CN1112943C - 气体驱动的基因送递装置 - Google Patents
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Abstract
一种基因送递装置(10,110),它可以始终如一的和重复的方式将遗传物质送递给组织或细胞。该装置包括:一壳体(33,133),它具有一在其内形成的微粒加速通道(22,44,144),并且其一端敞口;一阀(18,34,134),它可与所述压力气体源(12)连接,并有选择地将压缩气体导入微粒加速通道(22),形成一加速气流;至少一个筒孔(38),它具有在其内接纳微粒筒(14)的形状,而该微粒筒内置有包被遗传物质的载体微粒(16),该孔位于所述壳体和微粒加速通道内,膨胀通过微粒加速通道的气流将通过毗连的微粒筒,并从该筒吸起和加速载体微粒;以及一锥形的喷出口(24,46,146),它位于壳体的微粒加速通道的敞口处,其使载体微粒分布在一较宽的区域上。
Description
发明的技术领域
本发明涉及将物质送递细胞的技术领域,特别涉及将遗传物质送递活组织。
发明的背景
在过去的十年中,已经出现以加速的微粒为媒介将物质、特别是将遗传物质送入活细胞和组织,并已作为植物和动物生物工程的重要工具。导入的DNA的瞬时表达和种系整合已在微生物、植物和动物中得到证实。
由于该技术的基本原理已被证明有效,人们的注意力就日益转向装置的改进,这种装置给使用者提供了能够快速并连续地执行一批以微粒为媒介的基因转移。这种装置将特别适用于采用遗传疫苗对人或驯养动物进行群体免疫。
现存的以微粒为媒介的基因转移装置的一个缺陷是样本提供的形式。在所有的这些装置里,样本是沉积在一种如金或铂材料的小的、致密的微粒表面。然后,包被微粒本身或置于一刚性表面(如金属板)上,或置于一用易碎材料(如聚酯薄膜)制成的载片上。再将该包被微粒加速射向靶子。这种方法既有优点也有缺点。优点是平面载片能产生非常均匀扩散的加速微粒。缺点是每一块置有微粒的平板或载片是分别准备的,而且只能使用一次,使得微粒加速工作成为一件耗时和缺乏效率的事,特别是当准备进行许多重复的基因转移时。每一块置有微粒的载片相当大,且必须仔细握持,以避免损坏或污染。有时候也难于区别载片哪一侧置有微粒。载片的错误放置也会减少物料通过量从而浪费样本。
对于某些用途,如希望发生种系事件时,载体微粒分布或散发情况可能比其它用途特别是只需导入的基因瞬时表达时更重要。当要求发生一种稀有的种系转化事件时,必须使微粒均匀地加速朝向大面积的细胞或组织。然而,到目前为止,已经考虑到包被微粒在加速朝向一个靶前最好成单层分布在一较大的面上,以便在非常均匀状态下最大限度地增加接受微粒的细胞数量,由此提高每个细胞将经受一次种系转化的可能性。相反,当加速微粒进入细胞诱导在体细胞(如皮肤)内的瞬时基因表达时,不一定需要非常均匀的加速微粒,因为即使只有少量透入微粒的细胞也会产生足够的表达。因此,至今不令人满意的微粒送递技术将变得吸引人技术。
为了克服这些和其它的不足之处,希望有一种高物料通过量的基因送递装置,该装置能接受大量的样本,以便快速地和连续地送递靶组织。还希望有一种样本储存装置和送递平台,它们与现有平台相比较耐用,并且容易准备、储存和握持。
本发明的简介
本发明的一个目的是提供一种装置,该装置可以始终如一的和重复的方式将遗传物质送递给组织或细胞。
本发明的目的是通过以下技术方案实现的,提供一种基因送递装置,可与一压缩气体源连接,该装置包括:一壳体,它具有一在其内形成的微粒加速通道,并且其一端敞口;一阀,它可与所述压力气体源连接,并有选择地将压缩气体导入微粒加速通道,形成一加速气流;至少一个筒孔,它具有在其内接纳微粒筒的形状,而该微粒筒内置有包被遗传物质的载体微粒,该孔位于所述壳体和微粒加速通道内,膨胀通过微粒加速通道的气流将通过毗连的微粒筒,并从该筒吸起和加速载体微粒;以及一锥形的喷出口,它位于壳体的微粒加速通道的敞口处,锥形喷出口的圆锥形状是这样的:喷出口的锥形在气流方向上的长度较之垂直于气流方向的宽度要大,该锥形使从壳体输出的气流膨胀喷出,较之喷出口不是锥形的而言,其使载体微粒分布在一较宽的区域上。
