CN102482672B - 通过抑制唐氏综合征基因的天然反义转录物治疗唐氏综合征基因相关疾病 - Google Patents
通过抑制唐氏综合征基因的天然反义转录物治疗唐氏综合征基因相关疾病 Download PDFInfo
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Abstract
本发明涉及反义寡核苷酸,所述反义寡核苷酸尤其通过靶向唐氏综合征基因的天然反义多核苷酸来调节唐氏综合征基因的表达和/或功能。本发明还涉及这些反义寡核苷酸的鉴定及其在治疗与唐氏综合征基因表达有关的疾病和病症中的用途。
Description
发明领域
本申请要求2009年6月26日提交的美国临时专利申请61/220,747和2009年8月21日提交的美国临时专利申请号61/235,752的优先权,所述申请通过引用以其整体结合到本文中。
本发明的实施方案包括调节唐氏综合征(Dow Syndrome)基因和相关分子的表达和/或功能的寡核苷酸。
背景
DNA-RNA和RNA-RNA杂交对包括DNA复制、转录和翻译在内的核酸功能的许多方面均很重要。杂交对检测特定核酸或改变其表达的各种技术也很重要。例如,反义核苷酸通过与靶RNA杂交扰乱基因表达,从而干扰RNA剪接、转录、翻译和复制。反义DNA具有额外的特点是,DNA-RNA杂合体作为存在于大多数细胞类型中的核糖核酸酶H消化活性的底物。可将反义分子递送到细胞中,正如寡脱氧核苷酸(ODN)的情况,或可自内源基因将其表达为RNA分子。FDA最近批准了一种反义药物VITRAVENETM(用于治疗巨细胞病毒性视网膜炎),这反映了反义物具有治疗效用。
概述
在一个实施方案中,本发明提供通过使用靶向天然反义转录物的任何区域的反义寡核苷酸导致相应的有义基因上调而抑制天然反义转录物作用的方法。本文还预期可通过被视为属于本发明范围内的siRNA、核酶和小分子实现对天然反义转录物的抑制。
一个实施方案提供体内或体外调节患者细胞或组织中的唐氏综合征基因多核苷酸的功能和/或表达的方法,所述方法包括将所述细胞或组织与长度为5-30个核苷酸的反义寡核苷酸接触,从而体内或体外调节患者细胞或组织中的唐氏综合征基因多核苷酸的功能和/或表达,其中所述寡核苷酸与包含以下核苷酸内的5-30个连续核苷酸的多核苷酸的反向互补序列具有至少50%序列同一性:SEQ ID NO:3的1-3814、SEQ ID NO:4的1-633、SEQID NO:5的1-497和SEQ ID NO:6的1-545。
在另一个实施方案中,寡核苷酸靶向唐氏综合征基因多核苷酸的天然反义序列,例如SEQ ID NO:3-6所示核苷酸及其任何变体、等位基因、同源物、突变体、衍生物、片段和互补序列。反义寡核苷酸的实例如SEQ ID NO:7-24所示。
另一个实施方案提供体内或体外调节患者细胞或组织中的唐氏综合征基因多核苷酸的功能和/或表达的方法,所述方法包括将所述细胞或组织与长度为5-30个核苷酸的反义寡核苷酸接触,从而体内或体外调节患者细胞或组织中的唐氏综合征基因多核苷酸的功能和/或表达,其中所述寡核苷酸与唐氏综合征基因多核苷酸的反义序列的反向互补序列具有至少50%序列同一性。
另一个实施方案提供体内或体外调节患者细胞或组织中的唐氏综合征基因多核苷酸的功能和/或表达的方法,所述方法包括将所述细胞或组织与长度为5-30个核苷酸的反义寡核苷酸接触,从而体内或体外调节患者细胞或组织中的唐氏综合征基因多核苷酸的功能和/或表达,其中所述寡核苷酸与唐氏综合征基因反义多核苷酸的反义寡核苷酸具有至少50%序列同一性;。
在一个实施方案中,组合物包含一种或多种与有义和/或反义唐氏综合征基因多核苷酸结合的反义寡核苷酸。
在另一个实施方案中,所述寡核苷酸包含一种或多种修饰或取代核苷酸。
在另一个实施方案中,所述寡核苷酸包含一个或多个修饰键。
在又一个实施方案中,修饰核苷酸包含修饰碱基,其包含硫代磷酸酯、甲基膦酸酯、肽核酸、2’-O-甲基、氟-或碳、亚甲基或其它锁定核酸(LNA)分子。优选修饰核苷酸是锁定核酸分子,包括α-L-LNA。
在另一个实施方案中,将该寡核苷酸经皮下、肌内、静脉内或腹膜内给予患者。
在另一个实施方案中,寡核苷酸以药物组合物给予。治疗方案包括将反义化合物给予患者至少一次;然而,可对这种治疗进行修改以在一段时间内包括多个剂量。该治疗可与一种或多种其它治疗类型结合。
在另一个实施方案中,可将寡核苷酸包封在脂质体中或与载体分子(例如胆固醇、TAT肽)连接。
下文阐述其它方面。
附图简述
图1是实时PCR结果的柱状图,表示与对照相比,HepG2细胞用使用Lipofectamine2000引入的硫代磷酸酯寡核苷酸治疗后,DYRK1AmRNA的倍数变化+标准差。实时PCR结果表明,在用设计成DYRK1a反义Hs.713879(CUR-0885-CUR-0890)的寡核苷酸之一治疗后48小时,HepG2细胞中DYRK1A mRNA的水平显著提高。表示为CUR-0891、CUR-0892、CUR-0893、CUR-0885、CUR-0889、CUR-0889、CUR-0886、CUR-0888和CUR-0590的条形柱分别相当于用SEQ IDNO:7-15治疗的样品。
图2是实时PCR结果的柱状图,表示与对照相比,用使用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸治疗Vero细胞后,DYRK1A mRNA的倍数变化+标准差。实时PCR结果表明,用设计为DYRK1A反义Hs.713879的寡核苷酸之一治疗后48小时,Vero细胞中的DYRK1AmRNA的水平显著提高。表示为CUR-0889的条形柱相当于用SEQ ID NO:11治疗的样品。
图3是实时PCR结果的柱状图,表示与对照相比,用使用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸治疗HepG2细胞后DSCR1 mRNA的倍数变化+标准差。表示为CUR-0902、CUR-0901、CUR-0900、CUR-0899、CUR-0905、CUR-0906、CUR-0904和CUR-0907的条形柱分别相当于用SEQ ID NO:16-23治疗的样品。
图4是实时PCR结果的柱状图,表示与对照相比,用使用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸治疗Vero细胞后DSCR1 mRNA的倍数变化+标准差。表示为CUR-0907和CUR-0904的条形柱分别相当于用SEQ ID NO:23和22治疗的样品。
序列表描述
SEQ ID NO:1:人(Homo sapiens)双重特异性酪氨酸-(Y)-磷酸化调节激酶1A(DYRK1A),转录物变体3,mRNA(NCBI登录号:NM_101395)。
SEQ ID NO:2:人钙调磷酸酶调节子1(RCAN1),转录物变体1,mRNA(NCBI登录号:NM_004414)。
SEQ ID NO:3-6:SEQ ID NO:3:天然DYRK1A反义序列(Hs.713879);SEQ ID NO:4:天然DYRK1A反义序列(Hs.624346);SEQ ID NO:5:天然DSCR1反义序列(Hs.664668)和SEQID NO:6:天然DSCR1反义序列(DA403464)
SEQ ID NO:7-24:反义寡核苷酸。‘r’表示RNA,*表示硫代磷酸酯键。
详述
下面参照用于说明的实例应用来描述本发明的几个方面。应当理解的是,本文给出许多具体细节、关系和方法以供全面理解本发明。然而,相关领域普通技术人员应易了解的是,不需要一个或多个具体细节或者用其它方法便可实施本发明。本发明不受行动或事件的顺序的限制,因为某些行动可以不同顺序发生和/或与其它行动或事件同时发生。此外,并不是所有列举的行动或事件都是实施本发明的方法所必需的。
本文公开的所有基因、基因名称和基因产物旨在与本文公开的组合物和方法适用的任何物种的同源物相对应。因此,所述术语包括但不限于人和小鼠的基因和基因产物。要理解的是,当公开特定物种的基因或基因产物时,这种公开旨在只是示例性的,不得解释为限制,除非在其出现的上下文中有明确说明。因此,例如,对于本文公开的基因,其在某些实施方案中涉及哺乳动物核酸和氨基酸序列,旨在包括其它动物(包括但不限于其它哺乳类、鱼类、两栖类、爬行类和鸟类)的同源和/或直系同源的基因和基因产物。在实施方案中,基因或核酸序列为人的基因或核酸序列。
定义
本文使用的术语仅用于描述具体实施方案的目的,并无意限制本发明。本文使用的单数形式还旨在包括复数形式,除非上下文中另有明确说明。此外,就用于发明详述和/或权利要求书的术语“包括”、“具有”、“有”或其变体而言,这类术语旨在以类似术语“包含”的方式是包括性的。
术语“约”或“大约”意指在由本领域普通技术人员测定的特定值的可接受的误差范围内,这部分取决于该值是如何测量或确定的,即测量系统的局限。例如,“约”可指根据本领域实践在1或超过1的标准差内。或者,“约”可意味着给定值的高达20%、优选高达10%、更优选高达5%、还更优选高达1%的范围。或者,特别对于生物系统或过程,该术语可指在数值的数量级范围内,优选5倍以内,更优选2倍以内。在本申请和权利要求书中描述特定值时,除非另有说明,否则应假定术语“约”的含义在该特定值的可接受的误差范围内。
本文所用术语“mRNA”是指目前已知的靶基因的mRNA转录物和可以阐明的任何其它转录物。
“反义寡核苷酸”或“反义化合物”是指与另外的RNA或DNA(靶RNA、DNA)结合的RNA或DNA分子。例如,如果是RNA寡核苷酸,则其通过RNA-RNA相互作用与另外的RNA靶标结合,并改变靶RNA的活性。反义寡核苷酸可上调或下调特定多核苷酸的表达和/或功能。该定义意在包括从治疗、诊断或其它观点来看是有用的任何外源RNA或DNA分子。这类分子包括例如反义RNA或DNA分子、干扰RNA(RNAi)、微小RNA、诱骗RNA(decoy RNA)分子、siRNA、酶RNA(enzymatic RNA)、治疗性编辑RNA(therapeutic editing RNA)及激动剂RNA和拮抗剂RNA、反义寡聚化合物、反义寡核苷酸、外部指导序列(EGS)寡核苷酸、可变剪接体(alternatesplicer)、引物、探针和与靶核酸的至少一部分杂交的其它寡聚化合物。因此,可以单链、双链、部分单链或环状寡聚化合物的形式引入这些化合物。
在本发明的情况下,术语“寡核苷酸”是指核糖核酸(RNA)或脱氧核糖核酸(DNA)或其模拟物的寡聚体或多聚体。术语“寡核苷酸”还包括天然和/或修饰单体或键的线性或环状寡聚体,所述单体或键包括脱氧核糖核苷、核糖核苷、其取代和α-异头形式、肽核酸(PNA)、锁定核酸(LNA)、硫代磷酸酯、甲基膦酸酯等。通过单体与单体相互作用的常规方式,例如Watson-Crick型碱基配对、型或反向型碱基配对等,寡核苷酸能够与靶多核苷酸特异性结合。
寡核苷酸可以是“嵌合的”,也就是说由不同区(region)组成。在本发明的情况下,“嵌合”化合物是含有两个或更多个化学区(例如DNA区、RNA区、PNA区等)的寡核苷酸。每个化学区由至少一个单体单元(即在寡核苷酸化合物的情况下为核苷酸)组成。这些寡核苷酸通常包含至少一个区,其中寡核苷酸被修饰以具有一种或多种所需性质。寡核苷酸的所需性质包括但不限于例如对核酸酶降解的抗性提高、细胞摄取提高和/或对靶核酸的结合亲合力提高。因此,寡核苷酸的不同区可具有不同的性质。可以上述两种或更多种寡核苷酸、修饰寡核苷酸、寡核苷和/或寡核苷酸类似物的混合结构形成本发明的嵌合寡核苷酸。
寡核苷酸可由以“登记簿(register)”方式连接(也就是说单体像在天然DNA中一样连续连接)或通过间隔区连接的区组成。间隔区旨在构成区之间的共价“桥”,在某些情况下长度不超过约100个碳原子。间隔区可携带不同的官能,例如具有正电荷或负电荷、携带特殊的核酸结合性质(嵌入剂、沟结合剂(groove binder)、毒素、荧光团等)、具有亲脂性、诱导特殊的二级结构,例如诱导α-螺旋的含丙氨酸的肽。
本文使用的“唐氏综合征基因”包括所有的家族成员、突变体、等位基因、片段、种类(species)、编码和非编码序列、有义和反义多核苷酸链等。
本文所用术语‘双重特异性酪氨酸磷酸化调节激酶1A’、‘双重特异性YAK1相关激酶’、DYRK、DYRK1、hMNB、HP86、MNB、MNBH和蛋白激酶minibrain同源物,在文献中被视为相同的,在本申请中可互换使用。
本文所用术语DSCR1、唐氏综合征关键区基因1、RCAN1钙调磷酸酶调节子1、Adapt78、ADAPT78、Calcipressin-1、CSP1、DSC1、MCIP1、肌细胞富含的钙调磷酸酶相互作用蛋白1(Myocyte-enriched calcineurin-interacting protein 1)、RCN 1和钙调磷酸酶调节子1在文献中被视为是相同的,在本申请中可互换使用。
本文所用术语“对……有特异性的寡核苷酸”或“靶向……的寡核苷酸”是指具有以下序列的寡核苷酸:(i)能够与靶基因的一部分形成稳定复合体,或(ii)能够与靶基因的mRNA转录物的一部分形成稳定双链体。复合体和双链体的稳定性可通过理论计算和/或体外测定来确定。下面的实施例中描述了测定杂交复合体和双链体的稳定性的示例性测定。
本文所用术语“靶核酸”包括DNA、由这类DNA转录的RNA(包括前mRNA和mRNA)以及来源于这类RNA的cDNA、编码序列、非编码序列、有义或反义多核苷酸。寡聚化合物与其靶核酸的特异性杂交干扰该核酸的正常功能。这种通过与靶核酸特异性杂交的化合物对靶核酸功能的调节通常称为“反义”。被干扰的DNA的功能包括例如复制和转录。被干扰的RNA的功能包括所有重要功能,例如RNA转运到蛋白质翻译位点、由RNA翻译蛋白质、剪接RNA得到一种或多种mRNA物类,以及RNA可参与或促进的催化活性。这种干扰靶核酸功能的总体效果是调节编码产物或寡核苷酸的表达。
RNA干扰“RNAi”由与其“靶”核酸序列具有序列特异同源性的双链RNA(dsRNA)分子介导。在本发明的某些实施方案中,介体是5-25核苷酸的“小干扰”RNA双链体(siRNA)。通过称为切酶的RNA酶加工dsRNA得到siRNA。siRNA双链体产物被募集到称为RISC(RNA诱导沉默复合体)的多蛋白siRNA复合体中。虽然不希望受任何特定理论的束缚,但认为RISC被引导至靶核酸(适宜为mRNA),其中siRNA双链体以序列特异性方式相互作用而介导催化方式的切割。可按照本发明使用的小干扰RNA,可根据本领域众所周知且本领域普通技术人员熟悉的方法合成并使用。用于本发明方法的小干扰RNA适宜包含约1-约50个核苷酸(nt)。在非限制性实施方案的实例中,siRNA可包含约5-约40nt、约5-约30nt、约10-约30nt、约15-约25nt或约20-25个核苷酸。
通过应用自动比对核酸序列并指明同一性或同源性区的计算机程序,有助于合适寡核苷酸的选择。例如,通过检索数据库(例如GenBank)或通过对PCR产物测序,运用这类程序比较所得到的核酸序列。比较一系列物种的核酸序列可供选出物种间具有适当同一性程度的核酸序列。在未测序的基因的情况下,进行DNA印迹可供确定靶物种和其它物种基因之间的同一性程度。通过在本领域众所周知的不同严格程度下进行DNA印迹,可得到同一性的近似测量。这些方法可供选择与待受控制的受试者的靶核酸序列具有高度互补性而与其它物种的相应核酸序列具有较低程度互补性的寡核苷酸。本领域技术人员应了解的是,在选择用于本发明的合适基因区时有相当的自由。
“酶RNA”是指具有酶促活性的RNA分子。酶核酸(核酶)通过首先与靶RNA结合而起作用。这种结合通过酶核酸的靶结合部分发生,所述酶核酸的靶结合部分与起切割靶RNA的作用的该分子的酶促部分保持得十分靠近。因此,酶核酸首先识别,随后通过碱基配对结合靶RNA,并且一旦与正确位点结合,便起酶的作用切割靶RNA。
所谓“诱骗RNA”是指模拟配体的天然结合结构域的RNA分子。因此,诱骗RNA与天然结合靶标竞争结合特定的配体。例如,已表明,HIV反式激活反应(TAR)RNA过表达可用作“诱饵”,并且有效结合HIVtat蛋白,从而防止其与HIV RNA中编码的TAR序列结合。这意指具体实例。本领域技术人员应了解,这不过是一个实例,可采用本领域广为人知的技术容易地产生其它实施方案。
本文所用术语“单体”通常表示通过磷酸二酯键或其类似物连接形成大小从几个单体单元(例如约3-4个)到约数百个单体单元的寡核苷酸的单体。磷酸二酯键的类似物包括:硫代磷酸酯、二硫代磷酸酯、甲基膦酸酯、硒代磷酸酯(phosphoroselenoate)、氨基磷酸酯等,如下文更全面的描述。
术语“核苷酸”包括天然存在的核苷酸以及非天然存在的核苷酸。本领域技术人员应当清楚的是,后来在自然界中发现了之前被视为“非天然存在”的各种核苷酸。因此,“核苷酸”不仅包括已知含有嘌呤和嘧啶杂环的分子,而且还包括其杂环类似物及互变异构体。其它核苷酸类型的说明性实例是含有以下的分子:腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶、尿嘧啶、嘌呤、黄嘌呤、二氨基嘌呤、8-氧代-N6-甲基腺嘌呤、7-脱氮黄嘌呤、7-脱氮鸟嘌呤、N4,N4-亚乙基胞嘧啶、N6,N6-亚乙基-2,6-二氨基嘌呤、5-甲基胞嘧啶、5-(C3-C6)-炔基胞嘧啶、5-氟尿嘧啶、5-溴尿嘧啶、假异胞嘧啶(pseudoisocytosine)、2-羟基-5-甲基-4-三唑并吡啶、异胞嘧啶(isocytosine)、异鸟嘌呤、肌苷和美国专利申请号5,432,272中描述的“非天然存在的”核苷酸。术语“核苷酸”意在包括全部的实例及其类似物和互变异构体。尤其引人关注的核苷酸是含有腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶和尿嘧啶的核苷酸,它们被认为是与人的治疗和诊断应用有关的天然存在的核苷酸。核苷酸包含天然2′-脱氧和2′-羟基糖(例如Kornberg和Baker,DNA Replication,第二版(Freeman,San Francisco,1992)所述)以及它们的类似物。
