 2006-12-08 | 2010-01-06 | 奥斯瑞根公司 | 作为治疗性干预靶标的miR-21调节的基因和途径 |
AU2008207735B2 (en) | 2007-01-26 | 2013-10-03 | University Of Louisville Research Foundation, Inc. | Modification of exosomal components for use as a vaccine |
PT2129680E (pt) | 2007-03-21 | 2015-08-28 | Brookhaven Science Ass Llc | Composições combinadas de gancho de cabelo e antissentido e métodos para modulação da expressão |
PE20090064A1 (es) | 2007-03-26 | 2009-03-02 | Novartis Ag | Acido ribonucleico de doble cadena para inhibir la expresion del gen e6ap humano y composicion farmaceutica que lo comprende |
JP5350360B2 (ja) | 2007-03-29 | 2013-11-27 | アルナイラム ファーマシューティカルズ, インコーポレイテッド | エボラ由来の遺伝子の発現を阻害するための組成物および方法 |
US20090232893A1 (en) * | 2007-05-22 | 2009-09-17 | Bader Andreas G | miR-143 REGULATED GENES AND PATHWAYS AS TARGETS FOR THERAPEUTIC INTERVENTION |
US20090131354A1 (en) * | 2007-05-22 | 2009-05-21 | Bader Andreas G | miR-126 REGULATED GENES AND PATHWAYS AS TARGETS FOR THERAPEUTIC INTERVENTION |
WO2008154333A2 (en) * | 2007-06-08 | 2008-12-18 | Asuragen, Inc. | Mir-34 regulated genes and pathways as targets for therapeutic intervention |
EP2319926B1 (en) | 2007-07-05 | 2016-08-31 | Arrowhead Research Corporation | DSRNA for treating viral infection |
US8361714B2 (en) * | 2007-09-14 | 2013-01-29 | Asuragen, Inc. | Micrornas differentially expressed in cervical cancer and uses thereof |
EP2190995A2 (en) * | 2007-09-18 | 2010-06-02 | Intradigm Corporation | Compositions comprising k-ras sirna and methods of use |
US20100280097A1 (en) * | 2007-09-18 | 2010-11-04 | Intradigm Corporation | Compositions comprising hif-1 alpha sirna and methods of use thereof |
WO2009070805A2 (en) * | 2007-12-01 | 2009-06-04 | Asuragen, Inc. | Mir-124 regulated genes and pathways as targets for therapeutic intervention |
EP2848688A1 (en) | 2007-12-10 | 2015-03-18 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of factor VII gene |
WO2009086156A2 (en) * | 2007-12-21 | 2009-07-09 | Asuragen, Inc. | Mir-10 regulated genes and pathways as targets for therapeutic intervention |
EP2260110B1 (en) * | 2008-02-08 | 2014-11-12 | Asuragen, INC. | miRNAs DIFFERENTIALLY EXPRESSED IN LYMPH NODES FROM CANCER PATIENTS |
KR101397407B1 (ko) | 2008-03-05 | 2014-06-19 | 알닐람 파마슈티칼스 인코포레이티드 | Eg5 및 VEGF 유전자의 발현을 억제하기 위한 조성물 및 방법 |
WO2009111643A2 (en) * | 2008-03-06 | 2009-09-11 | Asuragen, Inc. | Microrna markers for recurrence of colorectal cancer |
WO2009114726A1 (en) * | 2008-03-12 | 2009-09-17 | Intradigm Corporation | Compositions comprising notch1 sirna and methods of use thereof |
WO2009154835A2 (en) * | 2008-03-26 | 2009-12-23 | Asuragen, Inc. | Compositions and methods related to mir-16 and therapy of prostate cancer |
WO2009126726A1 (en) * | 2008-04-08 | 2009-10-15 | Asuragen, Inc | Methods and compositions for diagnosing and modulating human papillomavirus (hpv) |
WO2009126727A1 (en) * | 2008-04-10 | 2009-10-15 | Alnylam Pharmaceuticals, Inc. | Rna compositions for modulating immune response |
US8258111B2 (en) * | 2008-05-08 | 2012-09-04 | The Johns Hopkins University | Compositions and methods related to miRNA modulation of neovascularization or angiogenesis |
US8431692B2 (en) * | 2008-06-06 | 2013-04-30 | Quark Pharmaceuticals, Inc. | Compositions and methods for treatment of ear disorders |