本发明的一个特征是,带压力的惰性气体的储存脉冲移动微粒,并以足够的力从装置里携带着它们进入组织或细胞。
本发明的一个优点是,该装置可接纳许多样本,而不象现有的设备只能接纳单个样本。
本发明的还有一个优点是,本装置送递的样本可以方便使用的方式进行准备,而且可方便地储存和握持。
本发明的其它目的,特征和优点可通过下面结合附图的说明而变得更加清楚。
附图的简要说明
图1是本发明的示意图;
图2是改变喷出口角度效果的示意图;
图3是本发明第一实施例的侧视图;
图4是图3所示实施例中的样本筒夹持器的前视图;
图5是图3所示实施例中的管状样本筒的侧视剖面图;
图6是质粒pWRG1602的图谱;
图7是本发明另一实施例的侧视图;
图8是图7所示实施例的部件分解图;
图9是图7所示实施例中的阀的横剖视图;
图10是图7所示实施例中的致动机构的横剖视图;
图11是可用于图3和7所示实施例的扩散器网屏的平面图。
较佳的实施例的详细说明
本发明提供可将包被遗传物质的微粒迅速地、可重复地连续送递活的靶组织和细胞的装置和方法。图1所示的是用来说明一种加速微粒送递遗传物质的设备的概括的操作方法示意图,该设备根据这里推荐的实施例的原理进行操作。为了清楚起见,图1所示的装置中的部件被分解为几个部分。该附图只是用来说明该装置的基本操作原理,而不是它的结构细节。
参看图1,载体微粒筒14位于装置的中间处。该微粒筒14是一凹入状的或管状的结构,有一凹入的中空通道朝向它的中心。在载体微粒筒内置有许多载体微粒16。载体微粒(下面将详细讨论)是小的致密的粒子,已预先包被可进入靶组织的生物材料,即DNA或RNA,以便进入靶生物体,也可在该微粒上包被其它类型的生物材料,例如肽、细胞素、激素或蛋白质。气阀18位于载体微粒筒的上游,并通过一适当的流体导管17连接在载体微粒筒14内。气阀通过一适当的管子13与压缩气源12连接。压缩气源12可以是一种普通的商业上的压缩气筒,最好装有惰性压缩气体,例如氦气。在气源12和气阀18之间可设一储存压缩气体的容器,但已经发现,管子13可用作储存容器。
载体微粒筒的右面是小孔20,它是流体通向加速室22的入口,而加速室终止于锥形的喷出口24。在图1中用标号19表示的被治疗患者、组织或细胞位于图的右侧。
其概括的操作过程是,气阀18主要用来放出储存在由管子13形成的容器里的压缩气体脉冲。在气阀18和喷出口24之间的中间部件形成微粒加速通道,通过该通道,先前在压力下的膨胀气体产生快速流动的气流。该气流加速通过微粒加速通道,当它通过微粒筒14内部时,加速的气流吸起载体微粒16,并由其携带。然后,加速的气体通过室22到达喷出口24。再后,微粒从装置进入患者19的组织,载体微粒只是进入,而不是杀死靶细胞或患者细胞。
图1所示装置的非常重要的特有功能是喷出口24的几何结构。其重要性的理由由图2示意说明,图2用方案A、B和C说明喷出口24三个不同的、可能的几何结构,以及它们对微粒16飞行的影响。在方案A中,喷出口24没有朝着装置的输出端显著地扩展。其结果是,喷出的气流呈直线状地离开喷出口24的端部,并继续直对着靶19行进。由此使载体微粒在一条相当直的途径上延续,并全部命中在图2中用标号25表示的、患者19的一个相当狭窄的区域。虽然微粒16略有扩散,但这种扩散是非常小的和不显著的。
同样地,在图2的方案B中,喷出口24有一个朝向装置输出端的、角度非常大的锥形。在这个实施例里,气流同样是完全直线状地从装置喷出,而载体微粒也不广泛地扩散。此外,微粒也只命中患者19的一个非常小的部位25。
如图2的方案C所示,假如锥形喷出口的锥角小于一临界角,那将产生不同的现象。在这个例子里,当加速的气流通过喷出口时,由于涡旋作用,在气流经过的路径和喷出口24的两侧之间会形成真空。该真空使气流沿着垂直于气流运动方向的所有方向被向外抽吸。换句话说,气流和微粒的扩散相对于微粒的运动方向来说是横向的,而该微粒的运动方向是从装置向着患者19。这样,如图2中的方案C所示,通过装置的气体在一个较宽的区域内横向扩散,从而由其携带的载体微粒16也在一个较宽的区域内扩散,因此如图2中的方案C所示,产生一个载体微粒较扩散的型式。其结果是,较之如果锥形喷出口不是这种形状将发生的情况而言,微粒被分布在靶组织的一个较宽的区域25上。这样,可避免在患者的任何一个小区域内出现超剂量的载体微粒,从而不需要机械地分配微粒或精心制作气体转向或分配装置就可获得相当宽的载体微粒的均匀分布。