提及核苷酸时的“类似物”包括具有修饰碱基部分和/或修饰糖部分的合成核苷酸。这种类似物包括设计成提高结合性质(例如双链体或三链体稳定性、特异性等)的合成核苷酸。
本文使用的“杂交”是指寡聚化合物的大致互补链的配对。配对的一种机制包括氢键结合,其可以是寡聚化合物链的互补核苷或核苷酸碱基(核苷酸)之间的Watson-Crick、或反向氢键结合。例如,腺嘌呤和胸腺嘧啶是通过形成氢键而配对的互补核苷酸。杂交可在不同的情况中发生。
当反义化合物与靶核酸的结合干扰靶核酸的正常功能以产生功能和/或活性的调节,并存在足够程度的互补性以避免在需要特异性结合的条件下(即在体内测定或治疗性治疗情况中的生理条件和体外测定情况中进行测定的条件下)该反义化合物非特异性结合非靶核酸序列时,反义化合物是“可特异性杂交的”。
本文所用表述“严格杂交条件”或“严格条件”是指本发明的化合物可与其靶序列杂交,但只与最低限度的其它序列杂交的条件。严格条件是序列依赖性的,在不同的环境下不同,而在本发明的情况下,寡聚化合物与靶序列杂交的“严格条件”通过寡聚化合物的性质和组成以及对其进行研究的测定法来确定。通常,严格杂交条件包括低浓度(<0.15M)的含Na++或K++等无机阳离子的盐(即低离子强度)、温度高于20℃-25℃却低于寡聚化合物:靶序列复合体的Tm,和存在变性剂,例如甲酰胺、二甲基甲酰胺、二甲亚砜或去污剂十二烷基硫酸钠(SDS)。例如,对于每1%的甲酰胺,杂交率降低1.1%。高严格杂交条件的实例是0.1X氯化钠-柠檬酸钠缓冲液(SSC)/0.1%(w/v)SDS在60℃下为时30分钟。
本文所用“互补的”是指在一条或两条寡聚链上的两个核苷酸之间精确配对的能力。例如,如果反义化合物某一位置上的核碱基(nucleobase)能够与靶核酸(所述靶核酸是DNA、RNA或寡核苷酸分子)某一位置上的核碱基发生氢键结合,则认为寡核苷酸和靶核酸之间的氢键结合位置是互补位置。当每个分子中足够数目的互补位置被可相互发生氢键结合的核苷酸占据时,寡聚化合物和其它DNA、RNA或寡核苷酸分子彼此互补。因此,“可特异性杂交的”和“互补的”两个术语用来表明在足够数量的核苷酸内足以使寡聚化合物和靶核酸之间发生稳定的特异性结合的精确配对程度或互补性。
本领域认识到,寡聚化合物序列不必与其可特异性杂交的靶核酸序列100%互补。此外,寡核苷酸可越过一个或多个区段杂交,使得间插或相邻区段不参与杂交事件(例如环结构、错配或发夹结构)。本发明寡聚化合物与其靶向的靶核酸序列内的靶区具有至少约70%、或至少约75%、或至少约80%、或至少约85%、或至少约90%、或至少约95%、或至少约99%的序列互补性。例如,反义化合物中18/20的核苷酸与靶区互补并因此与之特异性杂交的反义化合物可呈90%互补性。在该实例中,剩余的非互补核苷酸可集簇或散布在互补核苷酸之间,不必彼此邻接或与互补核苷酸邻接。同样地,长度为18个核苷酸且具有两侧是与靶核酸完全互补的两个区的4(四)个非互补核苷酸的反义化合物与靶核酸具有77.8%的总体互补性,并因此落入本发明的范围内。反义化合物与靶核酸的区的互补性百分比可利用本领域已知的BLAST程序(基础局部比对检索工具(basic local alignment searchtools))和PowerBLAST程序按常规测定。同源性、序列同一性或互补性百分比可通过例如Gap程序(Wisconsin Sequence Analysis Package,Unix版本第8版,Genetics ComputerGroup,University Research Park,Madison Wis)使用默认设置测定,该程序利用Smith和Waterman的算法(Adv.Appl.Math.,(1981)2,482-489)。
本文所用术语“热解链温度(Tm)”是指在规定的离子强度、pH和核酸浓度下,与靶序列互补的寡核苷酸有50%与靶序列杂交达到平衡的温度。严格条件通常是指其中盐浓度在pH 7.0-8.3下为至少约0.01-1.0M Na离子浓度(或其它盐),温度对于短寡核苷酸(例如10-50个核苷酸)为至少约30℃的条件。严格条件也可以加入去稳定剂(例如甲酰胺)的方式实现。
本文所用“调节”是指提高(刺激)或降低(抑制)基因的表达。
术语“变体”当在多核苷酸序列情况下使用时,可包括与野生型基因有关的多核苷酸序列。该定义也可包括例如“等位”变体、“剪接”变体、“物种”变体或“多态”变体。剪接变体可与参比分子具有显著同一性,但通常由于mRNA加工过程中外显子的可变剪接而具有更多或更少量的多核苷酸。相应多肽可具有另外的功能域或缺乏结构域。物种变体是指物种彼此不同的多核苷酸序列。本发明特别利用了野生型基因产物的变体。变体在核酸序列中可产生至少一个突变,并可导致产生改变的mRNA或者其结构或功能可能改变或不改变的多肽。任何给定的天然或重组基因可具有0、1或多个等位形式。产生变体的常见突变一般归因于核苷酸的天然缺失、添加或取代。这些变化类型的每一种可在给定序列中单独发生或与其它变化联合发生一次或多次。
所得多肽通常相互之间具有显著的氨基酸同一性。多态变体是给定物种的个体之间特定基因的多核苷酸序列的变异。多态变体还可包括“单核苷酸多态性”(SNP)或单个碱基突变,其中多核苷酸序列因一个碱基而不同。SNP的存在可表明例如某群体具有疾病状态的倾向,即易感性与抗性。
衍生多核苷酸包括经过化学修饰的核酸,例如氢被烷基、酰基或氨基置换。衍生物(例如衍生寡核苷酸)可包括非天然存在的部分,例如改变的糖部分或糖间键。这其中的实例是硫代磷酸酯和本领域已知的其它含硫种类。衍生核酸还可含有标签,包括放射性核苷酸、酶、荧光剂、化学发光剂、显色剂、底物、辅因子、抑制剂、磁性颗粒等。
“衍生”多肽或“衍生”肽是经过以下修饰的多肽或肽:例如通过糖基化、聚乙二醇化、磷酸化、硫酸化、还原/烷化、酰化、化学偶联或温和福尔马林处理。衍生物也可被修饰以含有可直接或间接检测的标记,包括但不限于放射性同位素标记、荧光标记和酶标记。
本文所用术语“动物”或“患者”意在包括例如人、绵羊、麋鹿、鹿、长耳鹿、水貂、哺乳动物、猴、马、牛、猪、山羊、狗、猫、大鼠、小鼠、禽、鸡、爬行动物、鱼类、昆虫和蜘蛛。
“哺乳动物”涵盖通常处在医疗护理下的温血哺乳动物(例如人和驯养动物)。实例包括猫、犬、马、牛和人,以及仅仅是人。
“治疗”涵盖治疗哺乳动物的疾病状态,包括:(a)预防在哺乳动物中发生该疾病状态,尤其是该哺乳动物易患该疾病状态但尚未确诊患病时;(b)抑制该疾病状态,例如抑制其进展;和/或(c)减轻该疾病状态,例如引起该疾病状态消退直到达到所需终点。治疗还包括改善疾病的症状(例如减少疼痛或不适),其中这种改善可直接影响或不影响该疾病(例如病因、传播、表达等)。
本文所用“癌症”是指哺乳动物中存在的所有类型的癌症或肿瘤或恶性肿瘤,包括但不限于:白血病、淋巴瘤、黑素瘤、癌和肉瘤。癌症自身表现为“肿瘤”或包含癌症恶性细胞的组织。肿瘤实例包括肉瘤和癌,例如但不限于:纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因瘤(Ewing′s tumor)、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝细胞瘤、胆管癌、绒膜癌、精原细胞瘤、胚胎癌、维尔姆斯瘤(Wilms′tumor)、宫颈癌、睾丸瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤、黑素瘤、神经母细胞瘤和视网膜母细胞瘤。可通过所公开的本发明的组合物治疗的其它癌症包括但不限于例如霍奇金病(Hodgkin′s Disease)、非霍奇金淋巴瘤、多发性骨髓瘤、神经母细胞瘤、乳腺癌、卵巢癌、肺癌、横纹肌肉瘤、原发性血小板增多症、原发性巨球蛋白血症、小细胞肺瘤、原发性脑瘤、胃癌、结肠癌、恶性胰岛瘤、恶性类癌、膀胱癌、癌前皮肤病变、睾丸癌、淋巴瘤、甲状腺癌、神经母细胞瘤、食管癌、生殖泌尿道癌、恶性高钙血症、宫颈癌、子宫内膜癌、肾上腺皮质癌和前列腺癌。
“神经系统疾病或障碍”指神经系统和/或视觉系统的任何疾病或障碍。“神经系统疾病或障碍”包括涉及中枢神经系统(脑、脑干和小脑)、外周神经系统(包括颅神经)和自主神经系统(其部分位于中枢和外周神经系统二者中)的疾病或障碍。神经系统障碍的实例包括但不限于头痛、木僵和昏迷、痴呆、癫痫发作、睡眠障碍、创伤、感染、肿瘤、神经眼科学疾病、运动障碍、脱髓鞘病、脊髓病症及外周神经、肌肉和神经肌接点的病症。瘾癖和精神病包括但不限于双相性精神障碍和精神分裂症,而且还包括在神经系统障碍的定义中。下面是可使用本发明的组合物和方法治疗的若干神经系统障碍、症状、体征和综合征的名目:获得性癫痫性失语;急性播散性脑脊髓炎;肾上腺脑白质营养不良;年龄相关性黄斑变性;胼胝体发育不全;失认症;艾卡迪综合征(Aicardi syndrome);亚力山大病(Alexanderdisease);阿尔珀斯病(Alpers′disease);交叉性偏瘫;血管性痴呆;肌萎缩性侧索硬化;无脑畸形;安吉尔曼综合征(Angelman syndrome);血管瘤病;缺氧症;失语症;失用症;蛛网膜囊肿;蛛网膜炎;阿-希畸形(Anronl-Chiari malformation);动静脉畸形;阿斯珀格综合征(Asperger syndrome);共济失调毛细血管扩张症(ataxia telegiectasia);注意力不集中的过度反应症;孤独症;植物神经功能紊乱(autonomic dysfunction);背痛;巴腾病(Batten disease);贝切特病(Behcet′s disease);面神经麻痹(Bell′s palsy);良性自发性睑痉挛;良性焦距协调(benign focal);肌萎缩;良性颅内高血压;宾斯旺格病(Binswanger′s disease);睑痉挛;Bloch Sulzberger综合征;臂丛神经损伤;脑脓肿;脑损伤;脑肿瘤(包括多形性成胶质细胞瘤);脊柱肿瘤;布朗-塞卡尔综合征(Brown-Sequardsyndrome);卡纳万病(Canavan disease);腕管综合征;灼性神经痛;中枢性疼痛综合征;脑桥中央髓鞘溶解;头部障碍(cephalic disorder);脑动脉瘤;脑动脉硬化;脑萎缩;大脑性巨人症;大脑性瘫痪;夏-马-图病(Charcot-Marie-Tooth disease);化疗引起的神经病变及神经性疼痛;希阿利畸形(Chiari malformation);舞蹈病;慢性炎性脱髓鞘性多发性神经病;慢性疼痛;慢性区域疼痛综合征;科-勒综合征(Coffin Lowry syndrome);昏迷,包括持续性植物状态;先天性面瘫;皮质基底节变性;颅动脉炎;颅缝早闭;克-雅病(Creutzfeldt-Jakob disease);累积性创伤障碍;库欣综合征(Cushing′s syndrome);巨细胞包涵体病;巨细胞病毒感染;舞蹈眼-舞蹈脚综合征;丹-沃综合征(Dandy Walkersyndrome);Dawson病;德摩西埃综合征(Morsier′s syndrome);代热林-克隆普克麻痹(Dejerine-Klumke palsy);痴呆;皮肌炎;糖尿病性神经病;弥漫性硬化;自主神经功能异常;书写困难;诵读困难;张力失常;早期幼儿癫痫性脑病;空蝶鞍综合征;脑炎;脑膨出;脑三叉神经血管瘤病;癫痫;欧勃麻痹(Erb′s palsy);特发性震颤;法布里病(Fabry′sdisease);法尔综合征(Fahr′s syndrome);昏厥;家族性痉挛性瘫痪;热性癫痫发作;费希尔综合征(Fisher syndrome);弗里德赖希共济失调;额颞痴呆和其它“Tau病变”;高歇病(Gaucher′s disease);格斯特曼综合征(Gerstmann′s syndrome);巨细胞动脉炎;巨细胞包涵体病;球形细胞脑白质营养不良;格-巴综合征(globoid cell leukodystrophy);HTLV-1相关脊髓病;哈-斯病(Hallervorden-Spatz disease);颅脑损伤;头痛;偏侧面肌痉挛;遗传性痉挛性截瘫;多神经炎型遗传性共济失调;耳部带状疱疹(herpes zosteroticus);带状疱疹;Hirayama综合征;HIV相关痴呆和神经病(亦为AIDS的神经系统表现);前脑无裂畸形;亨廷顿舞蹈病(Huntington′s disease)和其它多谷氨酰胺重复疾病;积水性无脑畸形;脑积水;皮质醇增多症;低氧;免疫介导的脑脊髓炎;包涵体肌炎;色素失调症;婴儿植烷酸贮积病;婴儿雷夫叙姆病;婴儿痉挛症;炎性肌病;颅内囊肿;颅内高血压;儒贝尔综合征(Joubert syndrome);克-塞综合征(Keams-Sayre syndrome);肯尼迪病(Kennedydisease);Kinsboume综合征;克-费综合征(Klippel Feil syndrome);克拉伯病(Krabbedisease);库-韦病(Kugelberg-Welander disease);库鲁病;拉福拉病(Lafora disease);朗-爱肌无力综合征(Lambert-Eaton myasthenic syndrome);Landau-Kleffner综合征;侧髓(瓦伦伯格)综合征;学习不能;利氏病(Leigh′s disease);伦-格综合征(Lennox-Gustaut syndrome);累-奈综合征(Lesch-Nyhan syndrome);脑白质营养不良;路易体痴呆(Lewy body dementia);无脑回;闭锁综合征;Lou Gehrig病(即运动神经元病或肌萎缩性侧索硬化症);腰椎间盘病(lumbar disc disease);莱姆病(Lyme disease)--神经系统后遗症;Machado-Joseph病;巨脑(macrencephaly/megalencephaly);梅-罗综合征(Melkersson-Rosenthal syndrome);梅尼埃病(Menieres disease);脑膜炎;门克斯病(Menkes disease);异染性脑白质营养不良;小头畸形;偏头痛;Miller Fisher综合征;小中风(mini-stroke);线粒体肌病;默比厄斯综合征(Mobius syndrome);单肢肌萎缩;运动神经元病;脑底异常血管网病;粘多糖贮积症;多发梗塞性痴呆;多灶性运动神经病;多发性硬化和其它脱髓鞘性病症;多系统萎缩伴随体位性低血压;肌营养不良;重症肌无力;髓鞘破坏性(myelinoclastic)弥漫性硬化症;婴儿肌阵挛性脑病;肌阵挛;肌病;先天性肌强直;发作性睡病;神经纤维瘤病;抗精神病药恶性综合征;AIDS的神经系统表现;狼疮神经性后遗症;神经性肌强直;神经元蜡样脂褐质沉积症;神经细胞迁移障碍;尼-皮病(Niemann-Pick disease);O′Sullivan-McLeod综合征;枕神经痛;隐性脊柱神经管闭合不全序列征;Ohtahara综合征;橄榄体脑桥小脑萎缩;视性眼肌阵挛;视神经炎;直立性低血压;过度使用综合征;感觉异常;神经退行性疾病或障碍(帕金森病(Parkinson′s disease)、亨廷顿舞蹈病、阿尔茨海默病(Alzheimer′s disease)、肌萎缩性侧索硬化症(ALS)、痴呆、多发性硬化和其它与神经元细胞死亡有关的疾病与障碍);先天性肌强直病;类肿瘤性疾病;阵发性发作(paroxysmal attack);帕-罗综合征(Parry Romberg syndrome);佩-梅病(Pelizaeus-Merzbacher disease);周期性麻痹;外周神经病;痛性神经病变和神经性疼痛;持续性植物状态;全身性发育迟缓;感光性喷嚏反射;植烷酸贮积病;皮克病(Pick′s disease);神经挟捏(pinched nerve);垂体瘤;多肌炎;脑穿通畸形;脊髓灰质炎后综合征;疱疹后神经痛;感染后脑脊髓炎;体位性低血压;普-韦综合征(Prader-Willi syndrome);原发性侧索硬化症;朊病毒病;进行性偏侧面肌萎缩;进行性多灶性白质脑病;进行性硬化灰质营养不良;进行性核上性麻痹;脑假瘤;拉姆齐-亨特综合征(Ramsay-Hunt syndrome)(I型和II型);Rasmussen脑炎;反射性交感神经营养不良综合征;雷夫叙姆病;重复性动作障碍;重复性应激损伤;下肢不宁综合征;逆转录病毒相关的脊髓病;雷特综合征(Rett syndrom);雷耶综合征(Reye′s syndrome);舞蹈病(Saint Vitus dance);山德霍夫病(Sandhoff disease);谢尔德病(Schilder′s disease);脑裂畸形;视隔发育不良(septo-optic dysplasia);惊吓婴儿综合征;带状疱疹;希-德综合征(Shy-Drager syndrome);斯耶格伦综合征(Sjogren′s syndrome);睡眠呼吸暂停;索托斯综合征(Soto′s syndrome);痉挛;脊柱裂;脊髓损伤;脊髓肿瘤;脊髓性肌萎缩;僵人综合征;中风;斯-韦综合征(Sturge-Webersyndrome);亚急性硬化性全脑炎;皮层下动脉硬化性脑病;西德纳姆舞蹈病(Sydenhamchorea);晕厥;脊髓空洞症;迟发性运动障碍;泰-萨病(Tay-Sachs disease);颞动脉炎;脊髓栓系综合征;先天性肌强直;胸出口综合征;三叉神经痛;托德麻痹(Todd′s paralysis);图雷特综合征(Tourette syndrome);短暂性脑缺血发作;传染性海绵状脑病;横贯性脊髓炎;外伤性脑损伤;震颤;三叉神经痛;热带痉挛性截瘫;结节性硬化症;血管性痴呆(多发梗塞性痴呆);血管炎,包括颞动脉炎;希-林病(Von Hippel-Lindau disease);瓦伦伯格综合征(Wallenberg′s syndrome);韦-霍病(Werdnig-Hoffman disease);韦斯特综合征(Westsyndrome);颈部扭伤(whiplash);威廉斯综合征(Williams syndrome);Wildon病和泽尔韦格综合征(Zellweger syndrome)。