WO2010021718A1 (en) | 2008-08-19 | 2010-02-25 | Nektar Therapeutics | Complexes of small-interfering nucleic acids |
EP2331690B1 (en) | 2008-09-02 | 2016-01-13 | Alnylam Pharmaceuticals Inc. | Compositions and methods for inhibiting expression of mutant egfr gene |
EP3109321B1 (en) | 2008-09-25 | 2019-05-01 | Alnylam Pharmaceuticals, Inc. | Lipid formulated compositions and methods for inhibiting expression of serum amyloid a gene |
EP3848461A1 (en) | 2008-10-20 | 2021-07-14 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of transthyretin |
WO2010056737A2 (en) * | 2008-11-11 | 2010-05-20 | Mirna Therapeutics, Inc. | Methods and compositions involving mirnas in cancer stem cells |
AU2009322279A1 (en) | 2008-12-04 | 2011-07-14 | Opko Pharmaceuticals, Llc | Compositions and methods for selective inhibition of pro-angiogenic VEGF isoforms |
JP5855462B2 (ja) | 2008-12-10 | 2016-02-09 | アルナイラム ファーマシューティカルズ, インコーポレイテッドAlnylam Pharmaceuticals, Inc. | GNAQを標的としたdsRNA組成物および発現を阻害するための方法 |
US20120041051A1 (en) | 2009-02-26 | 2012-02-16 | Kevin Fitzgerald | Compositions And Methods For Inhibiting Expression Of MIG-12 Gene |
EP2406376A1 (en) | 2009-03-12 | 2012-01-18 | Alnylam Pharmaceuticals, Inc. | LIPID FORMULATED COMPOSITIONS AND METHODS FOR INHIBITING EXPRESSION OF Eg5 AND VEGF GENES |
FR2944437B1 (fr) * | 2009-04-16 | 2013-05-10 | Oreal | Utilisation d'inhibiteurs de l'expression d'hif 1 alpha pour proteger la peau des dommages deleteres induits par le rayonnement uva |
US9200276B2 (en) | 2009-06-01 | 2015-12-01 | Halo-Bio Rnai Therapeutics, Inc. | Polynucleotides for multivalent RNA interference, compositions and methods of use thereof |
US9051567B2 (en) | 2009-06-15 | 2015-06-09 | Tekmira Pharmaceuticals Corporation | Methods for increasing efficacy of lipid formulated siRNA |
WO2010148013A2 (en) | 2009-06-15 | 2010-12-23 | Alnylam Pharmaceuticals, Inc. | Lipid formulated dsrna targeting the pcsk9 gene |
US9029338B2 (en) | 2009-08-14 | 2015-05-12 | Alnylam Pharmaceuticals, Inc. | Lipid formulated compositions and methods for inhibiting expression of a gene from the ebola virus |
US8916693B2 (en) | 2009-09-17 | 2014-12-23 | Nektar Therapeutics | Monoconjugated chitosans as delivery agents for small interfering nucleic acids |
JP5574258B2 (ja) * | 2009-10-01 | 2014-08-20 | 学校法人東京女子医科大学 | 膵臓がん治療用の組成物 |
MX369004B (es) | 2009-12-18 | 2019-10-24 | Novartis Ag | Composiciones orgánicas para tratar las enfermedades relacionadas con hsf1. |
EA201201113A1 (ru) | 2010-02-10 | 2013-03-29 | Новартис Аг | Способы и соединения для роста мышц |
WO2011123468A1 (en) | 2010-03-29 | 2011-10-06 | Alnylam Pharmaceuticals, Inc. | Sirna therapy for transthyretin (ttr) related ocular amyloidosis |
CA3102008A1 (en) | 2010-06-02 | 2011-12-08 | Alnylam Pharmaceuticals, Inc. | Compositions and methods directed to treating liver fibrosis |
WO2012027206A1 (en) | 2010-08-24 | 2012-03-01 | Merck Sharp & Dohme Corp. | SINGLE-STRANDED RNAi AGENTS CONTAINING AN INTERNAL, NON-NUCLEIC ACID SPACER |
EP2433644A1 (en) | 2010-09-22 | 2012-03-28 | IMBA-Institut für Molekulare Biotechnologie GmbH | Breast cancer therapeutics |
AR083445A1 (es) | 2010-10-14 | 2013-02-27 | Univ Mie | siARN CONTRA LA FIBROSIS |