锥形喷出口24的锥角的确切度数在不同的实施例里是不同的,它取决于所使用的气体压力和加速室22的大小。对于以商用氦气容器为动力工作的装置来说,当加速室22的直径是1/16英寸时,已发现具有从1/16英寸到2/3英寸与3.3英寸跨度之比的锥度的喷出口可以令人满意地喷射出直径从约1/16英寸到约2/3英寸的微粒分布形状,这样,其上喷射着微粒的面积增加100倍以上,而带来的结果是微粒分布的密度降低100倍以上。为了有效地工作,锥形喷出口在长度上较之它的初始或末端直径(例如,1/16到2/3英寸)而言必须足够长(例如,3.3英寸)。一个宽度大于长度的锥形结构不会使微粒适当地扩散。然而,锥形喷出口不必一定是光滑的圆锥形,例如,喷出口在直径上可以有几个小梯状的增加,而不是连续的增加,这对于它的综合功能没有负面影响。
通过改变气体的压力,使微粒命中靶19并进入其中的力可得到改变。气体压力必须足够高以便移动筒14里的包被微粒,但也不能太高从而伤害靶19。当送向无损伤的动物皮肤时,已发现气流不会损伤该皮肤。在较高的气体压力下,可使皮肤在容许水平上略微变红。已发现在商业上使用的压缩氦气容器里的气体压力完全可以分离微粒16,并将微粒16送入靶动物(如猪或鼠)的表皮细胞。在特定的情况下可使用较低的压力或较高的压力,这取决于微粒的密度,靶表面的性质,以及所需的微粒穿透深度。使用猪皮肤的经验类似于人们期待的用于人皮肤的经验,这是由于人皮肤和猪皮肤的基本相似性。
微粒筒14较佳的是锥形,但最好是管状,而微粒置于其内表面上,如果这样,就可不必接触载体微粒而方便地握住筒了。虽然微粒筒14可以有许多形状和几何结构,但一种简单的和有效的方案是立足于使用一小段惰性材料(如Tefzel)制成的管子。该管子形成一具有通过其中心的圆形通道的筒体。这种管状结构的优点是包被生物材料的载体微粒不会污染装置的壁。Tefzel材料的优点是它的透明,因此可用肉眼辨认装有东西的筒。这是通过辨认筒的外观而实现,这种筒将呈可见的金色,或具有可见的金色条纹。筒的内径只需大到可将微粒容纳其中,并容许压力高到足以移动微粒的足够气流通过其中。然而,筒14不必一定是管状的,而可以是任何凹入形状的,其中封闭着压力气体,这样,移动的微粒16不扩散,而是由气流携带着直接向着靶冲去。作为例子,筒14可以是半爿管子,其中,微粒16放置在半爿管子内,并由装置的平表面或不平表面严密复盖,从而形成一气体能通过其中的半圆筒状的通道。按照这些设计,样本筒和由装置表面形成的、被包围的室的几何结构不是要求严格的,只要将从储存器12来及向靶19去的两个方向的气流汇聚即可。
用任何高密度的生物惰性材料制成的、非常小的载体微粒16应可用作置放在样本筒表面的载体微粒。载体微粒16由致密物质制成,因此它们将容易地维持动量并且形状非常小,这样,相对于将要转化的组织细胞来说,它们是小的。已经发现,几微米大小的载体微粒可通过穿透细胞壁进入活细胞,且不会过度有害地影响大多数活细胞的生存能力。换句话说,载体微粒能进入活细胞且不会杀死它们,从而将微粒上的生物材料送入细胞。
在本发明中,金是微粒16最合适的材料,因为它密度高,对生物材料和氧化作用相对地不活跃,而且可方便地买到具有0.2到3微米直径的球形微粒。大小在1-3微米范围内的球形金微粒或小珠已被成功使用,就象具有0.2到3微大小的微晶粉末一样地被销售。
也可使用密度为19的钨。铱的密度是22,也可推荐使用,但申请人并未使用铱,因为可方便地买到的只有相对较粗的粉末。与金相比,钨大概也并不完全合乎需要,因为在空气中和在有少许水份的环境里它会被氧化。这样,载体微粒上的氧化层将与微粒粘结在一起,从而使微粒的平均大小急剧地增加。不规则聚集的微粒不合乎本发明的使用需要,因为这种聚集将使得微粒在质量和大小上相差悬殊,从而难以获得有规则的、可重复的结果。