“炎症”是指与单核细胞、白细胞和/或嗜中性粒细胞的局部迁移和吸引有关的一种和多种全身性炎性状况。炎症的实例包括但不限于因致病生物(包括革兰氏阳性菌、革兰氏阴性菌、病毒、真菌和寄生物(例如原生动物和蠕虫))感染、移植排斥(包括肾、肝、心脏、肺或角膜等实体器官排斥以及骨髓移植排斥包括移植物抗宿主病(GVHD))导因局限性慢性或急性自身免疫反应或变态反应导致的炎症。自身免疫病包括急性肾小球性肾炎;类风湿性关节炎或反应性关节炎;慢性肾小球性肾炎;炎性肠病,例如克罗恩病(Crohn′sdisease)、溃疡性结肠炎和坏死性小肠结肠炎;粒细胞输注相关综合征;炎性皮肤病,例如接触性皮炎、特应性皮炎、牛皮癣;系统性红斑狼疮(SLE)、自身免疫性甲状腺炎、多发性硬化和糖尿病的某些形式或受试者的自身免疫系统攻击导致病理性组织破坏的任何其它自身免疫状态。变态反应包括变应性哮喘、慢性支气管炎、急性过敏反应和迟发型过敏反应。全身炎性疾病状态,包括与创伤、烧伤、缺血事件(例如心脏、脑、肠或外周血管系统中的血栓性事件,包括心肌梗死和中风)后再灌注相关的炎症、脓毒症、ARDS或多器官功能障碍综合征。炎性细胞募集也出现在动脉粥样硬化斑中。炎症包括但不限于非霍奇金淋巴瘤、韦格纳肉芽肿病(Wegener′s granulomatosis)、桥本甲状腺炎(Hashimoto′s thyroiditis)、肝细胞癌、胸腺萎缩、慢性胰腺炎、类风湿性关节炎、反应性淋巴样增生、骨关节炎、溃疡性结肠炎、乳头状癌、克罗恩病、溃疡性结肠炎、急性胆囊炎、慢性胆囊炎、肝硬化、慢性涎腺炎、腹膜炎、急性胰腺炎、慢性胰腺炎、慢性胃炎、子宫内膜异位(adenomyosis/endometriosis)、急性宫颈炎、慢性宫颈炎、淋巴增生、多发性硬化、特发性血小板减少性紫癜继发性肥大、原发性IgA肾病、系统性红斑狼疮、牛皮癣、肺气肿、慢性肾盂肾炎和慢性膀胱炎。
心血管疾病或病症包括可能引起缺血或由心脏再灌注引起的病症。实例包括但不限于动脉粥样硬化、冠状动脉疾病、肉芽肿性心肌炎、慢性心肌炎(非肉芽肿性)、原发性肥厚型心肌病、外周动脉疾病(PAD)、中风、心绞痛、心肌梗死、由心脏停搏引起的心血管组织损伤、由心脏分流术引起的心血管组织损伤、心源性休克和本领域普通技术人员已知的或者涉及心脏或血管系统的功能障碍或组织损伤的相关病况,尤其是但不限于与唐氏综合征基因活化有关的组织损伤。CVS疾病包括但不限于动脉粥样硬化、肉芽肿性心肌炎、心肌梗死、心脏瓣膜病继发性心肌纤维化、无梗塞型心肌纤维化、原发性肥厚型心肌病和慢性心肌炎(非肉芽肿性)。
与氧化应激有关的疾病或病症的实例包括但不限于动脉粥样硬化、帕金森病、心脏衰竭、心肌梗死、阿尔茨海默病、慢性疲劳综合征、肌萎缩性侧索硬化(ALS)、慢性阻塞性肺病(COPD)、多发性硬化、肝脏疾病或病症、胃肠疾病或病症、糖尿病、癌症、自身免疫、免疫相关疾病或障碍、神经系统疾病或病症、神经退行性疾病或病症、神经修复和麻痹、神经内分泌分化、炎性疾病、肌肉疾病或病症、与感染性生物有关的疾病或病症等。
多核苷酸和寡核苷酸组合物和分子
靶标
在一个实施方案中,靶标包含唐氏综合征基因的核酸序列,包括而不限于与唐氏综合征基因有关的有义和/或反义非编码和/或编码序列。
在一个实施方案中,靶标包含DYRK1的核酸序列,包括而不限于与DYRK1基因有关的有义和/或反义非编码和/或编码序列。
在一个实施方案中,靶标包含DSCR1的核酸序列,包括而不限于与DSCR1基因有关的有义和/或反义非编码和/或编码序列。
DYRKIA(双重特异性酪氨酸磷酸化-调节激酶1A)是在酪氨酸残基自身磷酸化的丝氨酸/苏氨酸激酶。该蛋白质含有核定位信号,并定位于剪接因子区室(核小点),但还存在于胞质中。DYRKIA具有宽的底物谱,包括转录因子、剪接因子和突触蛋白。它在所有组织和细胞中无所不在地进行表达,但是表达不均匀,其中在胚胎脑和成体脑中具有高水平。人DYRKIA基因被认为是若干唐氏综合征特征的候选基因,包括由于其位于染色体21上的唐氏综合征关键区中及其在脑功能中的作用所致智力迟钝。值得注意的是,DYRKIA的果蝇属(Drosophila)直向同源物的蝇突变体(Minibrain),在中枢神经系统中神经元的数量减少。由于DYRK1a遭破坏的等位基因而是杂合的小鼠的存活力降低、生长延迟和行为改变。
DYRK1a编码双重特异性酪氨酸磷酸化调节激酶(DYRK)家族的成员。该成员含有核靶向信号序列、蛋白激酶结构域、亮氨酸拉链模体和高保守性13个连续组氨酸的重复序列。它催化其在丝氨酸/苏氨酸和酪氨酸残基上的自身磷酸化,可在调节细胞增殖的信号转导途径中起重要作用,并且可参与脑发育。该基因是果蝇mnb(minibrain)基因和大鼠Dyrk基因的同源物。DYRK1a位于染色体21的唐氏综合征关键区中,并且被视为与唐氏综合征相关的学习缺陷的强候选基因。该基因的可变剪接产生在5’UTR中或3’编码区中彼此不同的若干转录物变体。这些变体编码至少五种不同的同种型。
唐氏综合征关键区蛋白1(DSCR1)是VEGF靶基因和内皮细胞中的抗炎信号转导分子。人基因(DSCR1)是存在于人染色体21(HC21)的最小区域内的50-100个基因之一,其存在大于2个拷贝时,会引起智力迟钝,统称唐氏综合征(DS)。DSCR1属于保守蛋白质的家族,亦称calcipressin或调制性钙调磷酸酶相互作用蛋白(MCIP),在人中包含共有结合钙调磷酸酶的能力的3个成员,即DSCR1IMCIP1、ZAKI-4/DSCR1L1IMCIP2和DSCR1L2/MCIP3。DSCR1起小的胞质信号转导分子的作用,该分子由Ca2+/钙调蛋白依赖性丝氨酸/苏氨酸蛋白质磷酸酶2B(PP2B)或钙调磷酸酶A(CnA)调节。
许多癌症类型的发生率在患有唐氏综合征的个体中显著下降,一般认为这种广泛的癌症保护作用是由染色体21的额外拷贝上231个超数基因中的一种或多种的表达增加所赋予的。这类基因之一是唐氏综合征关键区蛋白1(DSCR1,亦称为RCAN1),其编码通过钙调磷酸酶途径抑制血管内皮生长因子(VEGF)介导的血管生成信号转导的蛋白质。DSCRI在唐氏综合征组织中和在唐氏综合征小鼠模型中增加。虽然不希望受理论的束缚,但因DSCR1连同另一个染色体21基因DYRK1a所致钙调磷酸酶活性的减弱,可能足以显著地减少血管生成。(DSCR1)的别名包括:唐氏综合征候选区-I、RCANI钙调磷酸酶调节子1、Adapt78、ADAPT78、Calcipressin-1、CSP1、DSC1、DSCR1、MCIP1、肌细胞富含的钙调磷酸酶相互作用蛋白1、RCN1、钙调磷酸酶调节子1。
DYRK1a编码双重特异性酪氨酸磷酸化调节激酶(DYRK)家族的成员。该成员含有核靶向信号序列、蛋白激酶结构域、亮氨酸拉链模体和高保守性13个连续组氨酸的重复序列。它催化其在丝氨酸/苏氨酸和酪氨酸残基上的自身磷酸化,可在调节细胞增殖的信号转导途径中起重要作用,并且可参与脑发育。该基因是果蝇mnb(minibrain)基因和大鼠Dyrk基因的同源物。DYRK1a位于染色体21的唐氏综合征关键区中,并且被视为与唐氏综合征相关的学习缺陷的强候选基因。该基因的可变剪接产生在5’UTR中或3’编码区中彼此不同的若干转录物变体。这些变体编码至少五种不同的同种型。
位于DSCR上的DYRKIA和RCANI基因,与DS患者的典型特征及其对DS的神经缺陷的发病机制的影响密切相关。DYRKIA使若干转录因子(例如CREB和NFAT)、胞吞复杂蛋白质(endocytic complex protein)和AD连锁基因产物磷酸化。同时,RCANI是钙调磷酸酶A的内源抑制剂,而且认为其不均衡的活性引起DS和AD中主要的神经元和/或非神经元机能障碍。令人感兴趣的是,这两者均促进学习和记忆缺陷、突触可塑性改变、细胞周期调节受损和DS中的AD样神经病理学。
在一些实施方案中,反义寡核苷酸用于预防或治疗与唐氏综合征基因家族成员有关的疾病或病症。可以用由使用所述反义化合物获得的干细胞再生的细胞/组织治疗的示例性唐氏综合征基因介导的疾病和病症包括:与DYRK1a或DSCR1的突变体、异常表达或功能有关的疾病或障碍;癌症、血管生成疾病或障碍、细胞凋亡疾病或障碍、细胞增殖性疾病或障碍、炎症、心血管疾病或病症、神经系统疾病或障碍、唐氏综合征、阿尔茨海默病、智力迟钝、记忆受损、三体性、神经病理学、神经退行性疾病或障碍、心肌细胞肥大、血管异常(例如婴儿血管瘤、血管生成依赖性血管肿瘤、血管畸形等)、高同型半胱氨酸血症(Hyperhomocysteinemia)、成骨细胞分化受损、破骨细胞发生、线粒体功能受损、氧化应激、与钙调磷酸酶介导的信号转导途径受损有关的疾病或障碍、与血管生成调节受损有关的疾病或障碍、钙介导的应激和与APC和/或Axin功能缺陷或受损有关的疾病或障碍。
在另一个实施方案中,唐氏综合征基因天然反义序列的反义寡核苷酸治疗有发生心脏疾病或病症风险或已发生心脏疾病或病症的患者。例如磷酸酶钙调磷酸酶及其下游靶标(NFAT家族的转录因子)的活化导致心肌细胞肥大。双重特异性酪氨酸(Y)磷酸化调节激酶1A(DYRK1a)能够直接使NFAT磷酸化来拮抗钙调磷酸酶信号转导。反义寡核苷酸在心脏疾病或病症(例如心肌细胞的肥大反应)治疗中调节DYRK1a。
在实施方案中,包含DYRK1a和/或DSCR1的反义寡核苷酸预防或治疗与体内生理异常水平、活性、功能、表达有关的疾病,其还可改变这些分子直接或间接参与的生理途径。因此,一种或多种DYRK1a和/或DSCR1反义寡核苷酸可用于预防疾病或病症或治疗这些患者。
在另一个实施方案中,DYRK1a和/或DSCR1天然反义序列的反义寡核苷酸治疗有发生心脏疾病或病症风险或已发生心脏疾病或病症的患者。例如,磷酸酶钙调磷酸酶及其下游靶标(NFAT家族的转录因子)的活化导致心肌细胞肥大。双重特异性酪氨酸(Y)磷酸化调节激酶1A(DYRK1a)能够通过直接使NFAT磷酸化来拮抗钙调磷酸酶信号转导。反义寡核苷酸在心脏疾病或病症(例如心肌细胞的肥大反应)的治疗中调节DYRK1a。
在一个实施方案中,所述寡核苷酸对唐氏综合征基因的多核苷酸(其包括而不限于非编码区)有特异性。唐氏综合征基因靶标包括唐氏综合征基因的变体;唐氏综合征基因的突变体,包括SNP;唐氏综合征基因的非编码序列;等位基因、片段等。优选所述寡核苷酸是反义RNA分子。
按照本发明的实施方案,靶核酸分子不只限于唐氏综合征基因多核苷酸,而是延伸到唐氏综合征基因的任何同种型、受体、同源物、非编码区等。
在另一个实施方案中,所述寡核苷酸靶向唐氏综合征基因靶标的天然反义序列(编码区和非编码区的天然反义序列),包括而不限于其变体、等位基因、同源物、突变体、衍生物、片段及互补序列。优选所述寡核苷酸是反义RNA或DNA分子。
在另一个实施方案中,本发明的寡聚化合物还包括其中不同碱基存在于化合物的一个或多个核苷酸位置上的变体。例如,如果第一核苷酸是腺嘌呤,则可产生在该位置上含有胸苷、鸟苷、胞苷或其它天然或非天然核苷酸的变体。这可在反义化合物的任何位置上进行。
在一些实施方案中,反义化合物和靶标之间的同源性、序列同一性或互补性为约50%-约60%。在一些实施方案中,同源性、序列同一性或互补性为约60%-约70%。在一些实施方案中,同源性、序列同一性或互补性为约70%-约80%。在一些实施方案中,同源性、序列同一性或互补性为约80%-约90%。在一些实施方案中,同源性、序列同一性或互补性为约90%、约92%、约94%、约95%、约96%、约97%、约98%、约99%或约100%。
当反义化合物与靶核酸的结合干扰靶核酸的正常功能而引起活性丧失,并存在足够程度的互补性以避免在需要特异性结合的条件下反义化合物与非靶核酸序列非特异性结合时,反义化合物是可特异性杂交的。这样的条件包括,即体内测定或治疗性治疗情况中的生理条件和体外测定情况中进行测定的条件。
当反义化合物与靶DNA或RNA分子的结合干扰靶DNA或RNA的正常功能而引起效用丧失,并存在足够程度的互补性以避免在需要特异性结合的条件下(即在体内测定或治疗性治疗情况中的生理条件下和在体外测定情况中进行测定的条件下)该反义化合物与非靶序列非特异性结合时,则不论该反义化合物是DNA、RNA、嵌合体、取代物等,其都是可特异性杂交的。
在另一个实施方案中,包括而不限于利用例如PCR、杂交等鉴定和扩增的反义序列、一个或多个SEQ ID NO:3-6所示序列等的唐氏综合征基因的靶向调节唐氏综合征基因的表达或功能。在一个实施方案中,与对照相比,表达或功能上调。在另一个实施方案中,与对照相比,表达或功能下调。
在另一个实施方案中,包含SEQ ID NO:7-24所示核酸序列的寡核苷酸包括利用例如PCR、杂交等鉴定和扩增的反义序列。这些寡核苷酸可包含一个或多个修饰核苷酸,较短片段或较长片段,修饰键等。修饰键或核苷酸间键的实例包括硫代磷酸酯、二硫代磷酸酯等。在另一个实施方案中,核苷酸包括磷衍生物。可与本发明的修饰寡核苷酸中的糖或糖类似物部分连接的磷衍生物(或修饰磷酸基)可以是单磷酸酯、二磷酸酯、三磷酸酯、烷基磷酸酯、链烷磷酸酯(alkanephosphate)、硫代磷酸酯等。上述磷酸酯类似物的制备和将它们整合入核苷酸、修饰核苷酸和寡核苷酸中本身亦是已知的,不必在此赘述。
本领域技术人员还为治疗用途控制反义序列的特异性和灵敏度。在动物和人的疾病状态的治疗中已利用反义寡核苷酸作为治疗部分。已将反义寡核苷酸安全有效地给予人,许多临床试验目前正在进行中。因此已确定的是,寡核苷酸可以是有用的治疗方式,其可被设计用于治疗细胞、组织和动物(尤其人)的治疗方案。
在本发明的实施方案中,寡聚反义化合物(特别是寡核苷酸)与靶核酸分子结合并调节由靶基因编码的分子的表达和/或功能。被干扰的DNA功能包括例如复制和转录。被干扰的RNA功能包括所有重要功能,例如RNA转运到蛋白质翻译位点、由RNA翻译蛋白质、剪接RNA产生一种或多种mRNA和RNA可能参与或促进的催化活性。功能可被上调或抑制,视所需功能而定。
反义化合物包括反义寡聚化合物、反义寡核苷酸、外部指导序列(EGS)寡核苷酸、可变剪接体、引物、探针及与靶核酸的至少一部分杂交的其它寡聚化合物。同样地,这些化合物可以单链、双链、部分单链或环状寡聚化合物的形式引入。
在本发明的情况下,反义化合物靶向特定核酸分子可以是多步骤过程。该过程通常始于识别待调节其功能的靶核酸。该靶核酸可以是例如其表达与特定病症或疾病状态有关的细胞基因(或转录自该基因的mRNA),或来自病原体的核酸分子。在本发明中,靶核酸编码唐氏综合征基因。
靶向过程通常还包括测定将发生反义相互作用的靶核酸内的至少一个靶区、区段或位点,使得产生所需要的作用(例如调节表达)。在本发明的情况下,术语“区”定义为具有至少一种可鉴定结构、功能或特性的靶核酸的一部分。区段在靶核酸的区中。“区段”定义为靶核酸中区的更小部分或次级部分。本发明所用“位点”定义为靶核酸中的位置。
在一个实施方案中,反义寡核苷酸与唐氏综合征基因的天然反义序列结合并调节唐氏综合征基因(SEQ ID NO:1-3)的表达和/或功能。反义序列的实例包括SEQ ID NOS:4-30。
在另一个实施方案中,反义寡核苷酸与唐氏综合征基因多核苷酸的一个或多个区段结合并调节唐氏综合征基因的表达和/或功能。区段包含唐氏综合征基因有义或反义多核苷酸的至少五个连续核苷酸。
在另一个实施方案中,反义寡核苷酸对唐氏综合征基因的天然反义序列有特异性,其中寡核苷酸与唐氏综合征基因的天然反义序列的结合调节唐氏综合征基因的表达和/或功能。
在另一个实施方案中,寡核苷酸化合物包含SEQ ID NOS:7-24所示序列,利用例如PCR、杂交等鉴定和扩增的反义序列。这些寡核苷酸可包含一个或多个修饰核苷酸、较短片段或较长片段、修饰键等。修饰键或核苷酸间键的实例包括硫代磷酸酯、二硫代磷酸酯等。在另一个实施方案中,核苷酸包括磷衍生物。可与本发明的修饰寡核苷酸的糖或糖类似物部分连接的磷衍生物(或修饰磷酸基)可以是单磷酸酯、二磷酸酯、三磷酸酯、烷基磷酸酯、链烷磷酸酯、硫代磷酸酯等。上述磷酸酯类似物的制备和将它们整合入核苷酸、修饰核苷酸和寡核苷酸本身亦是已知的,不必在此赘述。
如本领域所知,由于翻译起始密码子一般是5′-AUG(在转录的mRNA分子中;在对应的DNA分子中是5′-ATG),故翻译起始密码子也称为“AUG密码子”、“起始密码子”或“AUG起始密码子”。少数基因具有RNA序列为5′-GUG、5′-UUG或5′-CUG的翻译起始密码子;已表明5′-AUA、5′-ACG和5′-CUG在体内起作用。因此,术语“翻译起始密码子”和“起始密码子”可包括多种密码子序列,但是在所有情况下起始氨基酸通常为甲硫氨酸(在真核生物中)或甲酰甲硫氨酸(在原核生物中)。真核和原核基因可具有两个以上的备选起始密码子,在特定细胞类型或组织中或在特定系列条件下可优先将任一个用于翻译起始。在本发明的情况下,“起始密码子”和“翻译起始密码子”是指体内用于起始转录自编码唐氏综合征基因的基因的mRNA翻译的一个或多个密码子,而不考虑这种密码子的序列。基因的翻译终止密码子(或“终止密码子”)可具有三种序列即5′-UAA、5′-UAG和5′-UGA(对应的DNA序列分别是5′-TAA、5′-TAG和5′-TGA)之一。