EP3327125B1 (en) | 2010-10-29 | 2020-08-05 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of gene expression using short interfering nucleic acids (sina) |
CN110123830A (zh) | 2010-11-09 | 2019-08-16 | 阿尔尼拉姆医药品有限公司 | 用于抑制Eg5和VEGF基因的表达的脂质配制的组合物和方法 |
CA3191066A1 (en) | 2011-06-21 | 2012-12-27 | Alnylam Pharmaceuticals Inc. | Compositions and methods for inhibition of expression of apolipoprotein c-iii (apoc3) genes |
US9228188B2 (en) | 2011-06-21 | 2016-01-05 | Alnylam Pharmaceuticals, Inc. | Compositions and method for inhibiting hepcidin antimicrobial peptide (HAMP) or HAMP-related gene expression |
EP3564393A1 (en) | 2011-06-21 | 2019-11-06 | Alnylam Pharmaceuticals, Inc. | Assays and methods for determining activity of a therapeutic agent in a subject |
EP4134433A1 (en) | 2011-06-23 | 2023-02-15 | Alnylam Pharmaceuticals, Inc. | Serpina1 sirnas: compositions of matter and methods of treatment |
US9644241B2 (en) | 2011-09-13 | 2017-05-09 | Interpace Diagnostics, Llc | Methods and compositions involving miR-135B for distinguishing pancreatic cancer from benign pancreatic disease |
CN104302768A (zh) | 2012-01-09 | 2015-01-21 | 诺华股份有限公司 | 治疗β-联蛋白相关疾病的有机组合物 |
EP2700949A1 (en) | 2012-08-24 | 2014-02-26 | IMG Institut für medizinische Genomforschung Planungsgesellschaft M.B.H. | Use of biliverdin reductase proteins as cancer marker |
MX360560B (es) | 2013-03-13 | 2018-11-07 | Geneweave Biosciences Inc | Partículas de transducción no replicativas y sistemas indicadores a base de partículas de transducción. |
WO2014174511A1 (en) | 2013-04-21 | 2014-10-30 | Yeda Research And Development Co. Ltd. | Agents for downregulation of the activity and/or amount of bcl-xl and/or bcl-w |
HUE048558T2 (hu) | 2014-03-11 | 2020-07-28 | Cellectis | Eljárás allogén transzplantációra kompatibilis T-sejtek létrehozására |
WO2016077624A1 (en) | 2014-11-12 | 2016-05-19 | Nmc, Inc. | Transgenic plants with engineered redox sensitive modulation of photosynthetic antenna complex pigments and methods for making the same |
EP3261612A1 (en) | 2015-02-26 | 2018-01-03 | Yeda Research and Development Co. Ltd | Method of promoting hair growth |
CA2978431C (en) | 2015-03-02 | 2023-10-24 | 180 Therapeutics Lp | Method of treating a localized fibrotic disorder using a tnf receptor 2 antagonist |
WO2017035278A1 (en) | 2015-08-24 | 2017-03-02 | Halo-Bio Rnai Therapeutics, Inc. | Polynucleotide nanoparticles for the modulation of gene expression and uses thereof |
KR20180054640A (ko) | 2015-08-25 | 2018-05-24 | 알닐람 파마슈티칼스 인코포레이티드 | 전구단백질 컨버타제 서브틸리신 켁신 (pcsk9) 유전자-관련 장애를 치료하기 위한 방법 및 조성물 |
WO2017152073A1 (en) | 2016-03-04 | 2017-09-08 | University Of Louisville Research Foundation, Inc. | Methods and compositions for ex vivo expansion of very small embryonic-like stem cells (vsels) |
MA45469A (fr) | 2016-04-01 | 2019-02-06 | Avidity Biosciences Llc | Acides nucléiques de bêta-caténine et leurs utilisations |
MA45349A (fr) | 2016-04-01 | 2019-02-06 | Avidity Biosciences Llc | Acides nucléiques egfr et leurs utilisations |
MA45470A (fr) | 2016-04-01 | 2019-02-06 | Avidity Biosciences Llc | Acides nucléiques kras et leurs utilisations |