图3所示的是按照本发明制造的微粒加速装置10的一个实施例的侧视图。所示的装置可手控并可携带,因此可由实验者、技术人员或门诊医生方便容易地握持和移动。
现详细介绍图3的装置,该装置包括手柄28,手柄28最好是细长的,并可制成任何合适的形状和大小,以满足装置实际使用者的需要和舒适。如图3所示,手柄28被制成手枪柄的形状,以便使用者能牢牢地握住,并可以通向一阀门起动机构30。
进气管32通过手柄28,其两端敞开,并由固体材料制成,它能储存装置使用的带压力的气体。进气管32、以及与带压力的气流接触的装置的所有其它部分(除样本筒之外)最好是用不易变形的固体材料制做,如金属、较佳的是黄铜、或高密度的热塑性或树脂材料。作储存器用的进气管32如上所述可释放地储存着足够的、在操作压力下的气体,以便完成一次加速的微粒送递。进气管32的大小不是很严格的,可以增加或减少以容纳足够的压力气体。如果进气管32的容量不够,可提供一个分开的专用气体储存器。
进气管32的一端是接头31,它可与外接气源12连接。气源可以是生物学和化学上惰性的压缩气体的商用容器。较佳的惰性气体是氦气。最好用一普通的压力调节阀来调节气源里存留气体的压力,并使该压力显示在操作者可见的一个压力计上。
进气管34的另一端连接着阀34,它可控制气体从进气管32向装置10的细长壳体33的流动。在图3的第一个实施例里,阀34是由在手柄28上的阀门起动机构30操纵的一个电动的螺线管活塞阀。最好将阀34和起动机构30之间的连线埋在手柄28内,以改进装置在使用时的安全性和可操纵性。本发明不限于所示阀的具体类型,或任何具体的致动或起动机构。许多阀和起动器的组合众所周知,但本技术领域的熟练人员可以替换这里所示的组合结构一如下面将介绍的第二实施例所提出的。许多阀和起动器的组合是合乎需要的,只要阀的活塞和阀体能承受从进气管32进入的气流的压力。
阀34的流体出口与筒夹持器36连通。在一较佳的实施例里,为了能方便地快速装入样本,提供了一个多筒夹持器36。为了能最大限度地增加样本的数量(这些样本可在装置使用前的一个步骤内预先装入),多筒夹持器呈圆筒形。圆筒形的筒夹持器36的前视图如图4所示。许多筒孔38以固定间隔沿圆筒形夹持器的半径成环形布置,各筒孔38的大小正好可容纳一个微粒筒14,这样,一个筒孔38在每次送递期间可位于气流内。夹持器36绕着它的辐射轴线转动360°。在筒夹持器36的外周面上有许多掣子40,各掣子与一凸点啮合后可使一孔38正好位于气体的通道上。通过提供一穿过细长壳体33的弹簧加压的凸块42可获得所述凸点,并使该凸点啮合在筒夹持器上。筒夹持器可采用其它的形式,以根据使用者的需要夹持或多或少的样本筒。筒夹持器36不一定是图示的圆筒形,但要使样本筒直线布置,从而可移入位置以接受通过阀34而来的气流。
壳体33里的中空微粒加速室44提供了一条朝向靶的通道,以供气流携带微粒之用。室44被制成直径1/16英寸,长度12到15毫米。如果室44太长,气流将因为摩擦而减慢。如图3中的虚线部分所显示的,中空室44的直径在其末端增大而形成喷出口46,从而允许吸入气流里的包被微粒充分扩散。在微粒加速室44的末端、喷出口46的前面是分隔器48,从而使操作者可在装置10和靶之间建立一个固定的距离。适当的距离可根据需要来确定和固定,而该需要建立在靶细胞表现的实验观察和送递后基因表达程度的基础上。已经发现,对哺乳动物皮肤使用3/4到1英寸的分隔器较好。还发现,室44内部磨光有利于装置10的操作。这可通过涂一层带磨光化合物的管子清洁剂来做到,利用它来磨光室44内部。这样可减少室44侧面的磨擦和相互影响,从而有利于载体微粒流向预定的目标。喷出口46也可类似地磨光。已经发现,通过提供适当的分隔器以限制气流流过阀34之后和到达室44起点之前的这一区域是有利的,这将在下面参考图7所示的实施例进行详细介绍。
携带有包被微粒的、大量有用的样本筒14(如图5所示)如下所述可以许多不同的方法在单一工序内备妥。两种不同的方法已被成功地使用。