术语“起始密码子区”和“翻译起始密码子区”是指这类mRNA或基因的一部分,其包含在任何方向(即5′或3′)上自翻译起始密码子起的约25-约50个连续核苷酸。同样地,术语“终止密码子区”和“翻译终止密码子区”是指这类mRNA或基因的一部分,其包含在任何方向(即5′或3′)上自翻译终止密码子起的约25-约50个连续核苷酸。因此,“起始密码子区”(或“翻译起始密码子区”)和“终止密码子区”(或翻译终止密码子区)均为可用本发明的反义化合物有效靶向的区。
本领域已知可读框(ORF)或“编码区”是指翻译起始密码子和翻译终止密码子之间的区,亦即可有效靶向的区。在本发明的情况下,靶区是包含基因可读框(ORF)的翻译起始密码子或终止密码子的基因内区。
另一个靶区包含5′非翻译区(5′UTR),本领域中已知其是指在5′方向上从翻译起始密码子开始的mRNA部分,因此包含mRNA在5′加帽位点和翻译起始密码子之间的核苷酸(或基因上的对应核苷酸)。又一个靶区包含3′非翻译区(3′UTR),本领域中已知其是指在3′方向上从翻译终止密码子开始的mRNA部分,因此包含mRNA在翻译终止密码子和3′末端之间的核苷酸(或基因上的对应核苷酸)。mRNA的5′加帽位点含有与mRNA的5′-最末端残基通过5′-5′三磷酸酯键连接的N7-甲基化鸟苷残基。mRNA的5′帽区被认为包括5′帽子结构本身以及邻近加帽位点的前50个核苷酸。本发明的另一个靶区是5′帽区。
虽然一些真核mRNA转录物被直接翻译,但是多数包含一个或多个称为“内含子”的区,这些区在转录物翻译之前从转录物上切下。剩余(因此被翻译)的区被称为“外显子”,被剪接在一起形成连续的mRNA序列。在一个实施方案中,在异常剪接涉及疾病或特定剪接产物的过度产生涉及疾病的情况下,靶向剪接位点(即内含子-外显子连接点或外显子-内含子连接点)特别有用。因重排或缺失引起的异常融合连接点是靶位点的另一个实施方案。通过两个(或更多个)mRNA的剪接加工从不同基因来源产生的mRNA转录物称为“融合转录物”。利用靶向例如DNA或前mRNA的反义化合物可有效靶向内含子。
在另一个实施方案中,反义寡核苷酸与靶多核苷酸的编码和/或非编码区结合,并调节靶分子的表达和/或功能。
在另一个实施方案中,反义寡核苷酸与天然反义多核苷酸结合,并调节靶分子的表达和/或功能。
在另一个实施方案中,反义寡核苷酸与有义多核苷酸结合,并调节靶分子的表达和/或功能。
可变RNA转录物可产生自DNA的相同基因组区。这些可变转录物通常称为“变体”。更具体而言,“前mRNA变体”是产生自相同基因组DNA的转录物,与其它产生自相同基因组DNA的转录物在它们的起始或终止位置方面不同,并同时含有内含子和外显子序列。
当在剪接过程中切除一个或多个外显子或内含子区或其部分时,前mRNA变体产生更小的“mRNA变体”。因此,mRNA变体是经加工的前mRNA变体,每个独特的前mRNA变体由于剪接必定总是产生独特的mRNA变体。这些mRNA变体也称为“可变剪接变体”。如果未发生前mRNA变体的剪接,那么前mRNA变体与mRNA变体相同。
可通过利用开始或终止转录的可变信号产生变体。前mRNA和mRNA可具有多于一个的起始密码子或终止密码子。产生自利用可变起始密码子的前mRNA或mRNA的变体称为该前mRNA或mRNA的“可变起始变体”。利用可变终止密码子的转录物称为该前mRNA或mRNA的“可变终止变体”。一种具体类型的可变终止变体是“polyA变体”,其中产生的多个转录物产生自转录机器对“polyA终止信号”之一的可变选择,从而产生在独特的polyA位点终止的转录物。在本发明的情况下,本文所述变体类型也是靶核酸的实施方案。
靶核酸上反义化合物与之杂交的部位定义为活性反义化合物靶向的靶区的长度为至少5个核苷酸的部分。
虽然本文阐述了某些示例性靶区段的具体序列,但是本领域技术人员应认识到,这些用于阐明和描述本发明范围内的具体实施方案。根据此公开内容,本领域普通技术人员可容易地确定其它靶区段。
长度5-100个核苷酸、包含选自说明性靶区段中的一段至少五(5)个连续核苷酸的靶区段被认为也适合靶向。
靶区段可包含含有说明性靶区段之一的5′末端的至少5个连续核苷酸的DNA或RNA序列(剩余核苷酸为同一DNA或RNA的连续序列段,以紧接靶区段的5′末端上游开始,并持续直到该DNA或RNA含有约5-约100个核苷酸)。同样,靶区段由包含说明性靶区段之一的3′末端的至少5个连续核苷酸的DNA或RNA序列表示(剩余核苷酸是同一DNA或RNA的连续序列段,以紧接靶区段的3′末端下游开始,并持续直到该DNA或RNA含有约5-约100个核苷酸)。备有本文所述靶区段的本领域技术人员能够在无过度实验的情况下鉴定其它靶区段。
只要已鉴定了一个或多个靶区、区段或位点,便选择与靶标充分互补(即足够充分并以足够特异性杂交)的反义化合物,以得到所需要的效果。
在本发明实施方案中,寡核苷酸与特定靶标的反义链结合。寡核苷酸长度为至少5个核苷酸,可以对其进行合成使每个寡核苷酸靶向重叠序列,从而合成的寡核苷酸覆盖靶多核苷酸的完整长度。靶标还包括编码区和非编码区。
在一个实施方案中,通过反义寡核苷酸靶向特定核酸。反义化合物靶向特定核酸是多步骤过程。该过程通常始于鉴定待调节功能的核酸序列。这可以是例如其表达与特定病症或疾病状态相关的细胞基因(或转录自该基因的mRNA),或者非编码多核苷酸,例如非编码RNA(ncRNA)。
可将RNA分为(1)被翻译成蛋白质的信使RNA(mRNA)和(2)不编码蛋白的RNA(ncRNA)。ncRNA包括微小RNA、反义转录物及其它含有高密度的终止密码子并缺乏任何大范围“可读框”的转录单位(TU)。许多ncRNA似乎起始于编码蛋白的基因座的3′非翻译区(3′UTR)的起始位点。ncRNA通常很少,且已由FANTOM公司测序的ncRNA中至少一半似乎未被聚腺苷酸化。由于显而易见的原因,大多数研究人员已聚焦于经加工并输出到胞质中的聚腺苷酸化mRNA。最近表明,非聚腺苷酸化的核RNA类别可能非常大,且许多这样的转录物产生自基因间区。ncRNA可调节基因表达的机制是通过与靶转录物的碱基配对。可将通过碱基配对起作用的RNA分为:(1)顺式编码RNA,其在相同基因位置但在与它们作用的RNA的相对链上被编码,因此与其靶标具有完全互补性,和(2)反式编码RNA,其在不同于它们起作用的RNA的染色体位置上被编码,且通常不具有与其靶标进行完全碱基配对的潜力。
虽然不希望受理论的束缚,但是通过本文所述反义寡核苷酸对反义多核苷酸的干扰可改变相应有义信使RNA的表达。然而,这种调节可以是不一致的(反义敲减引起信使RNA增加)或一致的(反义敲减引起伴随的信使RNA减少)。在这些情况下,反义寡核苷酸可靶向反义转录物的重叠或非重叠部分,以引起其敲减或隔离。可以相同方式靶向编码或非编码反义序列,且任一种均能够调节相应的有义转录物-以一致或不一致的方式。用以鉴定新的针对靶标使用的寡核苷酸的策略可基于通过反义寡核苷酸或调节所需靶标的任何其它方法敲减反义RNA转录物。
策略1:在不一致的调节情况中,反义转录物的敲减提高常规(有义)基因的表达。如果后者的基因编码已知或推定的药物靶标,那么可想象得到,其反义对应物的敲减可模仿受体激动剂或酶刺激剂的作用。
策略2:在一致调节的情况中,可同时敲减反义和有义转录物,从而实现常规(有义)基因表达的协同性减少。例如,如果利用反义寡核苷酸完成敲减,则可利用该策略应用一个靶向有义转录物的反义寡核苷酸和另一个靶向相应反义转录物的反义寡核苷酸,或者应用同时靶向重叠的有义和反义转录物的单个有效的对称反义寡核苷酸。
按照本发明,反义化合物包括反义寡核苷酸、核酶、外部指导序列(EGS)寡核苷酸、siRNA化合物、单链或双链RNA干扰(RNAi)化合物(例如siRNA化合物)及与靶核酸的至少一部分杂交并调节其功能的其它寡聚化合物。因此,它们可以是DNA、RNA、类DNA、类RNA及其混合物,或者可以是这些中的一种或多种的模拟物。这些化合物可以是单链、双链、环状或发夹状的寡聚化合物,并可含有结构元件,例如内部或端部凸起、错配或环。按常规制备线性反义化合物,但可将其连接或另外制备成环状和/或分支的反义化合物。反义化合物可包括构建体,例如杂交形成完全或部分双链化合物的两条链或者具有足够的自我互补性以允许杂交和形成完全或部分双链化合物的单链。两条链可内部连接留下游离的3′或5′末端,或者可连接形成连续的发夹结构或环。发夹结构可含有5′或者3′末端的突出端,产生单链特征的延伸。双链化合物任选地可包括末端的突出端。其它修饰可包括与末端之一、选定核苷酸位置、糖位置或核苷间键之一连接的缀合基。或者,两条链可通过非核酸部分或连接基团连接。当仅由一条链形成时,dsRNA可呈自身互补的发夹型分子的形式,该发夹型分子自身对折形成双链体。因此,dsRNA可以是完全或部分双链的。基因表达的特异性调节可通过在转基因细胞系中稳定表达dsRNA发夹来实现,但是在某些实施方案中,基因表达或功能被上调。当由两条链形成或由呈自身对折形成双链体的自身互补的发夹型分子的形式的单链形成时,两条链(单链的双链体形成区)是以Watson-Crick方式进行碱基配对的互补RNA链。
一旦被引入系统,本发明化合物可引起一种或多种酶或结构蛋白的作用以影响靶核酸的切割或其它修饰,或可通过基于占用的机制起作用。通常,核酸(包括寡核苷酸)可被描述为“类DNA”(即通常具有一个或多个2′-脱氧糖,且通常具有T而非U碱基)或“类RNA”(即通常具有一个或多个2′-羟基或2′-修饰糖,且通常具有U而非T碱基)。核酸螺旋可采取多于一种类型的结构,最常见的是A型和B型。一般认为,具有类似B型结构的寡核苷酸为“类DNA”,而那些具有类似A型结构的寡核苷酸为“类RNA”。在一些(嵌合)实施方案中,反义化合物可同时包含A型区和B型区。
在另一个实施方案中,所需寡核苷酸或反义化合物包括以下的至少一种:反义RNA、反义DNA、嵌合反义寡核苷酸、含修饰键的反义寡核苷酸、干扰RNA(RNAi)、短干扰RNA(siRNA);微小干扰RNA(miRNA);小时序RNA(stRNA);或者短发夹RNA(shRNA);小RNA诱导的基因激活(RNAa);小激活RNA(saRNA)或其组合。
dsRNA还可激活基因表达,这是一种被称为“小RNA诱导的基因激活”或RNAa的机制。靶向基因启动子的dsRNA诱导相关基因的有效转录激活。在人细胞中利用称为“小激活RNA”(saRNA)的合成dsRNA证实了RNAa。
已经发现小双链RNA(dsRNA)(例如小干扰RNA(siRNA)和微小RNA(miRNA))是称为RNA干扰(RNAi)的进化保守机制的引发剂。RNAi总是引起基因沉默。然而,在紧接的实施例部分详述的情况下,表明寡核苷酸提高唐氏综合征基因多核苷酸及其编码产物的表达和/或功能。dsRNA也可作为小激活RNA(saRNA)。虽然不希望受理论的束缚,但通过靶向基因启动子的序列,saRNA在称为dsRNA诱导的转录激活(RNAa)的现象中诱导靶基因表达。
在另一个实施方案中,本文鉴定的“靶区段”可用于筛选调节唐氏综合征基因多核苷酸表达的其它化合物。“调节剂”是降低或提高编码唐氏综合征基因的核酸分子的表达且包含与靶区段互补的至少5个核苷酸部分的化合物。筛选方法包括下列步骤:使编码有义或天然反义的唐氏综合征基因多核苷酸的核酸分子的靶区段与一种或多种候选调节剂接触,选择降低或提高编码唐氏综合征基因多核苷酸的核酸分子表达的一种或多种候选调节剂,例如SEQ ID NO:7-24。一旦表明一种或多种候选调节剂能够调节(例如降低或提高)编码唐氏综合征基因多核苷酸的核酸分子的表达,那么调节剂便可用于唐氏综合征基因多核苷酸功能的进一步探索性研究,或用作本发明的研究、诊断或治疗物质。
靶向天然反义序列调节靶基因的功能。例如,唐氏综合征基因(例如登录号NM_101395和NM_004414)。在一个实施方案中,靶标是唐氏综合征基因的反义多核苷酸。在一个实施方案中,反义寡核苷酸靶向唐氏综合征基因多核苷酸的有义和/或天然反义序列(例如登录号NM_101395和NM_004414)、变体、等位基因、同种型、同源物、突变体、衍生物、片段及其互补序列。优选所述寡核苷酸是反义分子,所述靶标包括反义和/或有义唐氏综合征基因多核苷酸的编码区和非编码区。
本发明的靶区段还可与本发明的其各自的互补反义化合物结合,以形成稳定的双链(双链体)寡核苷酸。
本领域已证实这类双链寡核苷酸部分通过反义机制调节靶标表达并调节翻译以及RNA加工。此外,可对双链部分进行化学修饰。例如,已表明,这种双链部分通过双链体的反义链与靶标进行经典杂交而抑制该靶标,从而引发靶标的酶促降解。
在一个实施方案中,反义寡核苷酸靶向唐氏综合征基因多核苷酸(例如登录号NM_101395和NM_004414)、其变体、等位基因、同种型、同源物、突变体、衍生物、片段及互补序列。优选所述寡核苷酸是反义分子。
按照本发明的实施方案,靶核酸分子不只限于唐氏综合征基因,而是延伸到唐氏综合征基因分子的任何同种型、受体、同源物等。
在另一个实施方案中,寡核苷酸靶向唐氏综合征基因多核苷酸的天然反义序列,例如,SEQ ID NO:3-6所示多核苷酸及其任何变体、等位基因、同源物、突变体、衍生物、片段和互补序列。反义寡核苷酸的实例如SEQ ID NO:7-24所示。
在一个实施方案中,寡核苷酸与唐氏综合征基因反义序列的核酸序列(包括而不限于与唐氏综合征基因多核苷酸有关的非编码有义和/或反义序列)互补或结合,并调节唐氏综合征基因分子的表达和/或功能。
在另一个实施方案中,寡核苷酸与SEQ ID NO:3-6所示的唐氏综合征基因天然反义序列的核酸序列互补或结合,并调节唐氏综合征基因分子的表达和/或功能。
在一个实施方案中,寡核苷酸包含SEQ ID NOS:7-24的至少5个连续核苷酸的序列,并调节唐氏综合征基因分子的表达和/或功能。
多核苷酸靶标包含唐氏综合征基因,包括其家族成员、唐氏综合征基因的变体;唐氏综合征基因的突变体,包括SNP;唐氏综合征基因的非编码序列;唐氏综合征基因的等位基因;物种变体、片段等。优选所述寡核苷酸是反义分子。
在另一个实施方案中,靶向唐氏综合征基因多核苷酸的寡核苷酸包括:反义RNA,干扰RNA(RNAi),短干扰RNA(siRNA);微小干扰RNA(miRNA);小时序RNA(stRNA)或短发夹RNA(shRNA);小RNA诱导的基因激活(RNAa)或小激活RNA(saRNA)。
在另一个实施方案中,靶向唐氏综合征基因多核苷酸(例如SEQ ID NO:3-6)调节这些靶标的表达或功能。在一个实施方案中,与对照相比,表达或功能上调。在另一个实施方案中,与对照相比,表达或功能下调。
在另一个实施方案中,反义化合物包含SEQ ID NO:7-24所示序列。这些寡核苷酸可包含一个或多个修饰核苷酸、较短片段或较长片段、修饰键等。
在另一个实施方案中,SEQ ID NO:7-24包含一个或多个LNA核苷酸。
所需靶核酸的调节可以本领域已知的若干方法进行。例如,反义寡核苷酸、siRNA等。酶核酸分子(例如核酶)是能够催化多种反应中的一种或多种的核酸分子,包括以核苷酸碱基序列特异性方式重复切割其它分离的核酸分子的能力。这样的酶核酸分子可用于例如靶向几乎任何RNA转录物。
因为它们的序列特异性,反式切割酶核酸分子显示作为用于人疾病的治疗药物的前景。酶核酸分子可被设计成切割细胞RNA背景中的特异性RNA靶标。这样的切割事件使mRNA变得无功能,使该RNA不表达蛋白质。如此,可选择性抑制与疾病状态有关的蛋白质的合成。
通常,具有RNA切割活性的酶核酸首先通过结合靶RNA而起作用。这种结合通过酶核酸的靶结合部分而发生,该靶结合部分与起切割靶RNA作用的该分子的酶促部分保持得十分靠近。因此,酶核酸首先识别并接着通过互补碱基配对结合靶RNA,一旦结合到正确位点,则进行酶促作用切割靶RNA。这种靶RNA的策略性切割将破坏其直接合成编码蛋白的能力。在酶核酸已结合并切割其RNA靶标之后,便从该RNA上释放出来,寻找另一个靶标,并可重复地结合并切割新靶标。
数种方法例如体外选择(进化)策略已被用于发展能够催化例如切割和连接磷酸二酯键和酰胺键等多种反应的新的核酸催化剂。
催化活性最优的核酶的研发主要归因于为调节基因表达的目的而使用切割RNA的核酶的任何策略。例如,锤头核酶在饱和(10mM)浓度的Mg2+辅因子存在下以约1min-1的催化速率(kcat)起作用。已表明人工“RNA连接酶”核酶以约100min-1的速率催化相应的自我修饰反应。此外,已知具有由DNA组成的底物结合臂的某些修饰锤头核酶以接近100min-1的多倍周转率(multiple turn-over rate)催化RNA切割。最后,用某些核苷酸类似物取代锤头的催化核心内的特定残基得到催化率提升10倍的修饰核酶。这些研究结果说明,核酶可以比大多数天然自切割核酶体外表现的显著高的催化速率促进化学转变。因此有可能的是,可优化某些自切割核酶的结构以获得最大的催化活性,或者可产生RNA磷酸二酯切割速率显著更快的全新的RNA模体。
在1987年首次表明,符合“锤头”模型的RNA催化剂对RNA底物的分子间切割。回收RNA催化剂,并使之与多种RNA分子反应,证明了它确实有催化性。
根据“锤头”模体设计的催化性RNA已被用于通过在催化性RNA中进行适当碱基改变以切割特定靶序列来维持与靶序列的必要碱基配对。这使得能够利用催化性RNA切割特定靶序列,并且表明了按照“锤头”模型设计的催化性RNA可能体内切割特定的底物RNA。
RNA干扰(RNAi)已成为调节哺乳动物和哺乳动物细胞中基因表达的有力工具。该方法需要利用表达质粒或病毒和被加工成siRNA的小发夹RNA的编码序列将小干扰RNA(siRNA)作为RNA自身或DNA递送。该系统能够将前siRNA有效转运到细胞质中,在细胞质中它们有活性,并允许使用受调节和组织特异的启动子进行基因表达。