MA45328A (fr) | 2016-04-01 | 2019-02-06 | Avidity Biosciences Llc | Compositions acide nucléique-polypeptide et utilisations de celles-ci |
WO2018020012A1 (en) | 2016-07-29 | 2018-02-01 | Danmarks Tekniske Universitet | Methods for decoupling cell growth from production of biochemicals and recombinant polypeptides |
WO2018229251A1 (en) | 2017-06-16 | 2018-12-20 | Imba - Institut Für Molekulare Biotechnologie Gmbh | Blood vessel organoid, methods of producing and using said organoids |
AU2018378812A1 (en) | 2017-12-06 | 2020-07-09 | Avidity Biosciences, Inc. | Compositions and methods of treating muscle atrophy and myotonic dystrophy |
CA3172111A1 (en) | 2020-03-19 | 2021-09-23 | Barbora MALECOVA | Compositions and methods of treating facioscapulohumeral muscular dystrophy |
Family Cites Families (86)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5208149A (en) | 1983-10-20 | 1993-05-04 | The Research Foundation Of State University Of New York | Nucleic acid constructs containing stable stem and loop structures |
US5190931A (en) | 1983-10-20 | 1993-03-02 | The Research Foundation Of State University Of New York | Regulation of gene expression by employing translational inhibition of MRNA utilizing interfering complementary MRNA |
DE3681787D1 (de) | 1985-07-05 | 1991-11-07 | Whitehead Biomedical Inst | Expression von fremdem genetischem material in epithelzellen. |
US4980286A (en) | 1985-07-05 | 1990-12-25 | Whitehead Institute For Biomedical Research | In vivo introduction and expression of foreign genetic material in epithelial cells |
US5107065A (en) | 1986-03-28 | 1992-04-21 | Calgene, Inc. | Anti-sense regulation of gene expression in plant cells |
US4987071A (en) | 1986-12-03 | 1991-01-22 | University Patents, Inc. | RNA ribozyme polymerases, dephosphorylases, restriction endoribonucleases and methods |
US5712257A (en) | 1987-08-12 | 1998-01-27 | Hem Research, Inc. | Topically active compositions of mismatched dsRNAs |
WO1989002468A1 (en) | 1987-09-11 | 1989-03-23 | Whitehead Institute For Biomedical Research | Transduced fibroblasts and uses therefor |
DE3851153T2 (de) | 1987-12-11 | 1995-01-05 | Whitehead Biomedical Inst | Genetische modifizierung von endothelialen zellen. |
US5254678A (en) | 1987-12-15 | 1993-10-19 | Gene Shears Pty. Limited | Ribozymes |
WO1989007136A2 (en) | 1988-02-05 | 1989-08-10 | Whitehead Institute For Biomedical Research | Modified hepatocytes and uses therefor |
US5328470A (en) | 1989-03-31 | 1994-07-12 | The Regents Of The University Of Michigan | Treatment of diseases by site-specific instillation of cells or site-specific transformation of cells and kits therefor |
US5212295A (en) | 1990-01-11 | 1993-05-18 | Isis Pharmaceuticals | Monomers for preparation of oligonucleotides having chiral phosphorus linkages |
US5587361A (en) | 1991-10-15 | 1996-12-24 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
JP3418982B2 (ja) | 1990-10-31 | 2003-06-23 | ソマティクス セラピー コーポレイション | 内皮細胞の遺伝的変性 |
FR2675803B1 (fr) | 1991-04-25 | 1996-09-06 | Genset Sa | Oligonucleotides fermes, antisens et sens et leurs applications. |
DE69331543T2 (de) | 1992-03-05 | 2002-09-26 | Isis Pharmaceutical Inc | Kovalent vernetzte oligonukleotide |
ATE171210T1 (de) * | 1992-07-02 | 1998-10-15 | Hybridon Inc | Selbststabilisierte oligonukleotide als therapeutika |