在第一种方法里,将用众所周知的方法制备的生物材料包被的微粒悬浮液引入一长的塑料管内,而微粒在重力的作用下沉淀在管内表面的底部。当微粒沉淀后,在全长管子上形成一条微粒带,流体从管内流出,转动管子,当在氮气的作用下它们被干燥时就在内表面上布满小珠。然后将管子切成适当的长度并插入送递装置的样本室里。本技术领域的熟练人员将知道,通过调整微粒悬浮液的浓度,或通过调整用来形成一样本筒的管子长度可以改变适于转移的包被微粒的数量,熟练人员还将知道,用于本发明的样本筒还可通过不同于上述的其它方式来准备。本技术领域的熟练人员熟悉于用其它的方法将包被样本的微粒固定在一表面上。
第二种方法是利用轻微粘结的方式将载体微粒16固定在微粒筒14内。已经发现,这种通过将它们暂时粘附在微粒筒14的内部凹入表面上直到气流出现并充满压力的方法,有助于保证微粒得到较好的加速。为了使用这种方法,当微粒在酒精里悬浮时使用一种添加剂。只会轻微粘结并已成功使用的添加剂是聚乙烯吡咯烷酮(PVP)、胆固醇、丙三醇和水。例如,在悬浮液里,可以每毫升酒精1克胆固醇的比例使用胆固醇。微粒/酒精悬浮液经超声处理以促进悬浮,然后将该悬浮液放入就在它一侧的微粒筒14内。载体微粒沿着微粒筒内表面的一侧迅速地不再悬浮。然后当转动管子时利用氮气流可除去酒精并干燥微粒筒的内部。
图7和8所示的是按照本发明制造的微粒加速装置的另一实施例。在图7和8所示的装置110里,具有与图3所示实施例部件类似或相应功能的部件用相同的标号加100表示。例如,图7所示实施例中的手柄128和起动器130表示类似于图3所示实施例中的手柄28和起动器30。在图7所示的装置110里,用来释放气体脉冲的阀134由一流体致动系统操纵,而该系统在上述实施例中使用的是螺线管。阀134通过流体导管160与起动器130连接。
在图8所示的部件分解图中,可见到图7所示装置内的其它部件。阀门件151旋入阀134壳体的端部。该阀件包括一螺旋接头152,从其上延伸出一根安装着偏压弹簧的轴154,轴154的一端安装着阀件156。一具有约50微米开口的毛细管或氦气排放管158延伸通过阀134,以便连续地低水平地排放氦气通过装置110。管子160使阀134的左侧与致动块162连接。起动器/柱塞164安装在致动块162内。垫片166和接头168用来连接阀134和圆柱形壳体133。垫片166有一个约1/4英寸的内通孔,以限制来自阀134而进入其中的气流量。在气体通道进入圆柱体133的这一点处设一约0.11英寸的进口,这样,当膨胀的气体通过筒夹持器136时将被加速。另外,圆柱形壳体133和筒夹持器136类似于图3所示的实施例,只是筒夹持器136安装在圆柱形壳体133的顶部而不是底部。
阀134的细节如图9所示。类似于第一实施例中的进气管32的进气管132连接在阀的底部,并提供输入压力气体。当阀134在其正常的关闭状态时,阀件156抵顶着用标号170表示的锥形阀座。阀134的内腔呈圆筒172,它与阀件156密接,而不是与阀件156以流体密封方式接触。如图9所示,管子160在阀件156左侧的室处与阀134连接。
图10所示的是起动器162的细节。导孔174水平延伸进入致动块162,它只在致动块162的前侧敞口。三个垂直孔176、178和180从致动块162的顶部向下延伸,并与导孔174连通。垂直孔176的顶部被制成可接纳管子160另一端,而垂直孔178和180较小,并直接敞口与外界空气连通。限制销钉182延伸进入导孔174的封闭端,以限制起动器/柱塞164的移动,并且限制销钉包括一弹簧用以偏压柱塞处于图10所示的位置。柱塞164是一根细长轴,其上置有两个0型圈,它们与导孔174的内壁密封接触。轴延伸件186将在柱塞164一端的起动器按钮与在导孔174内的细长轴连在一起。
在使用装置10时,进气口131与高压气体、最好是氦气连通。毛细管158提供少量、低水平的氦气泄放或排放,使它们通过阀134并进入圆柱形壳体133,从而使氦气涌入喷出口146。这时,氦气是在喷出口146内、以及在喷出口和靶之间起主要作用的气体,即使在装置进行工作之前。在这个区域内的氦气对载体微粒的流动提供较低的拖动作用,并与装置110较一致地工作。