在一个实施方案中,寡核苷酸或反义化合物包含核糖核酸(RNA)和/或脱氧核糖核酸(DNA)的寡聚体或多聚体,或其模拟物、嵌合体、类似物或同源物。该术语包括由天然存在的核苷酸、糖和共价核苷间(骨架)键组成的寡核苷酸以及起类似作用的具有非天然存在部分的寡核苷酸。由于所需性质,例如细胞吸收增加、对靶核酸的亲和力提高以及在核酸酶存在下稳定性增强,因此通常需要优于天然形式的这类修饰或取代的寡核苷酸。
按照本发明,寡核苷酸或“反义化合物”包括反义寡核苷酸(例如RNA、DNA、其模拟物、嵌合体、类似物或同源物)、核酶、外部指导序列(EGS)寡核苷酸、siRNA化合物、单链或双链RNA干扰(RNAi)化合物例如siRNA化合物、saRNA、aRNA和与靶核酸的至少一部分杂交并调节其功能的其它寡聚化合物。因此,它们可以是DNA、RNA、类DNA、类RNA或其混合物,或者可以是这些中的一种或多种的模拟物。这些化合物可以是单链、双链、环状或发夹状的寡聚化合物,并可包含结构元件,例如内部或端部凸起、错配或环。按常规制备线性反义化合物,但可将其连接或另外制备成环状和/或分支状。反义化合物可包括构建体,例如杂交形成完全或部分双链化合物的两条链或者具有足够的自我互补性以允许杂交和形成完全或部分双链化合物的单链。两条链可内部连接留下游离的3′或5′末端,或者可连接形成连续的发夹结构或环。发夹结构可包含5′或者3′末端的突出端,产生单链特征的延伸。双链化合物任选可包括末端上的突出端。其它修饰可包括连接至末端之一、选定核苷酸位置、糖位置或核苷间键之一的缀合基。或者,两条链可通过非核酸部分或连接基团连接。当仅由一条链形成时,dsRNA可呈自身互补的发夹型分子的形式,该发夹型分子自身对折形成双链体。因此,dsRNA可以是完全或部分双链的。基因表达的特异性调节可通过在转基因细胞系中稳定表达dsRNA发夹来实现。当由两条链形成或由呈自身对折形成双链体的自身互补的发夹型分子形式的单链形成时,两条链(或单链的双链体形成区)是以Watson-Crick方式进行碱基配对的互补RNA链。
一旦被引入系统,本发明化合物可引起一种或多种酶或结构蛋白的作用以影响靶核酸的切割或其它修饰,或者可通过基于占用的机制起作用。通常,核酸(包括寡核苷酸)可被描述为“类DNA”(即通常具有一个或多个2′-脱氧糖,且通常具有T而非U碱基)或“类RNA”(即通常具有一个或多个2′-羟基或2′-修饰糖,且通常具有U而非T碱基)。核酸螺旋可采取多于一种类型的结构,最常见的是A型和B型。一般认为,具有类似B型结构的寡核苷酸为“类DNA”,而那些具有类似A型结构的寡核苷酸为“类RNA”。在一些(嵌合)实施方案中,反义化合物可同时包含A型区和B型区。
本发明的反义化合物可包含长度为约5-约80个核苷酸(即约5-约80个连接核苷)的反义部分。这是指反义化合物的反义链或部分的长度。换言之,本发明的单链反义化合物包含约5-约80个核苷酸,本发明的双链反义化合物(例如dsRNA)包含长度为约5-约80个核苷酸的有义和反义链或部分。本领域普通技术人员应理解的是,这包括以下长度或其中任何范围的反义部分:5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79或80个核苷酸。
在一个实施方案中,本发明的反义化合物具有长度为10-50个核苷酸的反义部分。本领域普通技术人员应理解的是,这包括具有以下长度或其中任何范围的反义部分的寡核苷酸:10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50个核苷酸。在一些实施方案中,寡核苷酸长度为15个核苷酸。
在一个实施方案中,本发明的反义化合物或寡核苷酸化合物具有长度为12或13-30个核苷酸的反义部分。本领域普通技术人员应理解的是,这包括具有以下长度或其中任何范围的反义部分的反义化合物:12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30个核苷酸。
在另一个实施方案中,本发明的寡聚化合物还包括变体,其中在所述化合物的一个或多个核苷酸位置上存在不同碱基。例如,如果第一个核苷酸是腺苷,则可产生在该位置含有胸苷、鸟苷或胞苷的变体。这可在反义或dsRNA化合物的任何位置上完成。然后,利用本文所述方法检验这些化合物,以测定其抑制靶核酸表达的能力。
在一些实施方案中,反义化合物和靶标之间的同源性、序列同一性或互补性为约40%-约60%。在一些实施方案中,同源性、序列同一性或互补性为约60%-约70%。在一些实施方案中,同源性、序列同一性或互补性为约70%-约80%。在一些实施方案中,同源性、序列同一性或互补性为约80%-约90%。在一些实施方案中,同源性、序列同一性或互补性为约90%、约92%、约94%、约95%、约96%、约97%、约98%、约99%或约100%。
在另一个实施方案中,反义寡核苷酸(例如SEQ ID NO:4-30所示核酸分子)包含一个或多个取代或修饰。在一个实施方案中,核苷酸被锁定核酸(LNA)取代。
在另一个实施方案中,寡核苷酸靶向与唐氏综合征基因有关的编码和/或非编码序列的有义和/或反义核酸分子的一个或多个区和SEQ ID NO:1-6所示序列。寡核苷酸还靶向SEQ ID NO:1-6的重叠区。
本发明的某些寡核苷酸是嵌合寡核苷酸。在本发明的情况下,“嵌合寡核苷酸”或“嵌合体”是含有两个以上化学上不同的区(每个区由至少一个核苷酸组成)的寡核苷酸。这些寡核苷酸通常包含至少一个赋予一种或多种有益性质(例如核酸酶抗性增加、细胞吸收增加、靶结合亲和力提高)的修饰核苷酸区,以及作为能够切割RNA:DNA或RNA:RNA杂合体的酶的底物的区。举例来说,RNA酶H是细胞内切核酸酶,它切割RNA:DNA双链体的RNA链。因此,RNA酶H的活化导致对RNA靶标的切割,从而极大地提高基因表达的反义调节的有效性。因此,比起与相同靶区杂交的硫代磷酸酯脱氧寡核苷酸,当使用嵌合寡核苷酸时,通常可利用较短的寡核苷酸获得相似结果。可按常规通过凝胶电泳和必要时通过本领域已知的相关核酸杂交技术检测RNA靶标的切割。在一个实施方案中,嵌合寡核苷酸包含经修饰以提高靶结合亲和力的至少一个区,并通常包含用作RNA酶H底物的区。按常规通过测量寡核苷酸/靶标对的Tm来测定寡核苷酸对其靶标(这种情况下为编码ras的核酸)的亲和力,Tm是寡核苷酸和靶标解离时的温度;解离通过分光光度法检测。Tm越高,寡核苷酸对靶标的亲和力越大。
本发明的嵌合反义化合物可形成为两种或更多种上述寡核苷酸、修饰寡核苷酸、寡核苷和/或寡核苷酸模拟物的混合结构。这样的化合物在本领域中也称为杂合体或gapmer。教导制备这种杂合体结构的代表性美国专利包括但不限于美国专利号5,013,830、5,149,797、5,220,007、5,256,775、5,366,878、5,403,711、5,491,133、5,565,350、5,623,065、5,652,355、5,652,356和5,700,922,上述各专利通过引用结合到本文中。
在另一个实施方案中,被修饰的寡核苷酸区包含至少一个在糖的2′位置被修饰的核苷酸,最优选2′-O-烷基、2′-O-烷基-O-烷基或2′-氟-修饰核苷酸。在其它实施方案中,RNA修饰包括在RNA 3′末端的嘧啶、脱碱基残基或反向碱基的核糖上的2′-氟、2′-氨基和2′O-甲基修饰。这种修饰被常规整合到寡核苷酸中,已经表明这些寡核苷酸针对给定靶标具有比2′-脱氧寡核苷酸高的Tm(即较高的靶结合亲和力)。这种亲和力提高的作用极大地增强RNAi寡核苷酸对基因表达的抑制。RNA酶H是细胞内切核酸酶,它切割RNA:DNA双链体的RNA链;因此该酶的活化导致对RNA靶标的切割,从而可极大地提高RNAi抑制的有效性。可按常规通过凝胶电泳证实RNA靶标的切割。在另一个实施方案中,还对嵌合寡核苷酸进行修饰以提高核酸酶抗性。细胞含有多种可降解核酸的外切核酸酶和内切核酸酶。已表明许多核苷酸和核苷修饰使整合有它们的寡核苷酸比天然寡脱氧核苷酸对核酸酶消化更具抗性。按常规通过将寡核苷酸与细胞提取物或分离的核酸酶溶液一起孵育,随时间变化测量余留的完整寡核苷酸的含量(一般通过凝胶电泳),来测量核酸酶抗性。已被修饰以提高其核酸酶抗性的寡核苷酸保持完整的时间比未修饰寡核苷酸更长。已经证明多种寡核苷酸修饰提高或赋予核酸酶抗性。目前更优选含有至少一个硫代磷酸酯修饰的寡核苷酸。在某些情况下,提高靶结合亲和力的寡核苷酸修饰还能够独立地提高核酸酶抗性。一些所需的修饰可参见De Mesmaeker等(1995)Acc.Chem.Res.,28:366-374。
预期用于本发明的一些寡核苷酸的具体实例包括含有修饰骨架的寡核苷酸,修饰骨架例如硫代磷酸酯、磷酸三酯、甲基膦酸酯、短链烷基或环烷基糖间键或短链杂原子或杂环糖间键。大多数为具有硫代磷酸酯骨架和具有杂原子骨架的寡核苷酸,特别是CH2--NH--O--CH2、CH,--N(CH3)--O--CH2[称为亚甲基(甲基亚氨基)或MMI骨架]、CH2--O--N(CH3)--CH2、CH2-N(CH3)--N(CH3)--CH2和O--N(CH3)--CH2--CH2骨架,其中天然磷酸二酯骨架表示为O--P--O--CH。还优选De Mesmaeker等(1995)Acc.Chem.Res.28:366-374所披露的酰胺骨架。还优选具有吗啉代骨架结构的寡核苷酸(Summerton和Weller,美国专利号5,034,506)。在其它实施方案中,例如寡核苷酸的肽核酸(PNA)骨架、磷酸二酯骨架被聚酰胺骨架(核苷酸与聚酰胺骨架的氮杂氮原子直接或间接结合)置换。寡核苷酸还可包含一个或多个取代糖部分。寡核苷酸在2′位置包含下述基团之一:OH、SH、SCH3、F、OCN、OCH3OCH3、OCH3O(CH2)nCH3、O(CH2)nNH2或O(CH2)nCH3,其中n为1-约10;C1-C10的低级烷基、烷氧基烷氧基、取代低级烷基、烷芳基或芳烷基;Cl;Br;CN;CF3;OCF3;O--、S--或N-烷基;O--、S--或N-烯基;SOCH3;SO2CH3;ONO2;NO2;N3;NH2;杂环烷基;杂环烷芳基;氨基烷基氨基;聚烷基氨基;取代甲硅烷基;RNA切割基;报道基;嵌入剂;用于改进寡核苷酸的药代动力学性质的基团;或者用于改进寡核苷酸的药效学性质的基团和其它具有类似性质的取代基。修饰包括2′-甲氧基乙氧基[2′-O-CH2CH2OCH3,亦称为′-O-(2-甲氧乙基)]。其它修饰包括2′-甲氧基(2′-O--CH3)、2′-丙氧基(2′-OCH2CH2CH3)和2′-氟(2′-F)。也可在寡核苷酸的其它位置上产生类似修饰,尤其是3′末端核苷酸的糖的3′位置和5′末端核苷酸的5′位置。寡核苷酸还可具有糖模拟物,例如取代呋喃戊糖基的环丁基。
此外或备选地,寡核苷酸还可包含核碱基(本领域中通常简称为“碱基”)修饰或取代。本文所用“未修饰”或“天然”核苷酸包含腺嘌呤(A)、鸟嘌呤(G)、胸腺嘧啶(T)、胞嘧啶(C)和尿嘧啶(U)。修饰核苷酸包括仅罕见或短暂存在于天然核酸中的核苷酸,例如次黄嘌呤、6-甲基腺嘌呤、5-甲基嘧啶、尤其5-甲基胞嘧啶(亦称为5-甲基-2′脱氧胞嘧啶,且本领域通常称为5-Me-C)、5-羟甲基胞嘧啶(HMC)、糖基HMC和龙胆二糖基(gentobiosyl)HMC,以及合成核苷酸,例如2-氨基腺嘌呤、2-(甲氨基)腺嘌呤、2-(咪唑基烷基)腺嘌呤、2-(氨基烷基氨基)腺嘌呤或其它杂取代烷基腺嘌呤、2-硫尿嘧啶、2-硫胸腺嘧啶、5-溴尿嘧啶、5-羟甲基尿嘧啶、8-氮鸟嘌呤、7-脱氮鸟嘌呤、N6(6-氨基己基)腺嘌呤和2,6-二氨基嘌呤。可包含本领域已知的“通用”碱基,例如肌苷。已表明5-Me-C取代提高核酸双链体稳定性0.6-1.2℃(Sanghvi,Y.S.,载于Crooke,S.T.和Lebleu,B.,主编,Antisense Research andApplications,CRC Press,Boca Raton,1993,第276-278页),是目前的碱基取代。
本发明寡核苷酸的另一种修饰涉及将提高寡核苷酸的活性或细胞摄取的一个或多个部分或缀合物与寡核苷酸化学连接。这样的部分包括但不限于脂部分(例如胆固醇部分、胆甾烯基部分)、硫醚(例如己基-S-三苯甲基硫醇、巯基胆固醇)、脂肪链(例如十二烷二醇(dodecandiol)或十一基残基、磷脂例如二-十六基-rac-甘油或1,2-二-O-十六基-rac-甘油基-3-H-膦酸三乙铵)、聚胺或聚乙二醇链或金刚烷乙酸。包含亲脂部分的寡核苷酸和用于制备这种寡核苷酸的方法是本领域已知的,例如美国专利号5,138,045、5,218,105和5,459,255。
给定寡核苷酸的所有位置不必一律被修饰,实际上可将不止一种上述修饰整合入单个寡核苷酸或甚至寡核苷酸的单个核苷中。本发明还包括作为上文定义的嵌合寡核苷酸的寡核苷酸。
在另一个实施方案中,本发明的核酸分子与包括但不限于以下的另一部分缀合:脱碱基核苷酸、聚醚、聚胺、聚酰胺、肽、糖类、脂质或聚烃化合物。本领域技术人员应认识到,可将这些分子与在糖、碱基或磷酸基的若干位置上包含核酸分子的任何核苷酸的一个或多个连接。
本发明使用的寡核苷酸可合宜地按常规通过熟知的固相合成技术制备。用于这种合成的设备由包括Applied Biosystems在内的若干供应商出售。也可利用适于这种合成的任何其它方法;寡核苷酸的实际合成完全为本领域普通技术人员所掌握。同样公知的是,利用类似技术制备其它寡核苷酸,例如硫代磷酸酯和烷基化衍生物。同样公知的是,利用类似技术及市售的修饰amidite和可控孔度玻璃(controlled-pore glass,CPG)产品,例如生物素、荧光素、吖啶或补骨脂素修饰的amidite和/或CPG(可获自Glen Research,SterlingVA),以合成荧光标记寡核苷酸、生物素化寡核苷酸或其它修饰寡核苷酸,例如胆固醇修饰的寡核苷酸。
根据本发明,使用修饰例如使用LNA单体以提高由例如MOE、ANA、FANA、PS等现有化学物质组成的寡核苷酸的作用的效能、特异性和持续时间并拓宽寡核苷酸的给药途径。这可通过用LNA单体取代现行寡核苷酸中的一些单体来实现。LNA修饰寡核苷酸可具有与母体化合物相似的大小,或者可较大或优选较小。正是这类LNA修饰寡核苷酸含有少于约70%、更优选少于约60%、最优选少于50%的LNA单体,且它们的大小为约5-25个核苷酸,更优选为约12-20个核苷酸。
修饰寡核苷酸骨架包括但不限于具有正常3′-5′键的硫代磷酸酯、手性硫代磷酸酯、二硫代磷酸酯、磷酸三酯、氨基烷基磷酸三酯、包括3′烯化膦酸酯和手性膦酸酯在内的甲基膦酸酯和其它烷基膦酸酯、亚膦酸酯、包括3′-氨基氨基磷酸酯和氨基烷基氨基磷酸酯在内的氨基磷酸酯、硫羰氨基磷酸酯、硫羰烷基磷酸酯、硫羰烷基磷酸三酯和硼烷基磷酸酯(boranophosphate)、它们的2′-5′连接的类似物,以及具有反向极性的修饰寡核苷酸骨架,其中相邻的核苷单元对为3′-5′连接至5′-3′或2′-5′连接至5′-2′。还包括多种盐、混盐和游离酸形式。
教导制备上述含磷键的代表性美国专利包括但不限于美国专利号3,687,808、4,469,863、4,476,301、5,023,243、5,177,196、5,188,897、5,264,423、5,276,019、5,278,302、5,286,717、5,321,131、5,399,676、5,405,939、5,453,496、5,455,233、5,466,677、5,476,925、5,519,126、5,536,821、5,541,306、5,550,111、5,563,253、5,571,799、5,587,361和5,625,050,所述每个专利通过引用结合到本文中。
本文不含磷原子的修饰寡核苷酸骨架具有由下述键组成的骨架:短链烷基或环烷基核苷间键、混合杂原子和烷基或环烷基核苷间键或者一个或多个短链杂原子或杂环核苷间键。这些包括具有吗啉代键(部分由核苷的糖部分形成)的骨架;硅氧烷骨架;硫化物、亚砜和砜骨架;甲酰乙酰基和硫代甲酰乙酰基骨架;亚甲基甲酰乙酰基和硫代甲酰乙酰基骨架;含链烯的骨架;氨基磺酸酯骨架;亚甲基亚氨基和亚甲基肼基骨架;磺酸酯和磺酰胺骨架;酰胺骨架以及具有混N、O、S和CH2成分的其它骨架。
教导制备上述寡核苷的代表性美国专利包括但不限于美国专利号5,034,506、5,166,315、5,185,444、5,214,134、5,216,141、5,235,033、5,264,562、5,264,564、5,405,938、5,434,257、5,466,677、5,470,967、5,489,677、5,541,307、5,561,225、5,596,086、5,602,240、5,610,289、5,602,240、5,608,046、5,610,289、5,618,704、5,623,070、5,663,312、5,633,360、5,677,437和5,677,439,各专利通过引用结合到本文中。
在其它寡核苷酸模拟物中,核苷酸单元的糖和核苷间键(即骨架)均被新的基团所取代。维持碱基单元以与合适的核酸靶化合物杂交。一种这样的寡聚化合物,即已表明具有优异杂交性质的寡核苷酸模拟物称为肽核酸(PNA)。在PNA化合物中,寡核苷酸的糖骨架被含酰胺的骨架、特别是氨基乙基甘氨酸骨架取代。核碱基被保留,并直接或间接与骨架的酰胺部分的氮杂氮原子结合。教导制备PNA化合物的代表性美国专利包括但不限于美国专利号5,539,082、5,714,331和5,719,262,上述专利各通过引用结合到本文中。PNA化合物的更多教导可参见Nielsen等(1991)Science 254,1497-1500。