US6423489B1 (en) | 1992-09-10 | 2002-07-23 | Isis Pharmaceuticals, Inc. | Compositions and methods for treatment of Hepatitis C virus-associated diseases |
US6054299A (en) | 1994-04-29 | 2000-04-25 | Conrad; Charles A. | Stem-loop cloning vector and method |
US6166197A (en) | 1995-03-06 | 2000-12-26 | Isis Pharmaceuticals, Inc. | Oligomeric compounds having pyrimidine nucleotide (S) with 2'and 5 substitutions |
US5674683A (en) | 1995-03-21 | 1997-10-07 | Research Corporation Technologies, Inc. | Stem-loop and circular oligonucleotides and method of using |
US5998203A (en) | 1996-04-16 | 1999-12-07 | Ribozyme Pharmaceuticals, Inc. | Enzymatic nucleic acids containing 5'-and/or 3'-cap structures |
DE19631919C2 (de) * | 1996-08-07 | 1998-07-16 | Deutsches Krebsforsch | Anti-Sinn-RNA mit Sekundärstruktur |
US6127533A (en) | 1997-02-14 | 2000-10-03 | Isis Pharmaceuticals, Inc. | 2'-O-aminooxy-modified oligonucleotides |
GB9710475D0 (en) | 1997-05-21 | 1997-07-16 | Zeneca Ltd | Gene silencing |
GB9720148D0 (en) | 1997-09-22 | 1997-11-26 | Innes John Centre Innov Ltd | Gene silencing materials and methods |
US6506559B1 (en) | 1997-12-23 | 2003-01-14 | Carnegie Institute Of Washington | Genetic inhibition by double-stranded RNA |
KR101054060B1 (ko) | 1998-03-20 | 2011-08-04 | 커먼웰쓰 사이언티픽 앤드 인더스트리얼 리서치 오가니제이션 | 유전자 발현 조절방법 |
DK1068311T3 (da) | 1998-04-08 | 2011-08-08 | Commw Scient Ind Res Org | Fremgangsmåder og midler til opnåelse af modificerede fænotyper |
AR020078A1 (es) | 1998-05-26 | 2002-04-10 | Syngenta Participations Ag | Metodo para alterar la expresion de un gen objetivo en una celula de planta |
GB9827152D0 (en) | 1998-07-03 | 1999-02-03 | Devgen Nv | Characterisation of gene function using double stranded rna inhibition |
US6271358B1 (en) | 1998-07-27 | 2001-08-07 | Isis Pharmaceuticals, Inc. | RNA targeted 2′-modified oligonucleotides that are conformationally preorganized |
US6486299B1 (en) | 1998-09-28 | 2002-11-26 | Curagen Corporation | Genes and proteins predictive and therapeutic for stroke, hypertension, diabetes and obesity |
AU6298899A (en) | 1998-10-09 | 2000-05-01 | Ingene, Inc. | Production of ssdna (in vivo) |
EP1117776A1 (en) | 1998-10-09 | 2001-07-25 | Ingene, Inc. | ENZYMATIC SYNTHESIS OF ssDNA |
AU776150B2 (en) | 1999-01-28 | 2004-08-26 | Medical College Of Georgia Research Institute, Inc. | Composition and method for (in vivo) and (in vitro) attenuation of gene expression using double stranded RNA |
US6200924B1 (en) | 1999-01-29 | 2001-03-13 | E. I. Du Pont De Nemours And Company | Porous highly fluorinated acidic polymer catalyst |
DE19956568A1 (de) | 1999-01-30 | 2000-08-17 | Roland Kreutzer | Verfahren und Medikament zur Hemmung der Expression eines vorgegebenen Gens |
JP2002542263A (ja) | 1999-04-21 | 2002-12-10 | ワイス | ポリヌクレオチド配列の機能を阻害するための方法および組成物 |
SK16222001A3 (sk) | 1999-05-10 | 2002-04-04 | Syngenta Participations Ag | Spôsob zmeny expresie vírusového genómu |
US6861220B2 (en) | 1999-09-08 | 2005-03-01 | Ramot University Authority For Applied Research & Industrial Development Ltd | Genetic screening methods |
US6569623B1 (en) | 1999-09-08 | 2003-05-27 | Ramot University Authority For Applied Research & Industrial Development Ltd. | Genetic screening methods |