如图9所示,阀件156抵顶着阀座170。阀134的整个内腔通过管子160与在致动块162内的垂直孔176连通。只要柱塞164在图10所示的位置上,孔176的下端就被O型圈184密封,气体就不可能通过这条路线出去。当使用者揿压起动器/柱塞164时,由于抵抗住在限制销钉182上的弹簧的力,使O形圈移到孔176底端的左侧。从而允许孔176里的气体通过孔180排放到大气里。这种排放具有降低在阀件156左侧的压力的效果。室172的壁阻止不受约束的流体流向阀134的左侧,这样,作用在阀件156右侧的压力将高于作用在其左侧的压力。弹簧154被挤压,这个压力差足以将阀件156压向图9所示的左侧,使阀体156与阀座170分离,打开了高压气体流,使其通过微粒筒进入圆柱形壳体133。这种状况将持续至起动器被释放,此后起动器/柱塞164仍回到图10所示的位置,并密封住孔176的底端。这样将使阀134的左侧恢复高压,使阀件156复位并抵顶着阀座170,从而阻止气流通过阀134。
在阀134后面,装置维持着一个相对稳定的区域以供给一个气流单元,直到约束居先进入微粒筒。垫片166安装在接头168和阀座170之间的空间左侧处,只是通过垫片166的中心孔在直径上大致等于通过圆柱形壳体133的孔的直径。这里的设计思想是,将气体膨胀的区域限制在1/4英寸的孔内,直至它到达通向筒夹持器的0.11英寸的进气口。
有证据说明,在装置10的输出端(在图7所示的右端)安装扩散器将有助于提高基因送递的效率。两个这样的扩散器如图11所示,并分别用标号190和191标示。各扩散器包括一圆环及利用金属丝194和195分别悬置在中央位置处的网屏192和193。扩散器用来有选择地挡住一部分来自中心的小珠,以便较均匀地将载体微粒分布在靶区上。
这里所述的装置可方便地使用遗传疫苗对人或驯养动物进行大批接种。遗传疫苗由遗传物质(通常是DNA)组成,它们取自病原制剂,然后利用类似这里所述的装置将其送入生物体的活细胞内。一旦进入细胞,利用细胞转录和翻译机制使遗传物质表达产生蛋白质或肽,它们在生物体内部产生免疫应答,该免疫应答使动物和人能利用制剂(遗传物质来自于它)抵抗以后的感染。这种装置还可用于基因治疗,以便将基因送递缺少它但又需要它的生物体。换句话说,将这种遗传物质稳定地整合在基因缺陷的生物体的遣传物质里是可能的,这样做至少在某些体细胞内可校正遗传缺陷。
虽然这里描述的装置被设计成用于大规模地,反复地送递遗传疫苗,但也可以相同的方式,即现有的微料加速装置用于单一送递方法,它包括(但并不限于)将遗传物质转移入植物和动物的器官、组织和培养的细胞。这种装置已成功地用来送递基因进入存活的植物的分生组织以产生转基因植物。此装置的所有优点,特别是它的轻便性和容易放置样本,在装置通过微粒加速一次发射送递基因时同样有利。然而,本发明的原理也可应用于一固定的、不可携带的设备里,并在速度、复验性和易使用方面具有实质性的优点。
实施例
1.质粒
如图6所示的质粒pWRG 1602图谱,人巨细胞病毒(hcMV)立即早期启动子指导人生长激素(hGH)基因的表达。人生长激素包被顺序包含在一约2.2千碱基对(Kbp)的XbaI-Eco RI片段中,该片段来自质粒pGH(Nichols研究所)。在第五卷EMBO杂志1367-1371页(1986)上描述的人巨细胞病毒立即早期启动子包含在一619碱基对的Acc II片段中,该片段包括巨细胞病毒立即早期转录起始区的522碱基对上游至96碱基对下游的区域。质粒DNA按标准的分子生物学技术制备。
2.
制备DNA包被微粒
然后,将pWRG1602质粒的拷贝包被在金载体微粒上。将26mg沉淀的金粉(0.95微米平均直径)与200μl含0.1M亚精胺的25μg的DNA混合。DNA与金粉的比例是每mg金粉2.5μg DNA。然后,将200μl的2.5M氯化钙溶液加入混合物中,并不断地搅拌,此后将该样本在室温下静置10分钟,以使DNA沉淀在载体微粒上。用一微型离心机将混合物离心3秒钟,以聚集带有DNA的载体微粒,然后用酒精温和地清洗载体微粒,并在一有3ml酒精的加盖小瓶里让其重新悬浮。通过将小瓶浸入一超声波水池里几秒钟以利于酒精中载体微粒的重新悬浮。
3.