在本发明另一个优选实施方案中,具有硫代磷酸酯骨架的寡核苷酸和具有杂原子骨架的寡核苷,特别是-CH2-NH-O-CH2-、称为亚甲基(甲基亚氨基)或MMI骨架的-CH2-N(CH3)-O-CH2-、-CH2-O-N(CH3)-CH2-、-CH2N(CH3)-N(CH3)CH2-和-O-N(CH3)-CH2-CH2-(其中天然磷酸二酯骨架表示为上文引用的美国专利号5,489,677的-O-P-O-CH2-)以及上文引用的美国专利号5,602,240的酰胺骨架。还有具有上文引用的美国专利号5,034,506的吗啉代骨架结构的寡核苷酸。
修饰寡核苷酸还可包含一个或多个取代糖部分。寡核苷酸在2′位置包含下述基团之一:OH;F;O-、S-或N-烷基;O-、S-或N-烯基;O-、S-或N-炔基;或者O烷基-O-烷基,其中烷基、烯基和炔基可以是取代或未取代的C到CO烷基(C to CO alkyl)或C2到CO烯基和炔基(C2 to CO alkenyl and alkynyl)。特别是O(CH2)nOmCH3、O(CH2)n,OCH3、O(CH2)nNH2、O(CH2)nCH3、O(CH2)nONH2和O(CH2nON(CH2)nCH3)2,其中n和m可以是1-约10。其它寡核苷酸在2′位置包含下列基团之一:C到CO(C to CO)、低级烷基、取代低级烷基、烷芳基、芳烷基、O-烷芳基或O-芳烷基、SH、SCH3、OCN、Cl、Br、CN、CF3、OCF3、SOCH3、SO2CH3、ONO2、NO2、N3、NH2、杂环烷基、杂环烷芳基、氨基烷基氨基、聚烷基氨基、取代甲硅烷基、RNA切割基、报道基、嵌入剂、用于改进寡核苷酸的药代动力学性质的基团或用于改进寡核苷酸的药效学性质的基团以及其它具有类似性质的取代基。修饰包括2′-甲氧基乙氧基(2′-O-CH2CH2OCH3,亦称为2′-O-(2-甲氧乙基)或2′-MOE),即一种烷氧基烷氧基。另一种修饰包括下文实施例所述的2′-二甲基氨基氧基乙氧基(即O(CH2)2ON(CH3)2基,亦称为2′-DMAOE)和2′-二甲基氨基乙氧基乙氧基(本领域亦称为2′-O-二甲基氨基乙氧基乙基或2′-DMAEOE),即2′-O-CH2-O-CH2-N(CH2)2。
其它修饰包括2′-甲氧基(2′-OCH3)、2′-氨基丙氧基(2′-OCH2CH2CH2NH2)和2′-氟(2′-F)。类似修饰也可在寡核苷酸的其它位置上进行,尤其是3′末端核苷酸的糖的3′位置或2′-5′连接的寡核苷酸中和5′末端核苷酸的5′位置。寡核苷酸还可具有糖模拟物,例如取代呋喃戊糖基糖的环丁基部分。教导制备这种修饰糖结构的代表性美国专利包括但不限于美国专利号4,981,957、5,118,800、5,319,080、5,359,044、5,393,878、5,446,137、5,466,786、5,514,785、5,519,134、5,567,811、5,576,427、5,591,722、5,597,909、5,610,300、5,627,053、5,639,873、5,646,265、5,658,873、5,670,633和5,700,920,各专利通过引用结合到本文中。
寡核苷酸还可包含核碱基(本领域中通常简称为“碱基”)修饰或取代。本文所用“未修饰”或“天然”核苷酸包括嘌呤碱基腺嘌呤(A)和鸟嘌呤(G),以及嘧啶碱基胸腺嘧啶(T)、胞嘧啶(C)和尿嘧啶(U)。修饰核苷酸包括其它合成和天然核苷酸,例如5-甲基胞嘧啶(5-me-C);5-羟甲基胞嘧啶;黄嘌呤;次黄嘌呤;2-氨基腺嘌呤;腺嘌呤和鸟嘌呤的6-甲基衍生物和其它烷基衍生物;腺嘌呤和鸟嘌呤的2-丙基衍生物和其它烷基衍生物;2-硫尿嘧啶;2-硫胸腺嘧啶和2-硫胞嘧啶;5-卤代尿嘧啶和胞嘧啶;5-丙炔基尿嘧啶和胞嘧啶;6-氮尿嘧啶、胞嘧啶和胸腺嘧啶;5-尿嘧啶(假尿嘧啶);4-硫尿嘧啶;8-卤基、8-氨基、8-巯基、8-硫烷基、8-羟基和其它8-取代的腺嘌呤和鸟嘌呤;5-卤代尤其5-溴、5-三氟甲基和其它5-取代的尿嘧啶和胞嘧啶;7-甲基鸟嘌呤(7-methylquanine)和7-甲基腺嘌呤;8-氮鸟嘌呤和8-氮腺嘌呤;7-脱氮鸟嘌呤和7-脱氮腺嘌呤以及3-脱氮鸟嘌呤和3-脱氮腺嘌呤。
此外,核苷酸包括美国专利号3,687,808披露的核苷酸、“The ConciseEncyclopedia of Polymer Science And Engineering”,第858-859页,Kroschwitz,J.I.主编,John Wiley & Sons,1990披露的核苷酸;Englisch等,“Angewandle Chemie,国际版”,1991,30,第613页披露的核苷酸和Sanghvi,Y.S.,第15章,“Antisense Research andApplications”,第289-302页,Crooke,S.T.和Lebleu,B.ea.,CRC Press,1993披露的核苷酸。这些核苷酸中的一些尤其可用于提高本发明寡聚化合物的结合亲和力。这些包括5-取代嘧啶、6-氮嘧啶和N-2、N-6和0-6取代嘌呤,包括2-氨基丙基腺嘌呤、5-丙炔基尿嘧啶和5-丙炔基胞嘧啶。已表明5-甲基胞嘧啶取代提高核酸双链体稳定性0.6-1.2℃(Sanghvi,Y.S.、Crooke,S.T.和Lebleu,B.,主编,′Antisense Research and Applications′,CRCPress,Boca Raton,1993,第276-278页),且是现有的碱基取代,更尤其当与2′-O甲氧乙基糖修饰组合时。
教导制备上述修饰核苷酸以及其它修饰核苷酸的代表性美国专利包括但不限于美国专利号3,687,808以及4,845,205、5,130,302、5,134,066、5,175,273、5,367,066、5,432,272、5,457,187、5,459,255、5,484,908、5,502,177、5,525,711、5,552,540、5,587,469、5,596,091、5,614,617、5,750,692和5,681,941,各专利通过引用结合到本文中。
本发明寡核苷酸的另一种修饰涉及将提高寡核苷酸的活性、细胞分布或细胞摄取的一个或多个部分或缀合物与寡核苷酸化学连接。
这样的部分包括但不限于脂质部分,例如胆固醇部分、胆酸、硫醚(例如己基-S-三苯甲基硫醇、巯基胆固醇)、脂肪链(例如十二烷二醇或十一基残基)、磷脂(例如二-十六基-rac-甘油或1,2-二-O-十六基-rac-甘油基-3-H-膦酸三乙铵)、聚胺或聚乙二醇链或金刚烷乙酸、棕榈基部分或者十八胺或己氨基-羰基-t羟胆固醇部分。
教导制备这类寡核苷酸缀合物的代表性美国专利包括但不限于美国专利号4,828,979、4,948,882、5,218,105、5,525,465、5,541,313、5,545,730、5,552,538、5,578,717、5,580,731、5,580,731、5,591,584、5,109,124、5,118,802、5,138,045、5,414,077、5,486,603、5,512,439、5,578,718、5,608,046、4,587,044、4,605,735、4,667,025、4,762,779、4,789,737、4,824,941、4,835,263、4,876,335、4,904,582、4,958,013、5,082,830、5,112,963、5,214,136、5,082,830、5,112,963、5,214,136、5,245,022、5,254,469、5,258,506、5,262,536、5,272,250、5,292,873、5,317,098、5,371,241、5,391,723、5,416,203、5,451,463、5,510,475、5,512,667、5,514,785、5,565,552、5,567,810、5,574,142、5,585,481、5,587,371、5,595,726、5,597,696、5,599,923、5,599,928和5,688,941,各专利通过引用结合到本文中。
药物发现:本发明的化合物也可应用于药物发现和靶标验证领域。本发明包括在药物发现努力中利用本文鉴定的化合物和靶区段以阐明在唐氏综合征基因多核苷酸和疾病状态、表型或病况之间存在的关系。这些方法包括检测或调节唐氏综合征基因多核苷酸,包括将样品、组织、细胞或生物体与本发明的化合物接触,在治疗后的某一时间测量唐氏综合征基因多核苷酸的核酸或蛋白水平和/或相关表型或化学终点,并任选地将测量值与未治疗样品或用本发明另一化合物治疗的样品作比较。这些方法也可与其它实验平行或联合进行,以测定靶标验证过程的未知基因的功能,或者测定作为治疗或预防特定疾病、病况或表型的靶标的特定基因产物的有效性。
评价基因表达的上调或抑制
外源核酸到宿主细胞或生物体内的转移可通过直接检测细胞或生物体中核酸的存在情况而评价。这种检测可通过本领域公知的若干方法完成。例如,外源核酸的存在情况可通过DNA印迹或利用特异扩增与该核酸相关的核苷酸序列的引物通过聚合酶链反应(PCR)技术来检测。外源核酸的表达也可利用包括基因表达分析在内的常规方法测量。例如,可利用RNA印迹和反转录PCR(RT-PCR)检测和定量分析从外源核酸产生的mRNA。
来自外源核酸的RNA表达也可通过测量酶活性或报道蛋白活性来检测。例如,可按作为外源核酸正在产生效应RNA的指示的靶核酸表达的减少或增加,来间接测量反义调节活性。基于序列保守,可设计并利用引物扩增靶基因的编码区。首先,可使用各基因的最高表达的编码区建立模型对照基因,虽然可使用任何编码或非编码区。通过将各个编码区插入报道编码区及其poly(A)信号之间来装配各对照基因。这些质粒将产生在基因上游部分带有报道基因和在3′非编码区中带有潜在RNAi靶标的mRNA。通过报道基因的调节来测定各个反义寡核苷酸的有效性。可用于本发明方法的报道基因包括乙酰羟酸合酶(AHAS)、碱性磷酸酶(AP)、β半乳糖苷酶(LacZ)、β葡糖醛酸糖苷酶(betaglucoronidase,GUS)、氯霉素乙酰转移酶(CAT)、绿色荧光蛋白(GFP)、红色荧光蛋白(RFP)、黄色荧光蛋白(YFP)、青色荧光蛋白(CFP)、辣根过氧化物酶(HRP)、萤光素酶(Luc)、胭脂氨酸合酶(NOS)、章鱼碱合酶(OCS)及其衍生物。可利用多种选择标记,其赋予对氨苄青霉素、博来霉素、氯霉素、庆大霉素、潮霉素、卡那霉素、林可霉素、甲氨蝶呤、膦丝菌素、嘌呤霉素和四环素的抗性。测定报道基因的调节的方法是本领域公知的,包括但不限于荧光测定法(例如荧光光谱法、荧光活化细胞分选术(FACS)、荧光显微术)、抗生素抗性测定。
可采用本领域技术人员已知的方法和本文其它部分描述的方法,测定DYRK1、DSCR1蛋白和mRNA表达。例如,可采用免疫测定(例如ELISA)测量蛋白质水平。用于ELISA的唐氏综合征基因抗体是市售的,例如来自R&D Systems(Minneapolis,MN),Abcam,Cambridge,MA。
在实施方案中,通过与对照样品中唐氏综合征基因表达进行比较,来评价使用本发明的反义寡核苷酸治疗的样品(例如体内或体外的细胞或组织)中的DYRK1、DSCR1表达(例如mRNA或蛋白质)。例如,可以用本领域技术人员已知的方法,将蛋白质或核酸的表达与模拟治疗或未治疗样品中的表达进行比较。或者,可根据所需的信息,与用对照反义寡核苷酸(例如具有改变序列或不同序列)治疗的样品进行比较。在另一实施方案中,可将治疗样品相对未治疗样品中唐氏综合征基因蛋白质或核酸表达的相异与治疗样品相对未治疗样品中不同核酸(包括研究人员认为适当的任何标准品,例如持家基因)表达的差异进行比较。
所观察到的差异可以按需要表示为例如比率或分数的形式,以便用于与对照比较。在实施方案中,与未治疗样品或用对照核酸治疗的样品相比,用本发明的反义寡核苷酸治疗的样品中唐氏综合征基因mRNA或蛋白质的水平提高或降低约1.25倍-约10倍或更多。在实施方案中,唐氏综合征基因mRNA或蛋白质的水平提高或降低至少约1.25倍、至少约1.3倍、至少约1.4倍、至少约1.5倍、至少约1.6倍、至少约1.7倍、至少约1.8倍、至少约2倍、至少约2.5倍、至少约3倍、至少约3.5倍、至少约4倍、至少约4.5倍、至少约5倍、至少约5.5倍、至少约6倍、至少约6.5倍、至少约7倍、至少约7.5倍、至少约8倍、至少约8.5倍、至少约9倍、至少约9.5倍、或至少约10倍或更多。试剂盒、研究试剂、诊断剂和治疗药
本发明的化合物可用于诊断、治疗和预防,和用作研究试剂和试剂盒的组分。此外,本领域普通技术人员常常使用能够以极高特异性抑制基因表达的反义寡核苷酸,以阐明特定基因的功能或区分生物途径的不同成员的功能。
对于在试剂盒和诊断以及多种生物系统中的使用,本发明的化合物可单独或与其它化合物或治疗药联合用作差别分析和/或组合分析中的工具,以阐明在细胞和组织中表达的基因的部分或完整互补序列的表达模式。
本文所用术语“生物系统”或“系统”定义为表达或使之有能力表达唐氏综合征基因产物的任何生物体、细胞、细胞培养物或组织。这些包括但不限于人、转基因动物、细胞、细胞培养物、组织、异种移植物、移植体及其组合。
作为一个非限制性实例,将用一种或多种反义化合物治疗的细胞或组织中的表达模式与未用反义化合物治疗的对照细胞或组织作比较,分析所产生模式的基因表达的不同水平,因为它们例如与受检基因的疾病关联性、信号转导途径、细胞定位、表达水平、大小、结构或功能有关。可在影响表达模式的其它化合物存在或不存在的情况下,对刺激或未刺激的细胞进行这些分析。
本领域已知的基因表达分析方法的实例包括DNA阵列或微阵列(Brazma和Vilo(2000)FEBS Lett.,480,17-24;Celis等(2000)FEBS Lett.,480,2-16)、SAGE(基因表达系列分析)(Madden等(2000)Drug Discov.Today,5,415-425)、READS(消化cDNA的限制酶扩增)(Prashar和Weissman(1999)Methods Enzymol.,303,258-72)、TOGA(总基因表达分析)(Sutcliffe等(2000)Proc.Natl.Acad.Sci.U.S.A.,97,1976-81)、蛋白质阵列和蛋白质组学(Celis等(2000)FEBS Lett.,480,2-16;Jungblut等,Electrophoresis,1999,20,2100-10)、表达序列标签(EST)测序(Celis等,FEBS Lett.,2000,480,2-16;Larsson等,J.Biotechnol.,2000,80,143-57)、消减式RNA指纹分析(subtractive RNAfingerprinting,SuRF)(Fuchs等(2000)Anal.Biochem.286,91-98;Larson等(2000)Cytometry 41,203-208)、消减式克隆(subtractive cloning)、差异展示(DD)(Jurecic和Belmont (2000)Curr.Opin.Microbiol.3,316-21)、比较基因组杂交(Carulli等(1998)J.Cell Biochem.Suppl.,31,286-96)、FISH(荧光原位杂交)技术(Going和Gusterson(1999)Eur.J.Cancer,35,1895-904)和质谱法(To,Comb.(2000)Chem.High ThroughputScreen,3,235-41)。
本发明的化合物可用于研究和诊断,因为这些化合物与编码唐氏综合征基因的核酸杂交。例如,作为有效的唐氏综合征基因调节剂以本文公开的这种效率和在这样的条件下杂交的寡核苷酸在有助于基因扩增或检测的条件下分别是有效的引物或探针。这些引物和探针可用于需要特异性检测编码唐氏综合征基因的核酸分子的方法和用于检测的所述核酸分子的扩增,或者用于唐氏综合征基因的其它研究。可通过本领域已知方法检测本发明的反义寡核苷酸(尤其是引物和探针)与编码唐氏综合征基因的核酸的杂交。这样的方法可包括将酶与寡核苷酸缀合、放射性标记寡核苷酸或任何其它适当的检测方法。也可制备利用这种检测方法检测样品中唐氏综合征基因水平的试剂盒。
为了治疗用途,本领域技术人员还对反义序列的特异性和灵敏度进行控制。在动物(包括人)疾病状态的治疗中已使用反义化合物作为治疗部分。已将反义寡核苷酸药物安全有效地给予人,多项临床试验目前正在进行中。因此确定的是,反义化合物可以是有用的治疗方式,其可设计成用于治疗细胞、组织和动物(尤其人)的治疗方案。
对于治疗,通过给予本发明的反义化合物来治疗动物(优选人),所述动物疑似患有可通过调节唐氏综合征基因多核苷酸的表达而治疗的疾病或病症。例如,在一个非限制性实施方案中,所述方法包括将治疗有效量的唐氏综合征基因调节剂给予需要治疗的动物的步骤。本发明的唐氏综合征基因调节剂有效调节唐氏综合征基因的活性或调节唐氏综合征基因蛋白的表达。在一个实施方案中,相比对照,动物的唐氏综合征基因的活性或表达被抑制约10%。优选动物的唐氏综合征基因的活性或表达被抑制约30%。更优选动物的唐氏综合征基因的活性或表达被抑制50%以上。因此,相比对照,寡聚化合物对唐氏综合征基因mRNA表达的调节为:至少10%、至少50%、至少25%、至少30%、至少40%、至少50%、至少60%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%。
在一个实施方案中,相比对照,动物的唐氏综合征基因的活性或表达提高约10%。优选动物的唐氏综合征基因的活性或表达提高约30%。更优选动物的唐氏综合征基因的活性或表达提高50%以上。因此,相比对照,寡聚化合物对唐氏综合征基因mRNA表达的调节为:至少10%、至少50%、至少25%、至少30%、至少40%、至少50%、至少60%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%。