JP2003516124A (ja) | 1999-10-15 | 2003-05-13 | ユニバーシティー オブ マサチューセッツ | 標的とした遺伝的干渉の手段としてのrna干渉経路遺伝子 |
GB9927444D0 (en) | 1999-11-19 | 2000-01-19 | Cancer Res Campaign Tech | Inhibiting gene expression |
DE10100586C1 (de) | 2001-01-09 | 2002-04-11 | Ribopharma Ag | Verfahren zur Hemmung der Expression eines Ziegens |
DE10160151A1 (de) | 2001-01-09 | 2003-06-26 | Ribopharma Ag | Verfahren zur Hemmung der Expression eines vorgegebenen Zielgens |
RU2164944C1 (ru) | 1999-12-09 | 2001-04-10 | Институт молекулярной биологии им. В.А. Энгельгардта РАН | Способ изменения генетических свойств организма |
GB9930691D0 (en) | 1999-12-24 | 2000-02-16 | Devgen Nv | Improvements relating to double-stranded RNA inhibition |
US20070026394A1 (en) | 2000-02-11 | 2007-02-01 | Lawrence Blatt | Modulation of gene expression associated with inflammation proliferation and neurite outgrowth using nucleic acid based technologies |
WO2001068836A2 (en) | 2000-03-16 | 2001-09-20 | Genetica, Inc. | Methods and compositions for rna interference |
MXPA02009069A (es) | 2000-03-17 | 2004-04-05 | Benitec Australia Ltd | Silenciamiento genetico. |
DE60140676D1 (de) | 2000-03-30 | 2010-01-14 | Massachusetts Inst Technology | Mediatoren von rns-interferenz, die rns-sequenzspezifisch sind |
WO2001092513A1 (en) | 2000-05-30 | 2001-12-06 | Johnson & Johnson Research Pty Limited | METHODS FOR MEDIATING GENE SUPPRESION BY USING FACTORS THAT ENHANCE RNAi |
CN1311081C (zh) | 2000-08-19 | 2007-04-18 | 爱克斯澳迪亚有限公司 | 干细胞分化 |
US7033801B2 (en) | 2000-12-08 | 2006-04-25 | Invitrogen Corporation | Compositions and methods for rapidly generating recombinant nucleic acid molecules |
US20030190635A1 (en) | 2002-02-20 | 2003-10-09 | Mcswiggen James A. | RNA interference mediated treatment of Alzheimer's disease using short interfering RNA |
AU2001296333A1 (en) | 2000-09-26 | 2002-04-08 | The Burnham Institute | Paad domain-containing polypeptides, encoding nucleic acids, and methods of use |
WO2002068637A2 (en) | 2000-10-20 | 2002-09-06 | Ribozyme Pharmaceuticals, Inc. | Nucleic acid-based treatment of diseases or conditions related to west nile virus infection |
US20020173478A1 (en) | 2000-11-14 | 2002-11-21 | The Trustees Of The University Of Pennsylvania | Post-transcriptional gene silencing by RNAi in mammalian cells |
DE60130583T3 (de) | 2000-12-01 | 2018-03-22 | Europäisches Laboratorium für Molekularbiologie | Kleine rns moleküle, die rns-interferenz vermitteln |
WO2003035869A1 (de) | 2001-10-26 | 2003-05-01 | Ribopharma Ag | Verwendung einer doppelsträngigen ribonukleinsäure zur gezielten hemmung der expression eines vorgegebenen zielgens |
US7521548B2 (en) | 2001-02-07 | 2009-04-21 | Burnham Institute For Medical Research | Apoptosis modulator Bcl-B and methods for making and using same |
GB0104948D0 (en) | 2001-02-28 | 2001-04-18 | Novartis Res Foundation | Novel methods |
WO2002072762A2 (en) | 2001-03-08 | 2002-09-19 | Advanced Cell Technology, Inc. | Use of rna interference for the creation of lineage specific es and other undifferentiated cells and production of differentiated cells in vitro by co-culture |