将包被微粒送递动物细胞
将麻醉的鼠夹紧,并除去靶区大部分软毛。转化作用将在动物的这个裸露区域进行。
将准备好的样本筒放入本发明的装置内,进行实验室试验。在第一次试验时,输入不同压力的压缩气体,以确定基因送递的有效气体压力。为了测定处理的效果,处理后24小时,切下靶皮肤并使其均浆化。利用普通的ELISA测定法对各样本中的人生长激素(hGH)水平进行定量。表1显示由鼠表皮每一送递区域的转化细胞产生人生长激素(hGH)的近似量。
表1
鼠 | 压力 | 输送区域 | 数量 |
A | 500psi | 1 | 40ng |
2 | 22ng | ||
700psi | 1 | 59ng | |
2 | 140ng | ||
B | 500psi | 1 | 40ng |
2 | 38ng | ||
300psi | 1 | 75ng | |
2 | 50ng |
在一种用来测定hGH蛋白表达的试验里,将用所述方式准备的另一个pWRG1602样本筒放入装置里,并将包被微粒在500psi的压力下体内送递入用外科术暴露的鼠肝内。当在送递后24小时检查肝和血浆时,两者都表现出低水平的hHG,分别是基础水平的三倍和两倍。
准备一组样本筒,每只筒含有总量约0.5毫克金和DNA。将这些筒放入装置里,使微粒在不同的压力下进入麻醉的猪表皮。在微粒送递前皮肤未做预处理。在处理后24小时时,切下处理过的皮肤块并且ELISA测定法测定hGH。在650psi压力下,送递区有几处显示红斑。显示最少红斑的一处中,测得937ng hGH。在800psi压力下,大多数区域显示出红斑,在显示最少红斑的区域里测得412ng hGH。在1100psi压力下,任何送递区域里测不出hGH,且在这个送递压力下全部显示出显著的红斑。
Claims (16)
1.一种基因送递装置(10,110),可与一压缩气体源(12)连接,该装置包括:
一壳体(33,133),它具有一在其内形成的微粒加速通道(22,44,144),并且其一端敞口;
一阀(18,34,134),它可与所述压力气体源(12)连接,并有选择地将压缩气体导入微粒加速通道(22),形成一加速气流;
其特征在于,还包括:
至少一个筒孔(38),它具有在其内接纳微粒筒(14)的形状,而该筒孔内置有包被遗传物质的载体微粒(16),该筒孔位于所述壳体和微粒加速通道内,膨胀通过微粒加速通道的气流将通过毗连的筒孔,并从该筒孔吸起和加速载体微粒;以及
一锥形的喷出口(24,46,146),它位于壳体的微粒加速通道的敞口处,喷出口的圆锥形状是这样的:喷出口的锥形在气流方向上的长度较之垂直于气流方向的宽度要大,该锥形使从壳体输出的气流膨胀喷出,较之喷出口不是锥形的而言,其使载体微粒分布在一较宽的区域上。
2.如权利要求1所述的装置,其特征在于,还包括一筒夹持器(36,136),所述筒夹持器上形成有上述若干筒孔(38),所述筒夹持器可拆卸地安装在所述壳体上,并且任何一个筒孔可位于微粒加速通道内。
3.如权利要求2所述的装置,其特征在于,筒夹持器(36,136)是一可相对壳体(33,133)转动的圆柱体,使不同的筒孔(38)位于微粒加速通道(22,44,144)内。
4.如权利要求3所述的装置,其特征在于,有一将筒夹持器(36,136)固定在一位置的限制机构(40,42),在每个位置处,筒孔(38)之一位于微粒加速通道(22,44,144)内。
5.如权利要求1所述的装置,其特征在于,在装置的喷出口(46,146)的端部安装着一分隔器(48,148),以便使装置(10,110)和被处理的组织或活体之间间隔一预定的距离。
6.如权利要求1所述的装置,其特征在于,所述的压缩气体源是氦气。
7.如权利要求1所述的装置,其特征在于,加速通道(22,44,144)被磨成光滑。
8.如权利要求6所述的装置,其特征在于,在装置(110)工作前,有一延伸通过阀(134)的氦气排放管(158),以便将少量的氦气导入喷出口(146)。
9.如权利要求1所述的装置,其特征在于,还包括所述的微粒筒(14)。
10.如权利要求9所述的装置,其特征在于,在筒孔(38)后面的微粒加速通道内有一小孔,该小孔比微粒筒(14)内部凹入的直径小,有利于气流从微粒筒将微粒吸起并离开后对载体微粒(16)加速。
11.如权利要9或10所述的装置,其特征在于,所述筒孔(38)是圆筒形的,而微粒筒(14)是管状的,载体微粒(16)置于筒的内部。
12.一种与权利要求1至8之一所述的基因送递装置配合使用的筒(14),其特征在于,它包括一其中有弧线通道的、凹入的刚性体,包被遗传物质的载体微粒置于筒的通道内,从而由膨胀的气流通过该通道移动载体微粒,该筒可由使用者手工操作,且使用者不会接触到筒里的载体微粒。
13.如权利要求12所述的筒,其特征在于,所述筒(14)是管状的,一圆形通道延伸通过其中心。
14.如权利要求12所述的筒,其特征在于,所述载体微粒(16)是金微粒。
15.如权利要求12所述的筒,其特征在于,所述载体微粒(16)以直线方式沿着通道的轴线置于通道内。
16.一种与权利要求1至8之一所述的基因送递装置配合使用的筒(14),其特征在于,它包括一圆形的刚性管状体,一圆形通道形成于并通过其内部,包被遗传物质的载体微粒(16)置于筒的通道内,从而在膨胀的气流通过该通道时可移动该微粒,该筒可由使用者手工操作,且使用者不会接触到筒里的载体微粒。
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- 1995-01-20 DE DE69534348T patent/DE69534348T2/de not_active Expired - Lifetime
- 1995-01-20 EP EP02023522A patent/EP1293559B1/en not_active Expired - Lifetime
- 1995-01-20 ES ES02023522T patent/ES2247248T3/es not_active Expired - Lifetime
- 1995-01-20 EP EP95909280A patent/EP0690732B1/en not_active Expired - Lifetime
- 1995-01-20 EP EP05006089A patent/EP1550713A3/en not_active Withdrawn