例如,可测量动物的血清、血液、脂肪组织、肝脏或任何其它体液、组织或器官中的唐氏综合征基因表达的减少。优选包含在待分析的所述体液、组织或器官中的细胞含有编码唐氏综合征基因肽的核酸分子和/或唐氏综合征基因蛋白自身。
可通过将有效量的化合物加入合适的药学上可接受的稀释剂或载体中,来将本发明的化合物用于药物组合物。本发明的化合物和方法也可用于预防用途。
缀合物:本发明寡核苷酸的其它修饰涉及将提高寡核苷酸的活性、细胞分布或细胞摄取的一个或多个部分或缀合物与寡核苷酸化学连接。这些部分或缀合物可包括与官能团共价连接的缀合基,例如伯羟基或仲羟基。本发明的缀合基包括嵌入剂、报道分子、聚胺、聚酰胺、聚乙二醇、聚醚、增强寡聚体的药效学性质的基团和增强寡聚体药代动力学性质的基团。典型的缀合基包括胆固醇、脂质、磷脂、生物素、吩嗪、叶酸、菲啶、蒽醌、吖啶、荧光素、罗丹明、香豆素和染料。在本发明的情况下,增强药效学性质的基团包括提高摄取、提高降解抗性和/或加强与靶核酸的序列特异性杂交的基团。在本发明的情况下,增强药代动力学性质的基团包括改善本发明化合物的摄取、分布、代谢或排出的基团。代表性缀合基披露于1992年10月23日提交的国际专利申请号PCT/US92/09196和美国专利号6,287,860,所述文献通过引用结合到本文中。缀合部分包括但不限于:脂部分(例如胆固醇部分)、胆酸、硫醚(例如己基-5-三苯甲基硫醇、巯基胆固醇)、脂肪链(例如十二烷二醇或十一基残基)、磷脂(例如二-十六基-rac-甘油或1,2-二-O-十六基-rac-甘油基-3-H膦酸三乙铵)、聚胺或聚乙二醇链、或金刚烷乙酸、棕榈基部分、或十八烷基胺或己氨基-羰基-氧基胆固醇部分。本发明的寡核苷酸还可与例如以下的活性药物缀合:阿司匹林、华法林、苯基丁氮酮、布洛芬、舒洛芬、芬布芬、酮洛芬、(S)-(+)-普拉洛芬、卡洛芬、丹磺酰肌氨酸、2,3,5-三碘苯甲酸、氟芬那酸、亚叶酸、苯并噻二嗪(benzothiadiazide)、氯噻嗪、二氮杂、吲哚美辛(indomethicin)、巴比妥类药物、头孢菌素、磺胺药、抗糖尿病药、抗菌药或抗生素。
教导制备这类寡核苷酸缀合物的代表性美国专利包括但不限于美国专利号4,828,979、4,948,882、5,218,105、5,525,465、5,541,313、5,545,730、5,552,538、5,578,717,5,580,731、5,580,731、5,591,584、5,109,124、5,118,802、5,138,045、5,414,077、5,486,603、5,512,439、5,578,718、5,608,046、4,587,044、4,605,735、4,667,025、4,762,779、4,789,737、4,824,941、4,835,263、4,876,335、4,904,582、4,958,013、5,082,830、5,112,963、5,214,136、5,082,830、5,112,963、5,214,136、5,245,022、5,254,469、5,258,506、5,262,536、5,272,250、5,292,873、5,317,098、5,371,241,5,391,723、5,416,203,5,451,463、5,510,475、5,512,667、5,514,785、5,565,552、5,567,810、5,574,142、5,585,481、5,587,371、5,595,726、5,597,696、5,599,923、5,599,928和5,688,941。
制剂:本发明的化合物还可与其它分子、分子结构或化合物混合物一起混合、包封、缀合或者以其它方式缔合,作为例如脂质体、靶向受体的分子、口服、直肠、局部或其它制剂,以有助于摄取、分布和/或吸收。教导制备这种有助于摄取、分布和/或吸收的制剂的代表性美国专利包括但不限于美国专利号5,108,921、5,354,844、5,416,016、5,459,127、5,521,291、5,543,165、5,547,932、5,583,020、5,591,721、4,426,330、4,534,899、5,013,556、5,108,921、5,213,804、5,227,170、5,264,221、5,356,633、5,395,619、5,416,016、5,417,978、5,462,854、5,469,854、5,512,295、5,527,528、5,534,259、5,543,152、5,556,948、5,580,575和5,595,756,各专利通过引用结合到本文中。
虽然不必在载体情况下给予反义寡核苷酸以调节靶标表达和/或功能,但是本发明的实施方案涉及用于表达反义寡核苷酸的表达载体构建体,其包含启动子、杂合启动子基因序列,并具有强的组成型启动子活性,或者可在所需情况下诱导的启动子活性。
在一个实施方案中,发明实践包括用适当的核酸递送系统给予至少一种前述反义寡核苷酸。在一个实施方案中,该系统包含与多核苷酸有效连接的非病毒载体。这种非病毒载体的实例只包括寡核苷酸(例如SEQ ID NO:7-24中的任一种或多种),或包括与合适的蛋白质、多糖或脂质制备物组合的寡核苷酸。
其它合适的核酸递送系统包括病毒载体,通常为来自腺病毒、腺伴随病毒(AAV)、依赖辅助病毒的腺病毒、反转录病毒或日本血凝病毒-脂质体(HVJ)复合体中至少一种的序列。优选病毒载体包含与多核苷酸有效连接的强真核启动子,例如巨细胞病毒(CMV)启动子。
另外,载体包括病毒载体、融合蛋白和化学缀合物。反转录病毒载体包括莫洛尼鼠白血病病毒和基于HIV的病毒。一种基于HIV的病毒载体包含至少两个载体,其中gag和pol基因来自HIV基因组,env基因来自另一种病毒。优选DNA病毒载体。这些载体包括痘病毒载体(例如正痘病毒载体或禽痘病毒载体)、疱疹病毒载体(例如单纯性疱疹I型病毒(HSV)载体)、腺病毒载体和腺伴随病毒载体。
本发明的反义化合物包括任何药学上可接受的盐、酯或这种酯的盐,或者任何其它在给予动物(包括人)时能够(直接或间接)提供其生物活性代谢物或残余物的化合物。
术语“药学上可接受的盐”是指本发明化合物的生理学和药学上可接受的盐:即保留所需要的母体化合物的生物活性且不使其具有不希望的毒理学作用的盐。对于寡核苷酸,药学上可接受的盐及其应用的实例另参见美国专利号6,287,860,其通过引用结合到本文中。
本发明还包括含有本发明反义化合物的药物组合物和制剂。本发明的药物组合物可以多种方式给予,视需要局部治疗还是需要全身治疗和待治疗部位而定。给药可以是局部的(包括经眼和粘膜,包括阴道和直肠递送);经肺,例如通过吸入或吹入粉剂或气雾剂(包括通过喷雾器);气管内;鼻内;表皮和透皮;口服或胃肠外。胃肠外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注;或颅内例如鞘内或心室内给药。
对于治疗中枢神经系统组织,可通过例如注射或输注到脑脊髓液中来完成给药。将反义RNA给予到脑脊髓液中,参见例如美国专利申请公开号2007/0117772“Methods forslowing familial ALS disease progression(用于减缓家族性ALS疾病进展的方法)”,其通过引用以其整体结合到本文中。
当预定将本发明的反义寡核苷酸给予中枢神经系统细胞时,可与能够促进主题反义寡核苷酸穿透血脑屏障的一种或多种物质一起给予。例如可在内嗅皮质或海马中进行注射。在例如美国专利号6,632,427“Adenoviral-vector-mediated gene transfer intomedullary motor neurons(腺病毒载体介导的基因转移到髓质运动神经元中)”(通过引用结合到本文中的)中,阐述了通过将腺病毒载体给予肌肉组织中的运动神经元来递送神经营养因子。本领域已知直接将载体递送到脑例如纹状体、丘脑、海马或黑质,并可参见例如美国专利号6,756,523“Adenovirus vectors for the transfer of foreign genes intocells of the central nervous system particularly in brain(用于将外源基因转移到中枢神经系统尤其大脑细胞中的腺病毒载体)”(通过引用结合到本文中)中。给药可以通过注射快速进行,或通过缓慢输注或缓释制剂给药在一段时间内进行。
亦可将主题反义寡核苷酸与提供所需药学或药效学性质的物质连接或缀合。例如,可将反义寡核苷酸与本领域已知的促进透过血脑屏障渗透或转运的任何物质(例如转铁蛋白受体的抗体)偶联,并通过静脉内注射给药。可将反义化合物与例如使反义化合物更有效和/或提高反义化合物透过血脑屏障转运的病毒载体相连。亦可通过例如输注糖或氨基酸来破坏渗透性血脑屏障,所述糖包括但不仅限于:内消旋赤藻糖醇、木糖醇、D(+)半乳糖、D(+)乳糖、D(+)木糖、卫矛醇、肌醇、L(-)果糖、D(-)甘露醇、D(+)葡萄糖、D(+)阿拉伯糖、D(-)阿拉伯糖、纤维二糖、D(+)麦芽糖、D(+)棉子糖、L(+)鼠李糖、D(+)蜜二糖、D(-)核糖、核糖醇、D(+)阿拉伯糖醇、L(-)阿拉伯糖醇、D(+)岩藻糖、L(-)岩藻糖、D(-)来苏糖、L(+)来苏糖和L(-)来苏糖;所述氨基酸包括但不限于:谷氨酰胺、赖氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酸、甘氨酸、组氨酸、亮氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、酪氨酸、缬氨酸和牛磺酸。用于提高血脑屏障渗透的方法和材料阐述于例如美国专利号4,866,042“Method for the delivery of genetic material across the blood brainbarrier(递送遗传物质通过血脑屏障的方法)、6,294,520“Material for passagethrough the blood-brain barrier(用于穿过血脑屏障的方法)”和6,936,589“Parenteral delivery systems(胃肠外递送系统)”,所述文献均通过引用以其整体结合在本文中。
为了帮助摄取、分布和/或吸收,可将主题反义化合物与其它分子、分子结构或化合物的混合物(例如脂质体、靶向受体的分子、口服制剂、直肠制剂、局部制剂或其它制剂)混合、包封、缀合或以其它方式缔合。例如,制剂中可包含阳离子脂质以促进寡核苷酸摄取。显示促进摄取的一种所述组合物是LIPOFECTIN(可获自GIBCO-BRL,Bethesda,MD)。
带有至少一个2′-O-甲氧乙基修饰的寡核苷酸被认为尤其可用于口服给药。用于局部给药的药物组合物和制剂可包括透皮贴剂、软膏剂、洗剂、乳膏剂、凝胶剂、滴剂、栓剂、喷雾剂、液体剂和散剂。常规药学载体、水性、粉状或油状基料、增稠剂等可能是必要或所需的。包被避孕套、手套等也可能是有用的。
可按照制药工业中公知的传统技术制备可合宜地以单位剂型提供的本发明的药物制剂。这样的技术包括使活性成分与药用载体或赋形剂混合的步骤。通常,通过使活性成分与液体载体或细碎的固体载体或者二者均一且紧密地混合,并视需要使产物成形来制备制剂。
可将本发明的组合物配制成多种可能剂型中的任何一种,例如但不限于片剂、胶囊剂、凝胶胶囊剂、液体糖浆剂、软凝胶剂、栓剂和灌肠剂。还可将本发明的组合物配制为水性介质、非水性介质或混合介质中的混悬剂。水性混悬剂还可包含增加混悬剂粘度的物质,其包括例如羧甲基纤维素钠、山梨糖醇和/或葡聚糖。混悬剂还可包含稳定剂。
本发明的药物组合物包括但不限于溶液剂、乳剂、泡沫剂和含脂质体的制剂。本发明的药物组合物和制剂可包含一种或多种渗透促进剂、载体、赋形剂或其它活性或无活性成分。
乳剂一般为一种液体以小滴形式分散在另一种液体中的多相系,小滴直径通常大于0.1μm。乳剂可包含除分散相外的其它组分和活性药物,活性药物可作为水相、油相中的溶液或自身作为分离相存在。还包括微乳剂作为本发明的实施方案。乳剂及其使用是本领域公知的,此外参见美国专利号6,287,860。
本发明的制剂包括脂质体制剂。本发明所用术语“脂质体”是指由排列在一个或多个球形双分子层中的两亲脂质组成的囊泡。脂质体为单层或多层囊泡,其具有由亲脂物质形成的膜和含有待递送组合物的水性内部。阳离子脂质体为带正电荷的脂质体,其被认为与带负电荷的DNA分子相互作用形成稳定的复合体。pH敏感或带负电荷的脂质体被认为诱捕DNA,而不是具有DNA的复合体。阳离子和非阳离子脂质体均已用于递送DNA到细胞。
脂质体还包括“空间稳定”脂质体,本文所用的该术语是指包含一种或多种特化脂质的脂质体。当被掺入到脂质体中时,这些特化脂质导致脂质体的循环寿命比缺乏这种特化脂质的脂质体延长。空间稳定脂质体的实例是这样的脂质体:其中脂质体的形成囊泡的脂质部分的一部分包含一种或多种糖脂或用一种或多种亲水聚合物衍生,例如聚乙二醇(PEG)部分。脂质体及其使用另参见美国专利号6,287,860。
本发明的药物制剂和组合物还可包含表面活性剂。药物制品、制剂和乳剂中的表面活性剂的使用是本领域公知的。表面活性剂及其使用另参见美国专利号6,287,860,其通过引用结合到本文中。
在一个实施方案中,本发明使用多种渗透促进剂,以实现核酸尤其是寡核苷酸的有效递送。除了协助非亲脂性药物跨细胞膜扩散外,渗透促进剂还提高亲脂性药物的通透性。渗透促进剂可归类为属于五大类(即表面活性剂、脂肪酸、胆汁盐、螯合剂和非螯合非表面活性剂)之一。渗透促进剂及其使用另参见美国专利号6,287,860,其通过引用结合到本文中。
本领域技术人员应认识到,按照制剂的预期应用(即给药途径)对制剂进行常规设计。
用于局部给药的制剂包括这样的制剂:其中本发明的寡核苷酸与局部递送物质混合,局部递送物质例如脂质、脂质体、脂肪酸、脂肪酸酯、类固醇、螯合剂和表面活性剂。脂质和脂质体包括中性的(例如二油酰-磷脂酰DOPE乙醇胺、二肉豆蔻酰磷脂酰胆碱DMPC、二硬脂酰磷脂酰胆碱)、阴性的(例如二肉豆蔻酰磷脂酰甘油DMPG)和阳离子型(例如二油酰四甲氨基丙基DOTAP和二油酰-磷脂酰乙醇胺DOTMA)。
对于局部或其它给药,可将本发明的寡核苷酸包封到脂质体中,或者可与脂质体(特别是阳离子型脂质体)形成复合体。或者,可将寡核苷酸与脂质(特别是阳离子脂质)络合。脂肪酸和酯、其药学上可接受的盐及其应用另参见美国专利号6,287,860。
用于口服给药的组合物和制剂包括散剂或颗粒剂、微粒剂(microparticulate)、纳米粒剂(nanoparticulate)、水或非水介质中的混悬剂或溶液剂、胶囊剂、凝胶胶囊剂、小药囊剂、片剂或小片。增稠剂、矫味剂、稀释剂、乳化剂、分散助剂或粘合剂可能是所需的。口服制剂是其中本发明的寡核苷酸与一种或多种渗透促进剂、表面活性剂和螯合剂联合给予的制剂。表面活性剂包括脂肪酸和/或其酯或盐、胆汁酸和/或其盐。胆汁酸/盐和脂肪酸及其应用另参见美国专利号6,287,860,其通过引用结合到本文中。还有渗透促进剂的组合,例如脂肪酸/盐与胆汁酸/盐的组合。特别是十二烷酸、癸酸和UDCA的钠盐的组合。其它渗透促进剂包括聚氧乙烯-9-十二烷基醚、聚氧乙烯-20-鲸蜡基醚。本发明的寡核苷酸可以颗粒形式(包括喷雾干燥颗粒)口服递送,或络合形成微粒或纳米粒。寡核苷酸络合剂及其应用另参见美国专利号6,287,860,其通过引用结合到本文中。
用于胃肠外、鞘内或心室内给药的组合物和制剂可包括无菌水溶液,该无菌水溶液还可含有缓冲剂、稀释剂和其它合适添加剂,例如但不限于渗透促进剂、载体化合物及其它药学上可接受的载体或赋形剂。
本发明的某些实施方案提供含有一种或多种寡聚化合物和一种或多种其它通过非反义机制起作用的化疗药物的药物组合物。这种化疗药物的实例包括但不限于癌症化疗药物,例如柔红霉素、道诺霉素、放线菌素、多柔比星、表柔比星、伊达比星、依索比星、博来霉素、马磷酰胺、异环磷酰胺、阿糖胞苷、氯乙亚硝脲、白消安、丝裂霉素C、放线菌素D、光神霉素、泼尼松、羟孕酮、睾酮、他莫昔芬、达卡巴嗪、丙卡巴肼、六甲蜜胺、五甲密胺、米托蒽醌、安吖啶、苯丁酸氮芥、甲基环己基亚硝脲(methylcyclohexylnitrosurea)、氮芥、美法仑、环磷酰胺、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷(cytarabine)、5-氮胞苷、羟基脲、脱氧考福霉素、4-羟基过氧环磷酰胺、5-氟尿嘧啶(5-FU)、5-氟脱氧尿苷(5-FUdR)、甲氨蝶呤(MTX)、秋水仙碱、泰素(taxol)、长春新碱、长春碱、依托泊苷(VP-16)、三甲曲沙、伊立替康、托泊替康、吉西他滨、替尼泊苷、顺铂和己烯雌酚(DES)。当与本发明的化合物一起使用时,这样的化疗药物可单独使用(例如5-FU和寡核苷酸)、序贯使用(例如5-FU和寡核苷酸使用一段时间后接着用MTX和寡核苷酸)或者与一种或多种其它这样的化疗药物联用(例如5-FU、MTX和寡核苷酸,或者5-FU、放射疗法和寡核苷酸)。抗炎药物(包括但不限于非甾类抗炎药物和皮质类固醇)和抗病毒药物(包括但不限于利巴韦林(ribivirin)、阿糖腺苷、阿昔洛韦和更昔洛韦)也可与本发明的组合物组合。反义化合物和其它非反义药物的组合也落入本发明的范围内。两种以上组合的化合物可同时或序贯使用。
在另一个相关实施方案中,本发明的组合物可包含一种或多种靶向第一核酸的反义化合物(尤其寡核苷酸)和一种或多种靶向第二核酸靶标的其它反义化合物。例如,第一靶标可以是唐氏综合征基因的特定反义序列,第二靶标可以是另一核苷酸序列的区。或者,本发明的组合物可包含两种或更多种靶向相同唐氏综合征基因核酸靶标的不同区的反义化合物。本文阐明了反义化合物的多个实例,其它可选自本领域已知的合适化合物。两种或更多种组合的化合物可同时或序贯使用。
给药:
一般认为治疗组合物的制剂及其后续用药(给药)为本领域技术人员所掌握。给药取决于待治疗的疾病状态的严重性和响应性,具有持续数天至数月的疗程,或者直到实现治愈或实现疾病状态减轻。可根据对患者体内蓄积药物的测量来计算最佳给药方案。普通技术人员可容易地测定最佳剂量、给药方法和重复率。最佳剂量可视各种寡核苷酸的相对效能而变化,且通常可根据被认为在体外和体内动物模型中有效的EC50来估计。通常,剂量为0.01μg-100g/kg体重,可每天、每周、每月或每年给予一次或多次,或者每2-20年给予一次。本领域普通技术人员可容易地根据测量的药物在体液或组织中的停留时间和浓度估计给药重复率。在成功治疗后,可能需要患者进行维持治疗以防止疾病状态复发,其中以维持剂量给予寡核苷酸,维持剂量为0.01μg-100g/kg体重,每天一次或多次至每20年一次。
在实施方案中,患者用以下药物剂量治疗:至少约1、至少约2、至少约3、至少约4、至少约5、至少约6、至少约7、至少约8、至少约9、至少约10、至少约15、至少约20、至少约25、至少约30、至少约35、至少约40、至少约45、至少约50、至少约60、至少约70、至少约80、至少约90或至少约100mg/kg体重。反义寡核苷酸的某些注射剂量阐述于例如美国专利号7,563,884“Antisense modulation of PTP1B expression(PTP1B表达的反义调节)”,其通过引用以其整体结合到本文中。
虽然上文描述了本发明的多个实施方案,但是应当理解的是,它们仅通过实例提供而并非限制。依据本文公开内容可对所公开的实施方案作出多种改变,而又不偏离本发明的精神或范围。因此,本发明的广度和范围将不受任何上述实施方案的限制。
本文提及的所有文献通过引用结合到本文中。本申请中引用的所有出版物和专利文献通过引用结合到本文中用于所有目的,其程度与每个独立出版物或专利文献所单独指明的一样。至于在本文件中对多种参考文献的引用,申请人不承认任何具体参考文献对于他们的发明是“现有技术”。以下实施例对发明组合物和方法的实施方案进行了说明。
实施例
以下非限制性实施例用来阐明本发明的选定实施方案。应当理解的是,所示组分要素的比例和备选方案中的变化对本领域技术人员而言是显而易见的,并属于本发明实施方案的范围内。
实施例1:对唐氏综合征基因的反义核酸分子和/或唐氏综合征基因多核苷酸的有义链有特异性的反义寡核苷酸的设计
如上所述,术语“对……有特异性的寡核苷酸”或“靶向…的寡核苷酸”是指具有下述序列的寡核苷酸:其(i)能够与靶基因的一部分形成稳定的复合体,或(ii)能够与靶基因的mRNA转录物的一部分形成稳定的双链体。
通过应用自动比对核酸序列并指明同一性或同源性区的计算机程序,有助于选择适当的寡核苷酸。这种程序用于比较所得核酸序列,例如通过检索数据库(例如GenBank)或通过对PCR产物测序。比较多个物种的核酸序列使能够选择在物种间具有适当的同一性程度的核酸序列。在未测序基因的情况下,进行DNA印迹以供测定靶物种和其它物种的基因间的同一性程度。通过在本领域熟知的不同严格程度下进行DNA印迹,可获得同一性的近似测量。这些方法可供选择这样的寡核苷酸,即对待受控制的受试者的靶核酸序列具有高度互补性,而对其它物种的对应核酸序列具有较低程度的互补性。本领域技术人员应了解的是,在选择用于本发明的合适基因区方面有相当大的自由。
当反义化合物与靶核酸的结合干扰靶核酸的正常功能而引起功能和/或活性的调节,并存在足够程度的互补性以避免在需要特异性结合的条件(即在体内测定或治疗性治疗情况下的生理条件和体外测定情况下进行测定的条件)下该反义化合物与非靶核酸序列非特异性结合时,反义化合物是“可特异性杂交的”。
本文所述寡核苷酸的杂交性质可通过本领域已知的一种或多种体外测定来确定。例如,可通过利用解链曲线测定来确定靶天然反义序列和潜在药物分子之间的结合强度而获得本文所述寡核苷酸的性质。
可利用任何已确立的测量分子间相互作用强度的方法(例如解链曲线测定)来估计靶天然反义序列和潜在药物分子(Molecule)之间的结合强度。
解链曲线测定测定天然反义序列/Molecule复合体发生从双链构象到单链构象快速转变的温度。该温度被公认为两个分子间相互作用强度的可靠度量。
可利用实际的天然反义RNA分子的cDNA拷贝或相当于Molecule的结合位点的合成DNA或RNA核苷酸进行解链曲线测定。可获得多种装有所有用于进行该测定的必需试剂的试剂盒(例如Applied Biosystems Inc.MeltDoctor试剂盒)。这些试剂盒包括合适的缓冲溶液,缓冲溶液含有一种双链DNA(dsDNA)结合染料(例如ABI HRM染料、SYBR Green、SYTO等)。dsDNA染料的性质在于其游离形式几乎不发出荧光,但与dsDNA结合时是强荧光的。
为进行该测定,将cDNA或相应的寡核苷酸与Molecule以具体制造商的方案规定的浓度混合。将混合物加热到95℃以解离所有预先形成的dsDNA复合体,之后缓慢冷却至室温或试剂盒制造商规定的其它更低温度,以使DNA分子退火。然后,将新形成的复合体缓慢加热到95℃,并同时连续收集由反应产生的荧光量的数据。荧光强度与反应中存在的dsDNA量成反比。数据采集可利用与试剂盒兼容的实时PCR仪器(例如ABI’s StepOne Plus RealTime PCR System或LightTyper instrument,Roche Diagnostics,Lewes,UK)。
通过利用合适的软件(例如LightTyper(Roche)或SDS Dissociation Curve,ABI)将荧光对温度的负导数(y轴上的-d(荧光)/dT)对温度(x轴)作图,构建解链峰。分析数据,以鉴定dsDNA复合体快速转变成单链分子的温度。该温度称为Tm,与两个分子间的相互作用强度成正比。Tm通常大于40℃。
实施例2:唐氏综合征基因多核苷酸的调节
用反义寡核苷酸治疗HepG2细胞
使得自ATCC(目录号HB-8065)的HepG2细胞在生长培养基(MEM/EBSS(Hyclone目录号SH30024或Mediatech目录号MT-10-010-CV)+10%FBS(Mediatech目录号MT35-011-CV)+青霉素/链霉素(Mediatech目录号MT30-002-CD)中在37℃和5%CO2下生长。在实验前一天,将细胞以1.5×105/ml的密度再次接种到6孔板中并在37℃和5%CO2下孵育。在实验当天,将6孔板中的培养基更换为新鲜生长培养基。将所有反义寡核苷酸稀释至20μM的浓度。将2μl该溶液与400μl Opti-MEM培养基(Gibco目录号31985-070)和4μl Lipofectamine 2000(Invitrogen目录号11668019)一起在室温下孵育20分钟,并加到具有HepG2细胞的6孔板各孔中。含有2μl代替寡核苷酸溶液的水的类似混合物用作模拟转染对照。在37℃和5%CO2下孵育3-18小时后,将培养基更换为新鲜生长培养基。在加入反义寡核苷酸48小时后,除去培养基,并按照制造商说明书利用Promega的SV Total RNA Isolation System(目录号Z3105)或Qiagen的RNeasy Total RNA Isolation试剂盒(目录号74181)提取细胞RNA。将600ng RNA加入反转录反应中,按制造商方案所述利用Thermo Scientific的Verso cDNA试剂盒(目录号AB1453B)或High Capacity cDNA Reverse Transcription Kit(目录号4368813)进行该反转录反应。使用ABI Taqman Gene Expression Mix(目录号4369510)和ABI(Applied Biosystems Taqman Gene Expression Assay:Hs00176369_m1和Hs00176369_m1,Applied Biosystems Inc.,Foster City CA)设计的引物/探针,通过实时PCR,使用得自该反转录反应的cDNA监测基因表达。采用Mx4000循环变温加热器(Stratagene),使用以下PCR循环:50℃2分钟、95℃10分钟,40个循环(95℃15秒,60℃1分钟)。
根据治疗样品和模拟转染样品之间的18S-标准化dCt值的差异,计算用反义寡核苷酸治疗后基因表达的倍数变化。
结果
实时PCR结果表明,用设计为DYRK1a反义Hs.713879(CUR-0885-CUR-0890)的寡核苷酸之一治疗后48小时,HepG2细胞中DYRK1a mRNA的水平显著提高(图1)。
实时PCR结果表明,用设计为DSCR1反义DA403464的寡核苷酸之一治疗后48小时,HepG2细胞的DSCR1 mRNA水平显著提高(图2)。用反义寡核苷酸治疗Vero 76细胞
使得自ATCC(目录号CRL-1587)的Vero 76细胞在生长培养基(MEM/EBSS(Hyclone目录号SH30024,或Mediatech目录号MT-10-010-CV)+10%FBS(Mediatech目录号MT35-011-CV)+青霉素/链霉素(Mediatech目录号MT30-002-CI))中于37℃和5%CO2下生长。在实验前一天,将细胞以1.5×105/ml的密度再次接种到6孔板中并在37℃和5%CO2下孵育。在实验当天,将6孔板中的培养基更换为新鲜生长培养基。将所有反义寡核苷酸稀释为20μM的浓度。将2μl该溶液与400μl Opti-MEM培养基(Gibco目录号31985-070)和4μl Lipofectamine2000(Invitrogen目录号11668019)一起在室温下孵育20分钟,并加入具有Vero 76细胞的6孔板的各孔中。含有2μl代替寡核苷酸溶液的水的类似混合物用作模拟转染对照。在37℃和5%CO2下孵育3-18小时后,将培养基更换为新鲜生长培养基。在加入反义寡核苷酸48小时后,除去培养基,并按照制造商说明书利用Promega的SV Total RNA Isolation System(目录号Z3105)或Qiagen的RNeasy Total RNA Isolation试剂盒(目录号74181)提取细胞RNA。将600ngRNA加入反转录反应,按制造商方案所述利用Thermo Scientific的Verso cDNA试剂盒(目录号AB 1453B)或High Capacity cDNA Reverse Transcription Kit(目录号4368813)进行该反转录反应。利用ABI Taqman Gene Expression Mix(目录号4369510)和由ABI(Applied Biosystems Taqman Gene Expression Assay:Hs00176369_m1和Hs00176369_m1,Applied Biosystems Inc.,Foster City CA)设计的引物/探针,通过实时PCR用得自该反转录反应的cDNA监测基因表达。采用Mx4000循环变温加热器(Stratagene)或StepOne Plus Real Time PCR Machine(Applied Biosystems),使用以下PCR循环:50℃2分钟、95℃10分钟,40个循环(95℃15秒,60℃1分钟)。
根据治疗样品和模拟转染样品之间的18S-标准化dCt值的差异,计算在用反义寡核苷酸治疗后基因表达的倍数变化。
实时PCR结果表明,在用设计为DYRK1a反义Hs.713879的寡核苷酸之一治疗后48小时,Vero细胞的DYRK1a mRNA水平显著提高(图3)。
实时PCR结果表明,在用设计为DSCR1反义DA403464的寡核苷酸之一治疗后48小时,Vero细胞的DSCR1mRNA水平显著提高。(图4)。
虽然按照一种或多种实现方式对本发明进行了解释和说明,但是在阅读和理解本说明书和附图时,本领域技术人员便会想到等同的改变和变化。此外,虽然可能仅按照若干实现方式之一来公开本发明的具体特征,但是当对于任何给定或具体的应用可能是需要且有利时,这种特征可与其它实现方式的一个或多个其它特征联合。
本说明书的摘要可供读者快速查明本技术公开的性质。它的提交不应理解为用来解释或限制所附权利要求书的范围或含义。
Claims (13)
1.至少一种长度为12-30个核苷酸的反义寡核苷酸在制备用于体内或体外上调患者细胞或组织的唐氏综合征基因多核苷酸的功能和/或表达的药物中的用途,其中所述至少一种寡核苷酸与由以下核苷酸内的12-30个连续核苷酸组成的多核苷酸的反向互补序列相同:SEQ ID NO: 5的1-497和SEQ ID NO: 6的1-545,其中所述唐氏综合征基因多核苷酸为DSCR1;其中所述至少一种寡核苷酸包含SEQ ID NO: 21-23所示的至少一种寡核苷酸序列。
2.至少一种长度为12-30个核苷酸的反义寡核苷酸在制备用于体内或体外上调患者细胞或组织的唐氏综合征基因多核苷酸的功能和/或表达的药物中的用途,其中所述至少一种寡核苷酸与选自DSCR1的唐氏综合征基因多核苷酸的天然反义多核苷酸的反向互补序列相同,其中所述天然反义多核苷酸选自SEQ ID NO: 6;其中所述至少一种寡核苷酸包含SEQID NO: 21-23所示的至少一种寡核苷酸序列。
3.靶向唐氏综合征基因多核苷酸的天然反义多核苷酸的区的至少一种长度为12-30个核苷酸的反义寡核苷酸在制备用于体内或体外上调患者细胞或组织的唐氏综合征基因多核苷酸的功能和/或表达的药物中的用途,其中所述唐氏综合征基因选自DSCR1;其中所述至少一种寡核苷酸包含SEQ ID NO: 21-23所示的至少一种寡核苷酸序列。
4.权利要求3的用途,其中与对照相比,体内或体外提高唐氏综合征基因的功能和/或表达。
5.权利要求3的用途,其中所述至少一种反义寡核苷酸靶向选自SEQ ID NO: 5或6的唐氏综合征基因多核苷酸的天然反义序列。
6.权利要求3的用途,其中所述至少一种反义寡核苷酸靶向与唐氏综合征基因多核苷酸的编码和/或非编码核酸序列反义的天然反义多核苷酸。
7.权利要求3的用途,其中所述至少一种反义寡核苷酸靶向与唐氏综合征基因多核苷酸具有重叠和/或非重叠序列的天然反义多核苷酸。
8.权利要求1的用途,其中所述至少一种寡核苷酸为SEQ ID NO: 21-23所示的至少一种寡核苷酸序列。
9.一种包含至少一种修饰的长度为12-30个核苷酸的合成的修饰寡核苷酸,其中所述寡核苷酸进一步与由天然反义多核苷酸内的12-30个连续核苷酸组成的多核苷酸的反向互补序列相同,所述天然反义多核苷酸具有SEQ ID NO: 5的核苷酸1-497和SEQ ID NO: 6的核苷酸1-545,所述至少一种修饰选自:至少一种修饰糖部分、至少一种修饰核苷酸间键、至少一种修饰核苷酸及其组合;其中所述寡核苷酸是与正常对照相比体内或体外与所述天然反义多核苷酸的区杂交并上调唐氏综合征基因DSCR1功能和/或表达的反义化合物;其中所述寡核苷酸包含SEQ ID NO: 21-23所示的至少一种寡核苷酸序列。
10.权利要求9的寡核苷酸,其中所述寡核苷酸与所述天然反义多核苷酸杂交并且与正常对照相比,体内或体外上调至少一种唐氏综合征基因多核苷酸的表达和/或功能。
11.权利要求9的寡核苷酸,其中所述寡核苷酸由SEQ ID NO: 21-23所示序列组成。
12.一种组合物,其包含一种或多种权利要求9的寡核苷酸和药学上可接受的赋形剂。
13.至少一种权利要求9的寡核苷酸在制备用于预防或治疗与至少一种唐氏综合征基因多核苷酸和/或至少一种其编码产物有关的疾病的药物中的用途,其中所述至少一种寡核苷酸与所述至少一种唐氏综合征基因多核苷酸的天然反义序列结合,并上调所述至少一种唐氏综合征基因多核苷酸的表达,其中与至少一种唐氏综合征基因多核苷酸有关的疾病选自:与DSCR1的突变体、异常表达或功能有关的疾病或病症,其选自癌症。
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EP2446037A4 (en) | 2013-11-06 |
US20120142758A1 (en) | 2012-06-07 |
US20200032263A1 (en) | 2020-01-30 |
EP2446037A2 (en) | 2012-05-02 |
US10450567B2 (en) | 2019-10-22 |
KR20120086282A (ko) | 2012-08-02 |
JP2012531427A (ja) | 2012-12-10 |
WO2010151674A2 (en) | 2010-12-29 |
JP5907866B2 (ja) | 2016-04-26 |
EP2446037B1 (en) | 2016-04-20 |
US10036014B2 (en) | 2018-07-31 |
KR101807324B1 (ko) | 2017-12-08 |
CA2765815A1 (en) | 2010-12-29 |
US20150073040A1 (en) | 2015-03-12 |
ES2583691T3 (es) | 2016-09-21 |
US20180305693A1 (en) | 2018-10-25 |
CN102482672A (zh) | 2012-05-30 |
WO2010151674A3 (en) | 2011-07-21 |
US8921330B2 (en) | 2014-12-30 |
US10876117B2 (en) | 2020-12-29 |
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