WO2003070972A2 (en) | 2002-02-20 | 2003-08-28 | Sirna Therapeutics Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF CHROMOSOME TRANSLOCATION GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
JP4210737B2 (ja) | 2001-07-12 | 2009-01-21 | ユニバーシティー オブ マサチューセッツ | 遺伝子サイレンシングを仲介する低分子干渉リボ核酸のインビボにおける製造方法 |
GB0118223D0 (en) | 2001-07-26 | 2001-09-19 | Univ Sheffield | Stem loop RNA |
WO2003012052A2 (en) | 2001-07-30 | 2003-02-13 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Specific inhibition of gene expression by small double stranded rnas |
WO2003016572A1 (en) | 2001-08-17 | 2003-02-27 | Eli Lilly And Company | Oligonucleotide therapeutics for treating hepatitis c virus infections |
US7101995B2 (en) | 2001-08-27 | 2006-09-05 | Mirus Bio Corporation | Compositions and processes using siRNA, amphipathic compounds and polycations |
US20030198627A1 (en) | 2001-09-01 | 2003-10-23 | Gert-Jan Arts | siRNA knockout assay method and constructs |
DE10163098B4 (de) | 2001-10-12 | 2005-06-02 | Alnylam Europe Ag | Verfahren zur Hemmung der Replikation von Viren |
WO2003035083A1 (de) | 2001-10-26 | 2003-05-01 | Ribopharma Ag | Medikament zur behandlung einer fibrotischen erkrankung durch rna interferenz |
DE10230996A1 (de) | 2001-10-26 | 2003-07-17 | Ribopharma Ag | Medikament zur Behandlung eines Pankreaskarzinoms |
WO2003035876A1 (de) | 2001-10-26 | 2003-05-01 | Ribopharma Ag | Verwendung einer doppelsträngigen ribonukleinsäure zur behandlung einer infektion mit einem (+)-strang-rna-virus |
WO2003035870A1 (de) | 2001-10-26 | 2003-05-01 | Ribopharma Ag | Medikament zur behandlung eines pankreaskarzinoms |
AU2002368202B2 (en) | 2001-11-02 | 2008-06-05 | Insert Therapeutics, Inc | Methods and compositions for therapeutic use of RNA interference |
FR2832154B1 (fr) * | 2001-11-09 | 2007-03-16 | Centre Nat Rech Scient | Oligonucleotides inhibiteurs et leur utilisation pour reprimer specifiquement un gene |
WO2003044161A2 (en) | 2001-11-15 | 2003-05-30 | Tularik Inc. | Gene amplification and overexpression in cancer |
AU2003213119A1 (en) | 2002-02-20 | 2003-09-09 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF BCL2 GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
AU2003207708A1 (en) | 2002-02-20 | 2003-09-09 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of map kinase genes |
ATE519774T1 (de) | 2002-02-20 | 2011-08-15 | Sirna Therapeutics Inc | Durch eine störung der rna vermittelte inhibierung der genexpression des hepatitis c virus (hcv) mit kurzer, störender nukleinsäure (short interfering nucleic acid, sina) |
AU2003206946A1 (en) | 2002-02-22 | 2003-09-09 | Klaus Strebhardt | Agent for inhibiting development or progress of proliferative diseases and especially cancer diseases and pharmaceutical composition containing said agent |
US20030180756A1 (en) | 2002-03-21 | 2003-09-25 | Yang Shi | Compositions and methods for suppressing eukaryotic gene expression |
DK2230304T3 (da) | 2005-01-07 | 2012-07-16 | Alnylam Pharmaceuticals Inc | IRNA-modulering af RSV og terapeutiske anvendelser deraf |
-
2001
- 2001-01-09 DE DE10100586A patent/DE10100586C1/de not_active Expired - Lifetime
-
2002
- 2002-01-09 EP EP10002422.3A patent/EP2213736B1/de not_active Expired - Lifetime
- 2002-01-09 AT AT02702247T patent/ATE460481T1/de active
- 2002-01-09 EP EP10011812A patent/EP2365075A1/de not_active Withdrawn