- 1995-01-20 BR BR9505691A patent/BR9505691A/pt not_active IP Right Cessation
- 1995-01-20 AT AT02023522T patent/ATE300609T1/de active
- 1995-01-20 CA CA002501743A patent/CA2501743C/en not_active Expired - Lifetime
- 1995-01-20 CA CA002158733A patent/CA2158733C/en not_active Expired - Lifetime
- 1995-01-20 AT AT95909280T patent/ATE231733T1/de active
- 1995-01-20 CN CN95190197A patent/CN1112943C/zh not_active Expired - Lifetime
- 1995-01-20 ES ES95909280T patent/ES2192573T3/es not_active Expired - Lifetime
- 1995-01-20 WO PCT/US1995/000780 patent/WO1995019799A1/en active IP Right Grant
- 1995-01-20 DK DK02023522T patent/DK1293559T3/da active
- 1995-01-20 DE DE69529495T patent/DE69529495T2/de not_active Expired - Lifetime
- 1995-01-20 US US08/376,319 patent/US5584807A/en not_active Expired - Lifetime
- 1995-01-20 AU AU17295/95A patent/AU674815B2/en not_active Expired
- 1995-01-20 DK DK95909280T patent/DK0690732T3/da active
- 1995-01-20 NZ NZ279995A patent/NZ279995A/en not_active IP Right Cessation
- 1995-01-20 JP JP51966695A patent/JP3221683B2/ja not_active Expired - Lifetime
- 1995-01-20 RU RU95122697A patent/RU2134295C1/ru active
- 1995-01-20 PT PT95909280T patent/PT690732E/pt unknown
-
1996
- 1996-12-16 US US08/767,374 patent/US5865796A/en not_active Expired - Lifetime
-
1998
- 1998-12-24 HK HK98115316A patent/HK1013804A1/xx not_active IP Right Cessation
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105820942B (zh) * | 2016-05-24 | 2017-12-19 | 中国农业科学院棉花研究所 | 一种基因枪用活塞样品架 |
Also Published As
Publication number | Publication date |
---|---|
DE69529495D1 (de) | 2003-03-06 |
AU674815B2 (en) | 1997-01-09 |
CA2158733C (en) | 2007-01-16 |
EP1293559A1 (en) | 2003-03-19 |
JPH08509131A (ja) | 1996-10-01 |
AU1729595A (en) | 1995-08-08 |
DK1293559T3 (da) | 2005-11-28 |
CA2158733A1 (en) | 1995-07-27 |
EP1293559B1 (en) | 2005-07-27 |
HK1013804A1 (en) | 1999-09-10 |
CA2501743A1 (en) | 1995-07-27 |
CN1124460A (zh) | 1996-06-12 |
CA2501743C (en) | 2008-11-18 |
DK0690732T3 (da) | 2003-05-19 |
DE69534348D1 (de) | 2005-09-01 |
ES2192573T3 (es) | 2003-10-16 |
DE69534348T2 (de) | 2006-05-24 |
DE69529495T2 (de) | 2003-06-12 |
PT690732E (pt) | 2003-06-30 |
WO1995019799A1 (en) | 1995-07-27 |
EP0690732B1 (en) | 2003-01-29 |
EP1550713A2 (en) | 2005-07-06 |
ATE231733T1 (de) | 2003-02-15 |
EP0690732A4 (en) | 1996-06-12 |
JP3221683B2 (ja) | 2001-10-22 |
ATE300609T1 (de) | 2005-08-15 |
EP0690732A1 (en) | 1996-01-10 |
US5865796A (en) | 1999-02-02 |
US5584807A (en) | 1996-12-17 |
RU2134295C1 (ru) | 1999-08-10 |
EP1550713A3 (en) | 2007-09-12 |
NZ279995A (en) | 1998-04-27 |
ES2247248T3 (es) | 2006-03-01 |
BR9505691A (pt) | 1996-01-16 |
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