- 2002-01-09 CA CA002432341A patent/CA2432341A1/en not_active Abandoned
- 2002-01-09 WO PCT/EP2002/000151 patent/WO2002055692A2/de active Application Filing
- 2002-01-09 EP EP02702247A patent/EP1349927B1/de not_active Revoked
- 2002-01-09 JP JP2002556739A patent/JP4209678B2/ja not_active Expired - Lifetime
- 2002-01-09 CN CNA028035550A patent/CN1650010A/zh active Pending
- 2002-01-09 DE DE50214266T patent/DE50214266D1/de not_active Expired - Lifetime
- 2002-01-09 ES ES02702247T patent/ES2204360T3/es not_active Expired - Lifetime
-
2003
- 2003-03-07 US US10/384,260 patent/US7473525B2/en not_active Expired - Lifetime
- 2003-05-28 ZA ZA200304127A patent/ZA200304127B/en unknown
- 2003-06-10 ZA ZA200304500A patent/ZA200304500B/xx unknown
Also Published As
Publication number | Publication date |
---|---|
US7473525B2 (en) | 2009-01-06 |
ZA200304500B (en) | 2003-11-18 |
ZA200304127B (en) | 2004-05-11 |
ATE460481T1 (de) | 2010-03-15 |
WO2002055692A2 (de) | 2002-07-18 |
JP2004519457A (ja) | 2004-07-02 |
EP2213736B1 (de) | 2018-03-07 |
JP4209678B2 (ja) | 2009-01-14 |
ES2204360T3 (es) | 2010-07-06 |
EP1349927B1 (de) | 2010-03-10 |
EP2365075A1 (de) | 2011-09-14 |
EP2213736A2 (de) | 2010-08-04 |
CA2432341A1 (en) | 2002-07-18 |
EP2213736A3 (de) | 2010-09-01 |
WO2002055692A3 (de) | 2003-06-12 |
ES2204360T1 (es) | 2004-05-01 |
DE50214266D1 (de) | 2010-04-22 |
DE10100586C1 (de) | 2002-04-11 |
EP1349927A2 (de) | 2003-10-08 |
US20040001811A1 (en) | 2004-01-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1650010A (zh) | 抑制靶基因表达的方法和治疗肿瘤疾病的药物 | |
US20100286241A1 (en) | Compositions comprising k-ras sirna and methods of use | |
CN102575252A (zh) | 用于多价rna干扰的多核苷酸、组合物及其使用方法 | |
Mook et al. | In vivo efficacy and off-target effects of locked nucleic acid (LNA) and unlocked nucleic acid (UNA) modified siRNA and small internally segmented interfering RNA (sisiRNA) in mice bearing human tumor xenografts | |
CN1608133A (zh) | 双链核糖核酸用于治疗正(+)链rna病毒感染的用途 | |
JP2010532163A5 (zh) | ||
WO2009114476A1 (en) | Compositions comprising survivin sirna and methods of use thereof | |
CN102191246B (zh) | 多靶标干扰核酸分子及其应用 | |
KR20090014673A (ko) | 다수 표적 유전자들을 제어하는 간섭 유도 rna들 및그들의 제조방법 | |
EP1638580A2 (en) | Use of double-stranded ribonucleic acid for inducing cell lysis | |
CN102102102B (zh) | hsa-miR-185的新用途 | |
CN105861551A (zh) | 联合表达microRNAs抑制乳腺癌细胞增殖的载体及其构建方法和应用 | |
US11939578B2 (en) | Double-stranded RNA molecule targeting CKIP-1 and use thereof | |
CN1804038A (zh) | 一种抑制VEGF表达的siRNA及其应用 | |
US20100280097A1 (en) | Compositions comprising hif-1 alpha sirna and methods of use thereof | |
WO2009143277A2 (en) | Compositions comprising hscn9a sirna and methods of use thereof | |
KR100848665B1 (ko) | 서바이빈의 발현을 억제하는 siRNA | |
CN1744886A (zh) | 使用pei/单链寡核糖核苷酸复合物下调靶基因 | |
CN1608131A (zh) | 治疗胰腺癌的药物 | |
CN100494380C (zh) | 一组抗丙型肝炎病毒感染及防治丙型肝炎的核苷酸序列、其片段及其应用 | |
CN113975408A (zh) | 一种基于非甲基化CpG纳米疫苗、制备方法和应用 | |
CN102174520B (zh) | 一种干扰核酸分子及应用 | |
WO2021061192A1 (en) | Novel trimethylglycylglycerin compositions and their use in developing anti-cancer drugs and rna vaccines | |
CN115927304A (zh) | 基于SARS-CoV-2RNA序列的新型siRNA及其应用 | |
CN102161991A (zh) | 一链多靶干扰核酸分子及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |