CN102695797B - 通过抑制针对胶原基因的天然反义转录物来治疗胶原基因相关的疾病 - Google Patents
通过抑制针对胶原基因的天然反义转录物来治疗胶原基因相关的疾病 Download PDFInfo
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Abstract
本发明涉及反义寡核苷酸,具体而言,其通过靶定胶原基因的天然反义多核苷酸,来调节胶原基因的表达和/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胶原基因表达有关的疾病和病症中的用途。
Description
发明领域
本申请要求保护提交于2009年6月16日的美国临时专利申请 61/187,384、提交于2009年12月16日的美国临时专利申请第 61/286,939号和提交于2009年12月16日的美国临时专利申请第 61/286,965号的优先权,所述申请通过引用以其整体结合于本文中。
本发明的实施方案包括调节胶原基因和相关分子的表达和/或功能的寡核苷酸。
发明背景
DNA-RNA和RNA-RNA杂交对于核酸功能的许多方面(包括 DNA复制、转录和翻译)而言为重要的。杂交对于探测特定核酸或者改变其表达的各种技术而言亦为主要的。反义核苷酸例如通过与靶 RNA杂交来扰乱基因表达,从而干扰RNA剪接、转录、翻译和复制。反义DNA具有附加的特征,该特征为DNA-RNA杂合体充当核糖核酸酶H消化的底物,该活性存在于大多数细胞类型中。可将反义分子递送到细胞中,这与寡脱氧核苷酸(ODN)的情况一样,或者它们如 RNA分子一样可由内源基因表达。FDA最近批准了一种反义药物, VITRAVENETM(用于治疗巨细胞病毒视网膜炎),这反映了反义物具有治疗应用。
发明概述
在一个实施方案中,本发明提供通过使用靶定天然反义转录物的任何区域的反义寡核苷酸来抑制天然反义转录物的作用,引起相应有义基因的增量调节的方法。本文也考虑天然反义转录物的抑制可通过siRNA、核酶和小分子来达到,认为所述siRNA、核酶和小分子在本发明的范围之内。
一个实施方案提供在体内或体外调节患者细胞或组织中的胶原基因多核苷酸的功能和/或表达的方法,所述方法包括使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,其中所述寡核苷酸与以下多核苷酸的反向互补序列具有至少50%的序列同一性,所述多核苷酸包含在SEQ ID NO:4的核苷酸1-387、SEQ ID NO:5的核苷酸 1-561、SEQID NO:6的核苷酸1-335、SEQ ID NO:7的核苷酸1-613、 SEQ ID NO:8的核苷酸1-177和SEQID NO:9的核苷酸1-285之内的 5-30个连续核苷酸;从而在体内或体外调节患者细胞或组织中胶原基因多核苷酸的功能和/或表达。
在另一个实施方案中,寡核苷酸靶定胶原基因多核苷酸的天然反义序列,例如SEQID NO:4-9所述的核苷酸,以及其任何变体、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:10-29所述。
另一个实施方案提供在体内或体外调节患者细胞或组织中胶原基因多核苷酸的功能和/或表达的方法,所述方法包括使所述细胞或组织长度为5-30个核苷酸的反义寡核苷酸接触,其中所述寡核苷酸与胶原基因多核苷酸的反义物的反向互补序列具有至少50%的序列同一性;从而在体内或体外调节患者细胞或组织中胶原基因多核苷酸的功能和/或表达。
另一个实施方案提供在体内或体外调节患者细胞或组织中胶原基因多核苷酸的功能和/或表达的方法,所述方法包括使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,其中所述寡核苷酸与胶原基因反义多核苷酸的反义寡核苷酸具有至少50%的序列同一性;从而在体内或体外调节患者细胞或组织中胶原基因多核苷酸的功能和/或表达。
在一个实施方案中,组合物包含一种或多种与有义和/或反义胶原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个或多个经修饰或取代的核苷酸。
在另一个实施方案中,所述寡核苷酸包含一个或多个经修饰的键。
在又一个实施方案中,所述修饰核苷酸包含经修饰的碱基,其包括硫代磷酸酯、甲基膦酸酯、肽核酸、2’-O-甲基、氟-或碳、亚甲基或其他锁定核酸(LNA)分子。优选地,所述修饰核苷酸为锁定核酸分子,包括α-L-LNA。
在另一个实施方案中,将所述寡核苷酸经皮下、肌内、静脉内或腹膜内施用给患者。
在另一个实施方案中,将所述寡核苷酸在药物组合物中施用。治疗方案包括至少一次给患者施用反义化合物;然而,可将此治疗修改成在一段时间内包含多个剂量。所述治疗可与一种或多种其它类型的疗法组合。
在另一个实施方案中,将所述寡核苷酸封装到脂质体中或附着于载体分子(例如胆固醇、TAT肽)。
其它方面描述于下文。
附图简述
图1为实时PCR结果的图表,显示相比于对照,用硫代磷酸寡核苷酸处理HepG2细胞后Col1a1 mRNA的倍数变化+标准偏差,所述硫代磷酸寡核苷酸使用Lipofectamine 2000引入。实时PCR结果显示, HepG2细胞中Col1a1 mRNA的水平在用针对Col1a1反义物 DW440457设计的寡核苷酸之一处理后48h显著增加。表示为 CUR-1361至CUR-1364的条分别对应于用SEQ ID NO:10-13处理的样品。
图2为实时PCR结果的图表,显示相比于对照,用硫代磷酸寡核苷酸处理HUVEC细胞后Col1a2 mRNA的倍数变化+标准偏差,所述硫代磷酸寡核苷酸使用Lipofectamine 2000引入。实时PCR结果显示 HUVEC细胞中Col1a2 mRNA的水平在用针对Col1a2反义物 Hs.571263设计的寡核苷酸之一处理后48h显著增加。表示为 CUR-0862、CUR-0864、CUR-0863、CUR-0865、CUR-0866和CUR- CUR-0867的条分别对应于用SEQ ID NO:14-19处理的样品。
图3为实时PCR结果的图表,显示相比于对照,用硫代磷酸寡核苷酸处理HUVEC细胞后Col7a1 mRNA的倍数变化+标准偏差,所述硫代磷酸寡核苷酸使用Lipofectamine 2000引入。实时PCR结果显示 HUVEC细胞中Col7a1 mRNA的水平在用针对Col7a1设计为 CV425857(CV425857.11、CV425857.12)的siRNA之一和针对 BU615800.1(BU615800.11)的一种siRNA处理后48h显著增加。表示为CUR-0356、CUR-0358、CUR-0360和CUR-0362的条分别对应于用SEQ ID NO:20-23处理的样品。
图4为实时PCR结果的图表,显示相比于对照,用硫代磷酸寡核苷酸处理HepG2细胞后Col7a1 mRNA的倍数变化+标准偏差,所述硫代磷酸寡核苷酸使用Lipofectamine 2000引入。实时PCR结果显示, HepG2细胞中Col7a1 mRNA的水平在用针对Col7a1设计为be142537和bg998538的两种寡核苷酸处理后48h显著增加。表示为CUR-0360 和CUR-0856至CUR-0860的条分别对应于用SEQ ID NO:22和SEQ ID NO:24-28处理的样品。
序列表描述
SEQ ID NO:1:人类(Homo sapiens)胶原,I型,α1(COL1A1),mRNA (NCBI检索号:NM_000088.3)。
SEQ ID NO:2:人类胶原,I型,α2(COL1A2),mRNA(NCBI检索号: NM_000089.3)。
SEQ ID NO:3:NM_024013.1|人类胶原,VII型,α1(COL7A1),mRNA (NCBI检索号:NM_000094.3)。
SEQ ID NO:4-9:SEQ ID NO:4:天然COL1A1反义序列(DW440457);
SEQ ID NO:5:天然COL1A2反义序列(Hs.571263);SEQ ID NO:6:天然COL7A1反义序列(CV425857.1);SEQ ID NO:7:天然COL7A1 反义序列(BU615800.1);SEQ ID NO:8:天然COL7A1反义序列 (BE142537)和SEQ ID NO:9:天然COL7A1反义序列(BG998538)。
SEQ ID NO:10-29——反义寡核苷酸。‘r’指RNA而*指硫代磷酸酯键。
SEQ ID NO:30-33分别为反义寡核苷酸SEQ ID NO:20-23的反向互补序列。‘r’指RNA。
发明详述
参考用于说明的示例应用在下文中描述本发明的数个方面。应当理解的是,陈述许多具体细节、关系和方法来提供对本发明的充分理解。然而,在相关领域的普通技术人员将容易地认识到,可在不含一个或多个具体细节的情况下实施本发明或者可用其他方法来实施本发明。本发明不受行为或事件的排序限制,因为一些行为可以不同的顺序进行和/或与其他行为或事件同时进行。此外,并非所有说明性的行为或事件对实施本发明的方法都为必需的。
意图本文公开的所有基因、基因名称和基因产物对应于来自任何物种的同源物,对该物种而言本文公开的组合物和方法为适用的。因此,该术语包括但不限于来自人和小鼠的基因和基因产物。理解的是,当公开来自具体物种的基因或基因产物时,意图此公开仅为示例性的,并且除非其出现的文段中明确指示,否则不应理解为限制。因此,例如,对于本文公开的在一些实施方案中有关哺乳动物核酸和氨基酸序列的基因而言,意图包括来自其他动物(包括但不限于其他哺乳动物、鱼类、两栖动物、爬行动物和鸟类)的同源和/或直向同源基因和基因产物。在实施方案中,所述基因或核酸序列为人的。
定义
本文所用的术语仅以描述具体的实施方案为目的而不意图限制本发明。除非文段另有明确指示,否则也意图本文所用的单数形式“一”、“一个”和“所述”包括复数形式。此外,就术语“包括的”、“包括”、“具有的”、“具有”、“含有”或其变型在详述和/或权利要求中所用的程度而言,意图这类术语以类似于术语“包含”的方式为包括在内的。
术语“约”或“大约”意为在由本领域普通技术人员所确定的具体值的可接受误差范围之内,这部分取决于该值是如何测定或确定的,即,测量系统的限制。例如,按照本领域的实践,“约”可意为在1个或大于1个标准偏差之内。或者,“约”可意为高达给定值的20%,优选10%,更优选5%,和还更优选1%的范围。或者,具体地关于生物系统或过程,该术语可意为在值的数量级之内,优选在值的5倍之内,更优选在2倍之内。当本申请和权利要求描述具体值时,除非另作说明,否则应假设术语“约”意为在具体值的可接受误差范围之内。
本文所用的术语“mRNA”意为目前已知的靶定基因的mRNA转录物,以及任何可阐明的其它转录物。
“反义寡核苷酸”或“反义化合物”意为与另一个RNA或DNA(靶 RNA、DNA)结合的RNA或DNA分子。例如,如果其为RNA寡核苷酸,则其通过RNA-RNA相互作用结合另一个RNA靶标并改变靶 RNA的活性。反义寡核苷酸可增量调节或减量调节特定多核苷酸的表达和/或功能。该定义意在包括从治疗、诊断或其他观点来看有用的任何外源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、诱饵RNA分子、siRNA、酶促 RNA、治疗用编辑RNA(therapeutic editing RNA)以及激动剂和拮抗剂 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、可变剪接物(alternate splicer)、引物、探针以及其他与靶核酸的至少一部分杂交的寡聚化合物。因此,可将这些化合物以单链、双链、部分单链或环状寡聚化合物的形式引入。
在本发明的文段中,术语“寡核苷酸”是指核糖核酸(RNA)或脱氧核糖核酸(DNA)或其模拟物的寡聚物或聚合物。术语“寡核苷酸”,也包括天然和/或经修饰单体或键(linkage)的线性或环状寡聚物,包括脱氧核糖核苷、核糖核苷、其取代和α-异头物形式、肽核酸(PNA)、锁定核酸(LNA)、硫代磷酸酯、甲基膦酸酯等。寡核苷酸能够通过单体与单体相互作用的规律模式(例如沃森-克里克(Watson-Crick)型碱基配对、或反型碱基配对等)特异地结合靶多核苷酸。
寡核苷酸可为“嵌合的”,即,由不同的区组成。在本发明的文段中,“嵌合的”化合物为寡核苷酸,其包含两个或更多个化学区,例如, DNA区、RNA区、PNA区等。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。这些寡核苷酸典型地包含至少一个区,其中所述寡核苷酸为经修饰的以表现出一种或多种所需特性。寡核苷酸的所需特性包括但不限于,例如增强的对核酸酶降解的抗性、增强的细胞摄取和/或增强的对靶核酸的结合亲和力。因此寡核苷酸的不同区可具有不同的特性。本发明的嵌合寡核苷酸可形成为两种或更多种如上所述的寡核苷酸、修饰寡核苷酸、寡聚核苷和/或寡核苷酸类似物的混合结构。
寡核苷酸可由可“全符合状态(in“register”)”地连接或通过间隔物连接的区组成,所述“全符合状态”地连接即此时单体像在天然DNA 一样连续地连接。所述间隔物意在构成区之间的共价“桥”,并在一些情况下具有不超过约100个碳原子的长度。所述间隔物可携带不同的功能性,例如具有正或负电荷、具有特殊的核酸结合特性(嵌入剂、沟结合剂、毒素、荧光团等)、为亲脂的、诱导特殊的二级结构如例如诱导α-螺旋的含丙氨酸的肽。
本文所用的“胶原基因”包括所有家族成员、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。
本文所用的措词胶原I型α1;胶原α-1(I)、COL1A1、α-1 I型胶原、胶原α-1(I)链、OI4,在文献中被认为是相同的且在本申请中可交换地使用。
本文所用的措词胶原α-2(I)、“胶原I型α2”、胶原α2(I)、α-2 I 型胶原、胶原α-2(I)链和COL1A2在文献中被认为是相同的且在本申请中可交换地使用。
本文所用的措词胶原α-1(VII)链、COL7A1、EBD1、EBDCT、 EBR1、LC胶原、长链胶原在文献中被认为是相同的且在本申请中可交换地使用。
本文所用的术语“对......特异的寡核苷酸”或“靶定......的寡核苷酸”是指具有以下序列的寡核苷酸,该序列(i)能够与靶定基因的一部分形成稳定的复合体,或(ii)能够与靶定基因的mRNA转录物的一部分形成稳定的双链体。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。用于确定杂交复合体和双链体的稳定性的示例性测定法描述于下文实施例中。
本文所用的术语“靶核酸”包括DNA、从这类DNA转录的RNA(包括前mRNA和mRNA)以及从这类RNA衍生的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核酸的正常功能。这种通过特异地与靶核酸杂交的化合物对该靶核酸功能的调节,一般称为“反义”。待干扰的DNA功能包括例如复制和转录。待干扰的RNA功能,包括所有的生活机能,例如,RNA 向蛋白质翻译位点的易位、蛋白质自RNA的翻译、产生一种或多种 mRNA种类的RNA剪接,以及可由RNA参与或促进的催化活性。对靶核酸功能的这类干扰的整体效果为对编码产物或寡核苷酸表达的调节。
RNA干扰“RNAi”由双链RNA (dsRNA)分子介导,该分子具有与其“靶”核酸序列的序列特异性同源性。在本发明的某些实施方案中,介体为5-25个核苷酸的“小干扰”RNA双链体(siRNA)。siRNA通过称为切酶的RNA酶对dsRNA的加工得到。siRNA双链体产物募集到叫做RISC(RNA诱导的沉默复合体)的多蛋白siRNA复合体中。不希望受任何具体理论所约束,认为随后RISC被引向靶核酸(适当地为 mRNA),在此处siRNA双链体以序列特异性的方式相互作用来介导催化方式的切割。可依照本发明使用的小干扰RNA,可根据本领域众所周知和普通技术人员熟悉的程序来合成和使用。用于本发明的方法中的小干扰RNA适当地包含约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。
适当寡核苷酸的挑选通过使用电脑程序来促进,该程序自动比对核酸序列并指出具有同一性或同源性的区。将这类程序用于比较例如通过搜索诸如GenBank等数据库或通过测序PCR产物而获得的核酸序列。对来自一系列物种的核酸序列的比较,允许选择在物种之间显示适度同一性的核酸序列。在未测序基因的情况下,进行DNA印迹来确定在靶物种和其他物种的基因之间的同一性程度。如本领域众所周知的,通过在不同的严格程度下进行DNA印迹,可能获得同一性的近似衡量。这些程序允许选择以下寡核苷酸,其对待控制的受试者中的靶核酸序列表现出高度的互补性,并且对其他物种中的相应核酸序列表现出较低程度的互补性。本领域的技术人员将认识到,在挑选用于本发明的适当的基因区方面具有相当大的自由。
“酶促RNA”意为具有酶活性的RNA分子。酶促核酸(核酶)通过首先结合靶RNA来起作用。这类结合通过酶促核酸的靶结合部分进行,所述靶结合部分保持紧密靠近进行切割靶RNA的分子的酶部分。因此,酶促核酸首先识别而后通过碱基配对结合靶RNA,且一旦结合到正确的位点,即进行酶促切割靶RNA。
“诱饵RNA”意为模拟配体的天然结合域的RNA分子。因此诱饵 RNA与天然结合靶标竞争结合特异性配体。例如,已显示HIV反式激活应答(TAR)RNA的过表达可充当“诱饵”并有效地结合HIV tat蛋白,从而阻止其结合到在HIV RNA中编码的TAR序列。这意指特定的实例。本领域人员将认识到,这只是一个实例,而其他的实施方案可使用本领域一般已知的技术容易地产生。
本文所用的术语“单体”通常指以下单体,其通过磷酸二酯键或其类似物连接以形成大小范围从少量单体单元(例如从约3-4)到约数百个单体单元的寡核苷酸。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、氨基磷酸酯等,如下文更充分地描述。
术语“核苷酸”涵盖天然存在的核苷酸和非天然存在的核苷酸。本领域的技术人员应清楚的是,先前认为“非天然存在”的多种核苷酸后来已在自然中发现。因此,“核苷酸”不仅包括已知的含嘌呤和嘧啶杂环的分子,而且还包括其杂环类似物和互变异构体。其他类型的核苷酸的说明性实例为以下分子,其含有腺嘌呤、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-脱氮杂黄嘌呤、7-脱氮杂鸟嘌呤、N4,N4-桥亚乙基胞嘧啶 (ethanocytosin)、N6,N6-桥亚乙基-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、2-羟基-5-甲基-4-三唑并吡啶、异胞嘧啶、异鸟嘌呤、肌苷,和在美国专利第5,432,272号中描述的“非天然存在的”核苷酸。术语“核苷酸”意在涵盖这些实例以及其类似物和互变异构体中的每一个和全部。尤其令人关注的核苷酸为含腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶和尿嘧啶的核苷酸,其被认为是有关人中的治疗和诊断应用的天然存在核苷酸。核苷酸包含天然2’-脱氧和2’-羟基糖,例如,如Kornberg和Baker,DNA 复制(DNA Replication),第2版(Freeman,SanFrancisco,1992)中所述的以及其类似物。
提及核苷酸的“类似物”包括具有经修饰的碱基部分和/或经修饰的糖部分的合成核苷酸。这类类似物包括设计以增强结合特性的合成核苷酸,所述结合特性为例如双链体或三链体稳定性、特异性等。
本文所用的“杂交”意为寡聚化合物的基本上互补链的配对。一种配对的机理涉及寡聚化合物的链的互补核苷或核苷酸碱基(核苷酸)之间的氢键合,其可为沃森-克里克、或反氢键合。例如,腺嘌呤和胸腺嘧啶为互补的核苷酸,其通过形成氢键配对。杂交可在各种环境下进行。
反义化合物为“可特异地杂交的”,如果所述化合物与靶核酸的结合干扰靶核酸的正常功能而导致功能和/或活性的调节,并且在需要特异性结合的条件下存在足够程度的互补性来避免所述反义化合物与非靶核酸序列的非特异性结合,所述条件即在体内测定或治疗性处理情况中的生理条件下,以及在体外测定情况下进行测定的条件下。
本文所用的短语“严格杂交条件”或“严格条件”是指以下条件,在该条件下本发明的化合物与其靶序列杂交,但与最少数量的其他序列杂交。严格条件为序列依赖的且在不同环境下将不同,在本发明的文段中,在其下寡聚化合物与靶序列杂交的“严格条件”由寡聚化合物的性质和组成以及正在其中研究它们的试验来确定。一般而言,严格杂交条件包括低浓度(<0.15M)的含有诸如Na++或K++等无机阳离子的盐(即,低离子强度)、温度高于20℃-25℃、低于寡聚化合物:靶序列复合体的Tm,以及存在变性剂,例如甲酰胺、二甲基甲酰胺、二甲基亚砜,或去污剂十二烷基硫酸钠(SDS)。例如,杂交率对于每1%甲酰胺减少1.1%。高严格杂交条件的实例为0.1X氯化钠-柠檬酸钠缓冲液(SSC)/0.1%(w/v)SDS、60℃下达30分钟。
本文所用的“互补的”是指在一条或两条寡聚链上两个核苷酸之间精确配对的能力。例如,如果在反义化合物的某个位置上的核碱基能够与在靶核酸的某个位置上的核碱基氢键合,所述靶核酸为DNA、 RNA或寡核苷酸分子,则认为所述寡核苷酸和所述靶核酸之间氢键合的位置为互补位置。当可彼此氢键合的核苷酸占据了每个分子中足够数量的互补位置时,寡聚化合物和另外的DNA、RNA或寡核苷酸分子为彼此互补的。因此,“可特异性杂交的”和“互补的”为以下术语,其用于表示在足够数量的核苷酸上有足够程度的精确配对或互补性,使得稳定和特异的结合发生在寡聚化合物和靶核酸之间。
据本领域了解,寡聚化合物的序列不需要与其可特异杂交的靶核酸的序列100%互补。此外,寡核苷酸可在一个或多个区段上杂交,使得间插或邻近的区段不涉及杂交事件(例如,环结构、错配或发夹结构)。本发明的寡聚化合物包含与其靶定的靶核酸序列内的靶区至少约 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,其中反义化合物的20个核苷酸中有18个与靶区互补且因而会特异地杂交的反义化合物,表示90%互补性。在此实例中,余下的非互补核苷酸可与互补核苷酸是聚簇或散布的且不需要彼此邻接或邻接互补核苷酸。因此,长度为18个核苷酸的反义化合物具有4(四)个非互补核苷酸,该非互补核苷酸位于与靶核酸完全互补的两个区的侧翼,所述反义化合物会具有与靶核酸77.8%的总互补性,因此落入本发明的范围内。反义化合物与靶核酸区的互补性百分比可使用本领域已知的BLAST程序(基本局部比对搜索工具)和PowerBLAST程序常规地确定。同源性、序列同一性或互补性百分比可通过例如Gap程序(Wisconsin序列分析包, Unix操作系统版本8,Genetics Computer Group,University Research Park,Madison Wis.)使用默认设置来确定,该程序使用Smith和Waterman的算法(Adv.Appl.Math.,(1981)2,482-489)。
本文所用的术语“解链温度(Tm)”是指以下温度,在限定的离子强度、pH和核酸浓度下,在该温度下平衡时50%与靶序列互补的寡核苷酸与靶序列杂交。典型地,严格条件为以下条件,其中盐浓度至少为约0.01-1.0M Na离子浓度(或其他盐),pH 7.0-8.3且温度对于短寡核苷酸(例如,10-50个核苷酸)而言至少为约30℃。严格条件也可通过外加诸如甲酰胺等去稳定剂来达到。
本文所用的“调节”意为在基因表达方面的增加(刺激)或减少(抑制)。
术语“变体”,当用于多核苷酸序列的文段中时,可包括有关野生型基因的多核苷酸序列。此定义也可包括,例如,“等位基因的”、“剪接”、“物种”或“多态的”变体。剪接变体可具有与参比分子显著的同一性,但因为在mRNA加工期间外显子的可变剪接而一般具有更多或更少数量的多核苷酸。对应的多肽可具有附加的功能域或不存在域。物种变体为在不同物种之间不同的多核苷酸序列。本发明中尤其实用的是野生型基因产物的变体。变体可由核酸序列中的至少一个突变产生并可导致产生改变的mRNA或者其结构或功能可能改变或不变的多肽。任何给定的天然或重组基因可不具有、具有一个或许多等位基因形式。产生变体的常见突变变化一般归因于核苷酸的自然缺失、添加或取代。这些变化类型中的每一个可单独或与其他类型联合发生,在给定序列中发生一次或多次。
产生的多肽一般将具有相对于彼此的显著的氨基酸同一性。多态变体为在给定物种的个体之间特定基因的多核苷酸序列的变化。多态变体也可包括“单核苷酸多态性”(SNP)或单碱基突变,其中多核苷酸序列因一个碱基而不同。SNP的存在可指示例如具有疾病状态倾向(即与抗性相对的易感性)的某个群体。
衍生多核苷酸包括经过化学修饰的核酸,例如用烷基、酰基或氨基置换氢。衍生物(例如,衍生寡核苷酸)可包含非天然存在的部分,例如改变的糖部分或糖间键。这些中示例性的是硫代磷酸酯及本领域已知的其他含硫的种类。衍生核酸也可含有标记,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。
“衍生的”多肽或肽为经修饰的多肽或肽,例如,通过糖基化、聚乙二醇化、磷酸化作用、硫酸盐化作用、还原/烷基化、酰化、化学偶联或温性福尔马林处理。也可将衍生物修饰以含有可检测标记(直接地或间接地),包括但不限于放射性同位素、荧光和酶标记。
本文所用的术语“动物”或“患者”意在包括例如人、绵羊、麋鹿、鹿、长耳鹿、貂、哺乳动物、猴、马、牛、猪、山羊、狗、猫、大鼠、小鼠、鸟、鸡、爬行动物、鱼、昆虫和蜘蛛类。
“哺乳动物”涵盖通常在医疗护理下的温血哺乳动物(例如,人和驯养动物)。实例包括猫科动物、犬、马、牛科动物和人,以及仅仅人。
“处理”或“治疗”涵盖对哺乳动物中疾病状态的治疗,并包括:(a) 防止疾病状态出现于哺乳动物中,特别是当这类哺乳动物倾向于疾病状态但尚未诊断为患有该疾病状态时;(b)抑制疾病状态,例如,阻止其发展;和/或(c)减轻疾病状态,例如,引起疾病状态的退行直到达到所需的终末点。治疗也包括改善疾病的症状(例如,减少疼痛或不适),其中这类改善可直接或可非直接地影响疾病(例如,原因、传递、表达等)。
本文所用的“癌症”是指在哺乳动物中发现的所有类型的癌症或新生物或恶性肿瘤,包括但不限于:白血病、淋巴瘤、黑素瘤、癌和肉瘤。癌症自身表现为包含癌症恶性细胞的“肿瘤”或组织。肿瘤的实例包括肉瘤和癌,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、尤因氏瘤(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、绒毛膜癌、精原细胞瘤、胚胎性癌、维尔姆斯氏肿瘤(Wilms′tumor)、子宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、髓母细胞瘤、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、成神经细胞瘤和视网膜母细胞瘤。可通过依照本发明的公开组合物治疗的其它癌症,包括但不限于,例如,何杰金病(Hodgkin′s Disease)、非何杰金淋巴瘤、多发性骨髓瘤、成神经细胞瘤、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、小细胞肺肿瘤、原发性脑肿瘤、胃癌、结肠癌、恶性胰腺胰岛素瘤(insulanoma)、恶性类癌、膀胱癌、恶化前皮肤病损、睾丸癌、淋巴瘤、甲状腺癌、成神经细胞瘤、食管癌、生殖泌尿道癌、恶性高钙血症、子宫颈癌、子宫内膜癌、肾上腺皮质癌和前列腺癌。
“神经疾病或病症”是指神经系统和/或视觉系统的任何疾病或病症。“神经疾病或病症”包括涉及中枢神经系统(脑、脑干和小脑)、周围神经系统(包括脑神经)和自主神经系统(其部分位于中枢和周围神经系统二者中)的疾病或病症。神经病症的实例包括但不限于,头痛、木僵和昏迷、痴呆、发作、睡眠障碍、创伤、感染、新生物、神经眼科学、运动障碍、脱髓鞘病、脊髓病症、以及周围神经、肌肉和神经肌肉接点的病症。成瘾和精神病也包含在神经病症的定义中,包括但不限于,双相性精神障碍和精神分裂症。以下为可使用依照本发明的组合物和方法治疗的数种神经病症、症状、体征和综合征的清单:获得性癫痫样失语症;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;亚历山大病;阿尔珀斯病(Alpers’disease);交叉性偏瘫;血管性痴呆;肌萎缩侧索硬化;无脑畸形;Angelma综合征;血管瘤病;缺氧;失语症;失用症;蛛网膜囊肿;蛛网膜炎;阿-基氏脑畸形(Anronl-Chiari malformation);动静脉畸形;阿斯佩各综合征;共济失调毛细血管扩张症(ataxia telegiectasia);注意不集中的过度反应症;孤独症;自主神经功能障碍;背痛;巴滕病;贝切特病;贝尔氏麻痹;良性自发性睑痉挛;良性灶;肌萎缩;良性颅内高血压;宾斯旺格病;睑痉挛;Bloch Sulzberger综合征;臂丛损伤;脑脓肿;脑损伤;脑肿瘤(包括多形性成胶质细胞瘤);脊髓肿瘤;布朗-塞卡尔综合征;卡纳万病;腕管综合征;灼痛;中枢性疼痛综合征;脑桥中央髓鞘溶解;头部病症(cephalicdisorder);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;化学疗法诱导的神经病和神经性疼痛;Chiari畸形;舞蹈症;慢性炎性脱髓鞘性多神经病;慢性痛;慢性区域性疼痛综合征;科-勒综合征;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;累积性创伤障碍(cumulative trauma disorder);库兴综合征(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(DandyWalker)综合征;Dawson病;德摩西埃综合征;Dejerine-Klumke麻痹;痴呆;皮肌炎;糖尿病神经病变;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;特发性震颤;法布里病;法尔综合征;昏厥;家族性痉挛性瘫痪;热性癫痫发作;费希尔综合征;弗里德赖希共济失调;额颞痴呆和其它“tau蛋白病变(tauopathies)”;高歇病;格斯特曼综合征;巨细胞动脉炎;巨细胞性包涵体病;细胞性脑白质营养不良;格-巴综合征;HTLV-1相关性脊髓病;哈-斯病;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;带状疱疹;Hirayama综合征;HIV相关性痴呆和神经病(还是AIDS的神经表现);前脑无裂畸形;亨廷顿舞蹈病和其它聚谷氨酰胺重复疾病(polyglutamine repeat disease;积水性无脑畸形;脑积水;皮质醇增多症;缺氧;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;婴儿性痉挛;炎性肌病;颅内囊肿;颅内高血压;Joubert综合征;基- 塞(Keams-Sayre)综合征;肯尼迪病Kinsboum综合征;克-费(Klippel Feil) 综合征;克拉伯病;库-韦病;库鲁病;拉福拉病;朗-爱(Lambert-Eaton) 肌无力综合征;Landau-Kleffner综合征;侧髓(瓦伦伯格)综合征;学习无能;利氏病;Lennox-Gustaut综合征;累-奈综合征;脑白质营养不良;路易(Lewy)体痴呆;无脑回;闭锁综合征;Lou Gehrig病(即,运动神经元病或肌萎缩侧索硬化);椎间盘疾病;莱姆病-神经后遗症;马-约病;巨脑(macrencephaly);巨脑(megalencephaly);梅-罗综合征;美尼尔症;脑膜炎;门克斯病;异染性脑白质营养不良;小头畸形;偏头痛;米勒费希尔综合征;小中风(mini-stroke);线粒体肌病;默比厄斯综合征;单肢肌萎缩;运动神经元病;脑底异常血管网病;粘多糖症;多发性梗塞性痴呆(milti-infarct dementia);多病灶运动神经病;多发性硬化和其它脱髓鞘病症;多系统萎缩伴随直立性低血压;p肌肉萎缩症;重症肌无力;髓鞘脱失(myelinoclastic)弥漫性硬化;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;神经阻滞剂恶性综合征;AIDS的神经表现;狼疮的神经后遗症;神经性肌强直;神经元腊样脂褐质症;神经元迁移障碍;尼曼 -皮克病;O’Sullivan-McLeod综合征;枕神经痛;隐性脊柱神经管闭合不全序列征;大田原(Ohtahara)综合征;橄榄体脑桥小脑萎缩;视性眼肌阵痉挛;视神经炎;直立性低血压;过度使用综合征;感觉异常;神经变性疾病或病症(帕金森病、亨廷顿舞蹈病、阿尔茨海默氏病、肌萎缩侧索硬化(ALS)、痴呆、多发性硬化以及其它和神经元细胞死亡有关的疾病和病症);先天性副肌强直;类肿瘤性疾病;发作性发作 (paroxysmal attacks);帕-罗(Parry Romberg)综合征;佩-梅病;周期性瘫痪;周围神经病;疼痛性神经病和神经性疼痛;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;神经挟捏;垂体瘤;多肌炎;脑穿通畸形;小儿麻痹症后期综合征;疱疹后神经痛;感染后脑脊髓炎;直立性低血压;普-韦(Prader-Willi)综合征;原发性侧索硬化;朊病毒病;进行性一侧面萎缩;进行性多灶性白质脑病;进行性硬化性灰质萎缩;进行性核上性麻痹;脑假瘤;拉姆齐·亨特综合征(I型和11型);拉斯马森(Rasmussen)脑炎;反射性交感神经营养不良综合征;雷夫叙姆病;反复性运动障碍;反复性应激损伤;腿多动综合征;逆转录病毒相关性脊髓病;雷特综合征;雷耶综合征;舞蹈病;桑德霍夫病;谢耳德病;脑裂;视隔发育不全(septo-optic dysplasia);惊吓婴儿综合征;带状疱疹;希-德综合征;斯耶格伦综合征;睡眠性呼吸暂停;索托斯综合征(Soto′s syndrome);痉挛状态;脊柱裂;脊髓损伤;脊髓瘤;脊髓性肌萎缩;僵人综合征(Stiff-Person syndrome);中风;斯-韦综合征;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;晕厥;脊髓空洞症;迟发性运动障碍;泰-萨病;颞动脉炎;脊髓栓系综合征(tethered spinal cord syndrome);肌强直性白内障;胸廓出口综合征;三叉神经痛;Todd麻痹;图雷特综合症;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;热带痉挛性轻截瘫;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(Von Hippel-Lindau)病;瓦伦伯格综合征;韦-霍(Werdnig-Hoffman)病;韦斯特综合征;急性颈部扭伤(whiplash);威廉斯综合征;Wildon病;以及泽尔韦格综合征。
“炎症”是指全身性炎性病况以及局部地与单核细胞、白细胞和/ 或中性粒细胞的迁移和吸引有关的病况。炎症的实例包括但不限于,因以下引发的炎症:感染致病生物(包括革兰氏阳性菌、革兰氏阴性菌、病毒、真菌、以及寄生物,例如原生动物和蠕虫)、移植排斥(包括实质器官的排斥,例如肾、肝、心、肺或角膜,以及骨髓移植的排斥,包括移植物抗宿主病(GVHD))或者局限性慢性或急性自身免疫反应或变态反应。自身免疫性疾病包括急性肾小球肾炎;类风湿性或反应性关节炎;慢性肾小球肾炎;炎性肠病,例如克罗恩氏病、溃疡性结肠炎和坏死性小肠结肠炎;与粒细胞输注有关的综合征;炎性皮肤病,例如接触性皮炎、特应性皮炎、银屑病;系统性红斑狼疮(SLE);自身免疫性甲状腺炎、多发性硬化、以及糖尿病的某些形式、或任何其它自体免疫状态(其中受试者自身免疫系统的攻击导致病理性组织破坏)。变态反应包括变应性哮喘、慢性支气管炎、急性和迟发型超敏反应。全身性炎性疾病状态包括与创伤、烧伤、缺血事件(例如在心、脑、肠或外周脉管系统中的血栓形成事件,包括心肌梗死和中风)后的再灌注、脓毒症、ARDS或多器官功能障碍综合征相关的炎症。炎性细胞募集也在粥样硬化斑块中发生。炎症包括但不限于,非何杰金淋巴瘤、韦格纳肉芽肿病、桥本甲状腺炎、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、克罗恩氏病、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)、子宫内膜异位症(endometriosis)、急性子宫颈炎、慢性子宫颈炎、淋巴样增生、多发性硬化、继发于特发性血小板减少性紫癜的肥大、原发性IgA肾病、系统性红斑狼疮、银屑病、肺气肿、慢性肾盂肾炎、以及慢性膀胱炎。
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,靶标包括胶原基因的核酸序列,包括但不限于与胶原基因有关的有义和/或反义非编码和/或编码序列。
在一个实施方案中,靶标包括COL1A1的核酸序列,包括但不限于与COL1A1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,靶标包括COL1A2的核酸序列,包括但不限于与COL1A2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,靶标包括COL7A1的核酸序列,包括但不限于与COL7A1基因有关的有义和/或反义非编码和/或编码序列。
I型胶原为脉管系统中最丰富的ECM成分且在斑块中被大量发现,其水平影响斑块的易损性且与动脉粥样硬化的死亡率和发病率相关(Libby P.,等(2000)J.Intern.Med.247:349-358;Rekhter MD.,(1993) Am.J.Pathol.143:1634-1648)。它由两个相当大的基因产生的两条α1(I) 链和一条α2(I)链组成,所述基因位于人和小鼠基因组二者的不同染色体上(Myllyharju,J.,等(2001)Ann.Med.33,7-21)。I型胶原为原纤维胶原家族的成员且占在骨中发现的蛋白质的80-90%。其也在诸如皮肤、韧带和腱等组织中被大量发现。COL1A1基因位于17号染色体长(q)臂的21.3-22.1位置之间,从碱基对45,616,455到碱基对 45,633,991。
I型胶原为脉管系统中最丰富的ECM成分且在斑块中被大量发现,其水平影响斑块的易损性且与动脉粥样硬化的死亡率和发病率相关(Libby P.,等(2000)J.Intern.Med.247:349-358;Rekhter MD.,(1993) Am.J.Pathol.143:1634-1648)。它由两个相当大的基因产生的两条α1(I) 链和一条α2(I)链组成,所述基因位于人和小鼠基因组二者的不同染色体上(Myllyharju,J.,等(2001)Ann.Med.33,7-21)。胶原α2(I)基因(COL1A2)位于染色体7q22.1。
胶原VII型α1(大疱性表皮松解症,营养不良性,显性和隐性),也称为COL7AI,为人基因。此基因编码VII型胶原的α链。由三条完全相同的α胶原链组成的VII型胶原原纤维局限在复层鳞状上皮下的基底区。它充当外部上皮和下面间质之间的固着性原纤维。此基因中的突变与所有形式的营养不良性大疱性表皮松解症有关。然而在没有突变时,对VII型胶原的自身免疫应答可导致此疾病的获得性形式,称为获得性大疱性表皮松解症。
在视网膜中也发现VII型胶原;其在此器官中的功能未知。
COL7A1位于人3号染色体的短臂,在表示为3p21.31的染色体区中。所述基因大小为约31,000个碱基对并且因为其编码序列极度断裂成118个外显子而值得注意。COL7A1转录成9,287个碱基对的 mRNA。在皮肤中,VII型胶原蛋白由角质形成细胞和真皮成纤维细胞合成。
营养不良性大疱性表皮松解症(DEB)为临床异质性可遗传皮肤病症,以轻微创伤之后皮肤和粘膜的起疱为特征,且具有宽范围的临床严重性。所有形式均由COL7AI中的突变引起,所述基因编码胶原 VII。此胶原(固着性原纤维的主要成分)在DEB皮肤中减少或缺失,且固着性原纤维在形态上改变或缺失并在功能上缺陷。值得注意的是,尽管有显著的科学成果,但基因突变的全谱以及导致这些视觉性和功能性改变的分子机制仍难以捉摸。
全世界而言,DEB影响数千家庭。因此,对于精确诊断、预测、遗传咨询和可靠的产前诊断以及重要地鉴定用于未来基因治疗试验的适宜候选者而言,迫切需要有效的COL7A1突变检测。COL7A1位于3p21区之内并跨越超过30.5kb。其与其它胶原基因共享结构特征且由118个小外显子和小内含子组成。迄今为止,虽然已报道多于200 种不同的突变,但是非常少频发突变或热点为已知的。
在一些实施方案中,使用反义寡核苷酸预防或治疗与胶原基因家族成员有关的疾病或病症。可用由利用反义化合物获得的干细胞再生的细胞/组织治疗的示例性胶原基因介导的疾病和病症包括:胶原障碍、年龄相关的胶原降解、成骨不全、耳硬化(OTSC)、骨质疏松、骨关节炎、食管鳞状上皮细胞癌、软骨发育不全、非典型马方综合征 (atypical Marfansyndrome)、埃-当综合征(Ehlers-Danlos syndrome) (EDS)、营养不良性大疱性表皮松解症(DEB)、卡菲病、动脉瘤(例如颅内动脉瘤)、特发性肺纤维化、肝硬化、肾纤维化、肝纤维化、心脏纤维化、硬皮病、肥厚性瘢痕、瘢痕疙瘩、癌症、炎症、遗传性疾病 (例如杜兴肌营养不良)、神经疾病或病症(例如帕金森病、阿尔茨海默氏病、亨廷顿舞蹈病、戈谢病(Gaucherdisease))、代谢病(例如I型糖尿病)、自身免疫性疾病或病症、创伤(例如脊髓损伤、烧伤等)、缺血,以及其它血管、心脏、皮肤疾病或病症,皮肤老化、需要皮肤工程的皮肤疾病或病症或病况、需要移植的肝脏或肾脏疾病;腱、骨或组织再生;骨骼修复、软骨和骨修复。
在另一个实施方案中,所述反义寡核苷酸调节患有与胶原基因有关的疾病或病症或处于形成与胶原基因有关的疾病或病症的风险中的患者中胶原基因的正常表达和/或正常功能。
本发明的一个实施方案提供基于胶原基因的基质组合物,所述组合物包含由胶原原纤维组成的三维纯化胶原基质,其中通过使胶原原纤维细胞或组织与靶定胶原基因多核苷酸的天然反义寡核苷酸的区的至少一种反义寡核苷酸接触,在体内或体外调节胶原原纤维细胞中胶原基因多核苷酸的功能和/或表达
本发明的一个实施方案提供体外、离体或体内伤口愈合或组织再生或组织工程的方法,所述方法包括给伤口施用本发明的胞外基质组合物。
本发明的一个实施方案提供制备基于胶原基因的基质组合物的方法,包括使胶原原纤维细胞或组织与靶定胶原基因多核苷酸的天然反义寡核苷酸的区的至少一种反义寡核苷酸接触;从而在体内或体外调节患者细胞或组织中胶原基因多核苷酸的功能和/或表达。
本发明的另一个实施方案提供用于支持干细胞的组合物,所述组合物包含含有胶原原纤维的工程改造的、纯化的基于胶原基因的基质,以及干细胞群。可将本发明工程改造的、纯化的基于胶原的基质组合物单独使用或与细胞联合使用,作为组织移植构建体增强受损或患病组织的修复。
依照一个实施方案,提供了用于培养干细胞的改进方法。所述方法包括:制备如本发明所提供的具有所需特性的经增溶的胶原基因组合物,向经增溶的胶原基因组合物中加入细胞和在受控条件下使胶原组合物聚合以提供由胶原原纤维形成并具有所需微观结构的基质。在一个实施方案中将细胞加入基于胶原基因的基质中,并在适于增殖所述细胞的条件下培养所述细胞。
在实施方案中,将基于胶原基因的基质组合物用于预防或治疗与损失特定细胞类型或组织有关的疾病或病症,所述细胞类型或组织可被由多能干细胞再生的新细胞/组织替换。
在实施方案中,将基于胶原基因的基质组合物与至少一种选自下列的转录因子联合使用:OCT4、c-myc、KLF4和/或Sox2、NANOG、 LIN28和从给定成体组织诱导多能干细胞所需的其它转录因子。可将这些细胞进一步引入损伤中并使其在体外或体内分化成所需细胞类型。
可用由利用干细胞和反义化合物从基于胶原基因的基质组合物中再生的细胞/组织治疗的疾病的实例包括癌症、遗传性疾病(例如杜兴肌营养不良)、神经变性疾病(例如帕金森病、阿尔茨海默氏病、亨廷顿舞蹈病、戈谢病)、代谢病(例如I型糖尿病)、创伤(例如脊髓损伤、烧伤,等等)、缺血,以及其它需要移植的血管、心脏、肝脏或肾脏疾病。
在实施方案中,也可将基于胶原基因的基质组合物用于腱、骨或组织再生;骨骼修复、软骨、骨修复过程、骨质疏松、用于关节成形术的假体等,其可原位注入轻微的无连接性骨折或软骨损伤中,注入骨质疏松个体的体循环中,或将其吸附在适当生物材料(胶原、羟磷灰石等)中植入以促进损伤中软骨或骨形成。此外,可将所述组合物吸附在覆盖用于髋、膝关节成形术的假体的羟磷灰石(periapatite)中,以增强这些假体在宿主中的生物整合,延长它们的寿命。还可将所述组合物用于脊柱关节固定术以促进脊柱融合和改善通过使用自体移植物或骨库的标准程序进行的这些程序的效率。
在本发明的实施方案中,给需要皮肤治疗的受试者或处于形成使他们需要皮肤治疗的病况的风险中的受试者,提供治疗和/或美容方案及相关的定制治疗。例如可基于受试者的胶原基因状态进行诊断。患者的给定组织例如皮肤中的胶原基因表达水平可通过本领域技术人员已知和本文别处所述的方法确定,例如,通过使用PCR或基于抗体的检测方法分析组织。
本发明的一个实施方案提供用于皮肤治疗和/或美容应用的组合物,所述组合物包含胶原基因反义寡核苷酸,例如以增量调节皮肤中胶原基因的表达。反义寡核苷酸的实例如SEQ ID NO:4-29所述。在实施方案中,用本发明的寡核苷酸在体内处理细胞,以增长细胞寿命或防止凋亡。例如,可如本文所述通过处理皮肤(例如上皮细胞)防止皮肤老化,例如形成皱纹。在一个示例性实施方案中,使皮肤与包含如本文所述的胶原基因反义化合物的药物或美容组合物接触。示例性皮肤困扰或皮肤病况包括与炎症、晒伤或自然老化有关或由它们引发的疾病或病症。例如,所述组合物在预防或治疗下列中具有效用:接触性皮炎(包括刺激性接触性皮炎和变应性接触性皮炎)、特应性皮炎 (也称为变应性湿疹)、光化性角化病、角质化病症(包括湿疹)、大疱性表皮松解症(包括penfigus)、剥脱性皮炎、脂溢性皮炎、红斑(包括多形性红斑和结节性红斑)、由日光或其它光源引发的损伤、盘状红斑狼疮、皮肌炎、皮肤癌和自然老化的作用。
在本发明的实施方案中,包含胶原基因反义寡核苷酸的组合物,例如增量调节头皮中胶原基因的表达并抑制雄激素受体信号转导,从而防止雄激素性脱发(脱发)。在实施方案中,给患脱发的患者施用局部或全身制剂。
在一个实施方案中,将本文所述的反义寡核苷酸掺入到含有局部载体和包含本领域已知的任何这类材料的局部制剂中,所述局部载体一般适于局部药物施用。所述局部载体可被挑选以便提供所需形式的组合物,例如作为软膏剂、洗剂、乳膏剂、微乳剂、凝胶剂、油剂、溶液剂等,以及可由天然存在或合成来源的材料组成。优选的是,所选载体对局部制剂的活性剂或其它成分没有不利影响。用于本文的适宜局部载体的实例包括水、醇和其它无毒有机溶剂、甘油、矿物油、硅酮、石油凝胶、羊毛脂、脂肪酸、植物油、对羟基苯甲酸酯类、蜡等。制剂可为无色无臭的软膏剂、洗剂、乳膏剂、微乳剂和凝胶剂。
可将本发明的反义寡核苷酸掺入到软膏剂中,所述软膏剂一般为半固体制剂,其典型地基于矿脂或其它石油衍生物。如将被本领域技术人员所领会,待使用的特定软膏基质为这样的软膏基质,其将提供最佳药物递送,并且优选地还将提供其它的所需特性,例如,润滑性等。当使用其它载体或溶媒时,软膏基质应当为惰性、稳定、无刺激和非致敏的。如在Remington′s Pharmaceutical Sciences(Mack Pub.Co.) 中所说明,可将软膏基质分成四类:油性基质;可乳化基质;乳剂基质;和水溶性基质。油性软膏基质包括例如植物油、获自动物的脂肪和获自石油的半固体碳氢化合物。可乳化软膏基质也称为可吸收软膏基质,含很少水或不含水且包括例如硫酸羟基甘油三硬脂酸酯、无水羊毛脂和亲水矿脂。乳剂软膏基质为油包水(W/O)乳剂或水包油(O/W) 乳剂,且包括例如鲸蜡醇、单硬脂酸甘油酯、羊毛脂和硬脂酸。示例性水溶性软膏基质由不同分子量的聚乙二醇(PEG)制备(参见,例如上述Remington′s)。
可将本发明的反义寡核苷酸掺入到洗剂中,所述洗剂一般为无摩擦施用给皮肤表面的制剂,且典型地为液体或半流体制剂,其中固体颗粒(包括活性剂)存在于水或醇基质中。洗剂通常为固体的混悬剂,且可包含水包油型液体油状乳剂。因为易于施用流动性较高的组合物,洗剂为用于处理大面积身体区域的优选制剂。一般必需的是,将洗剂中的不溶性物质细碎。洗剂将典型地含有助悬剂以形成更好的分散体,和含有用于定域和维持活性剂与皮肤接触的化合物,例如甲基纤维素、羧甲基纤维素钠等。用于与本发明方法联合使用的示例性洗剂包含与亲水矿脂混合的丙二醇,例如其可以AquaphorRTM商标获自 Beiersdorf,Inc.(Norwalk,Conn.)的。
可将本发明的反义寡核苷酸掺入到乳膏剂中,所述乳膏剂一般为水包油或油包水的粘性液体或半固体乳剂,。乳膏基质可水洗,且包含油相、乳化剂和水相。油相一般由矿脂和例如鲸蜡醇或硬脂醇等脂肪醇组成;尽管非必须,但水相通常体积超过油相,且一般含有湿润剂。如上述Remington′s中所说明,乳膏制剂中的乳化剂一般为非离子、阴离子、阳离子或两性表面活性剂。
可将本发明的反义寡核苷酸掺入到微乳剂中,所述微乳剂一般为两种不混溶液体(例如油和水)的热力学稳定的各向同性澄清分散体,其通过表面活性剂分子的界面膜稳定(制药工艺学百科全书 (Encyclopedia of Pharmaceutical Technology)(New York:Marcel Dekker,1992),第9卷)。对制备微乳剂而言,表面活性剂(乳化剂)、助表面活性剂(助乳化剂)、油相和水相为必需的。适宜表面活性剂包括用于制备乳剂的任何表面活性剂,例如典型地用于制备乳膏剂的乳化剂。助表面活性剂(或“助乳化剂”)一般选自聚甘油衍生物、甘油衍生物和脂肪醇。尽管非必须,但优选的乳化剂/助乳化剂组合一般选自:单硬脂酸甘油酯和聚氧乙烯硬脂酸酯;聚乙二醇和硬脂酸棕榈酸乙二醇酯;以及辛酸和癸酸甘油三酯和油酸聚乙二醇甘油酯。水相不仅包括水,还典型地包括缓冲液、葡萄糖、丙二醇、聚乙二醇、优选低分子量聚乙二醇(例如PEG 300和PEG 400)和/或甘油等,而油相将一般包括例如脂肪酸酯、改性植物油、硅酮油、甘油单酯二酯和三酯的混合物、PEG的单酯和二酯(例如,油酸聚乙二醇甘油酯)等。
将本发明的反义寡核苷酸掺入到凝胶制剂中,所述凝胶制剂一般为由小的无机颗粒构成的混悬液(两相系统)或在载液各处基本上均匀分布的大的有机分子(单相凝胶)组成的半固体系统。可通过例如使活性剂、载液和适宜胶凝剂(例如西黄蓍胶(在2-5%)、海藻酸钠(在 2-10%)、明胶(在2-15%)、甲基纤维素(在3-5%)、羧甲基纤维素钠(在 2-5%)、卡波姆(在0.3-5%)或聚乙烯醇(在10-20%))合并在一起并混合直至产生特征性半固体产物来制作单相凝胶。其它适宜胶凝剂包括甲基羟基纤维素、聚氧乙烯-聚氧丙烯、羟乙基纤维素和明胶。尽管凝胶通常使用水性载液,但是也可将醇和油用作载液。
可将本领域技术人员已知的多种添加剂包含在制剂例如局部制剂中。添加剂的实例包括但不限于:增溶剂、皮肤渗透促进剂、遮光剂、防腐剂(例如抗氧化剂)、胶凝剂、缓冲剂、表面活性剂(特别是非离子和两性表面活性剂)、乳化剂、软化剂、增稠剂、稳定剂、湿润剂、着色剂、香料等。特别优选连同乳化剂、软化剂和防腐剂一起包含增溶剂和/或皮肤渗透促进剂。最佳局部制剂包含大约:2%重量-60%重量、优选2%重量-50%重量的增溶剂和/或皮肤渗透促进剂;2%重量 -50%重量、优选2%重量-20%重量的乳化剂;2%重量-20%重量的软化剂;和0.01-0.2%重量的防腐剂,而活性剂和载体(例如水)组成制剂的余下部分。
皮肤渗透促进剂用来促进治疗水平活性剂的通行以通过合理大小面积的未破损皮肤。适宜促进剂在本领域众所周知且包括例如:低级链烷醇,例如甲醇、乙醇和2-丙醇;烷基甲基亚砜,例如二甲基亚砜(DMSO)、癸甲基亚砜(C10MSO)和十四烷基甲基亚砜;吡咯烷酮,例如2-吡咯烷酮、N-甲基-2-吡咯烷酮和N-(-羟乙基)吡咯烷酮;尿素; N,N-二乙基-间-甲苯酰胺;C2-C6链烷二醇;杂溶剂,例如二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)和四氢糠醇;以及1-取代氮杂环庚烷-2-酮、具体为1-n-十二烷基环氮杂环庚烷-2-酮(月桂氮酮;可以商标AzoneRTM获自Whitby Research Incorporated,Richmond,Va.)。
增溶剂的实例包括但不限于下列:亲水性醚,例如二乙烯二醇单乙醚(乙氧基二甘醇,可市购为TranscutolRTM)和二乙烯二醇单乙醚油酸酯(可市购为SoficutolRTM);聚乙烯蓖麻油衍生物,例如聚氧35蓖麻油、聚氧40氢化蓖麻油等;聚乙二醇、特别是低分子量聚乙二醇,例如PEG 300和PEG 400,以及聚乙二醇衍生物,例如PEG-8辛酸/ 癸酸甘油酯(可市购为LabrasolRTM);烷基甲基亚砜,例如DMSO;吡咯烷酮,例如2-吡咯烷酮和N-甲基-2-吡咯烷酮;以及DMA。许多增溶剂也可充当吸收促进剂。可将单独的增溶剂掺入到制剂中,或将增溶剂的混合物掺入其中。
适宜乳化剂和助乳化剂包括但不限于对微乳剂描述的那些乳化剂和助乳化剂。软化剂包括例如丙二醇、甘油、肉豆蔻酸异丙酯、聚丙二醇-2(PPG-2)肉豆蔻醚丙酸酯等。
其它活化剂也可包含在制剂中,例如其它抗炎剂、镇痛剂、抗微生物剂、抗真菌剂、抗生素、维生素、抗氧化剂和通常在防晒制剂中存在的防晒剂,其包括但不限于:邻氨基苯甲酸酯、二苯酮(特别是二苯酮-3)、樟脑衍生物、肉桂酸酯(例如甲氧肉桂酸辛酯)、二苯酰甲烷(例如丁基甲氧基二苯酰甲烷)、对氨基苯甲酸(PABA)及其衍生物和水杨酸酯(例如水杨酸辛酯)。
在一个实施方案中,寡核苷酸对于胶原基因(其包括但不限于非编码区)的多核苷酸而言为特异的。胶原基因靶标包括胶原基因的变体;胶原基因的突变体,包括SNP;胶原基因的非编码序列;等位基因、片段等。优选所述寡核苷酸为反义RNA分子。
依照本发明的实施方案,靶核酸分子不单独限于胶原基因多核苷酸,而是扩展到胶原基因的任何同种型、受体、同源物、非编码区等。
在另一个实施方案中,寡核苷酸靶定胶原基因靶标的天然反义序列(针对编码和非编码区的天然反义物),所述胶原基因靶标包括但不限于其变体、等位基因、同源物、突变体、衍生物、片段和互补序列。优选所述寡核苷酸为反义RNA或DNA分子。
在另一个实施方案中,本发明的寡聚化合物也包括变体,其中在所述化合物的一个或多个核苷酸位置上存在不同的碱基。例如,如果第一个核苷酸为腺嘌呤,则可产生在此位置含有胸苷、鸟苷、胞苷或其他天然或非天然核苷酸的变体。这可在所述反义化合物的任何位置上完成。
在一些实施方案中,反义化合物与靶标之间的同源性、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%。
反义化合物在以下情况时为可特异性杂交的:所述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损失,并且在需要特异性结合的条件下存在足够程度的互补性以避免所述反义化合物与非靶核酸序列的非特异性结合。这类条件包括,即,在体内测定或治疗性处理情况中的生理条件,以及在体外测定情况下进行测定的条件。
反义化合物,不论DNA、RNA、嵌合的、取代的等等,在以下情况时为可特异性杂交的:所述化合物与靶DNA或RNA分子的结合干扰靶DNA或RNA的正常功能而引起效用损失,并且在需要特异性结合的条件下存在足够程度的互补性以避免所述反义化合物与非靶序列的非特异性结合,所述条件即在体内测定或治疗性处理情况中的生理条件下,以及在体外测定情况下进行测定的条件下。
在另一个实施方案中,靶定胶原基因调节胶原基因的表达或功能,胶原基因包括但不限于使用例如PCR、杂交等鉴定和扩增的反义序列、一个或多个如SEQ ID NO:4-9所述的序列等。在一个实施方案中,表达或功能与对照相比为增量调节的。在另一个实施方案中,表达或功能与对照相比为减量调节的。
在另一个实施方案中,寡核苷酸包括如SEQ ID NO:10-29所述的核酸序列,包括使用例如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经修饰的核苷酸、较短或较长的片段、经修饰的键等。经修饰的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,所述核苷酸包括磷衍生物。可连接到本发明的修饰寡核苷酸中的糖或糖类似物部分的磷衍生物(或经修饰的磷酸基),可为单磷酸酯、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,以及它们掺入到核苷酸、修饰核苷酸和寡核苷酸中本身也为已知的且无需在此描述。
反义物的特异性和灵敏性也被本领域的技术人员掌握用于治疗用途。已将反义寡核苷酸用作在动物和人的疾病状态治疗中的治疗部分。已将反义寡核苷酸安全和有效地施用给人,并且目前正在进行许多临床试验。因此已确定寡核苷酸可为有用的治疗形式,其可将经配置以在用于治疗细胞、组织和动物尤其人的治疗方案中有用。
在本发明的实施方案中,寡聚反义化合物(具体地寡核苷酸)结合到靶核酸分子并调节由靶基因编码的分子的表达和/或功能。待干扰的 DNA功能包括例如复制和转录。待干扰的RNA功能包括所有的生活机能,例如RNA向蛋白质翻译位点的易位、蛋白质自RNA的翻译、产生一种或多种mRNA种类的RNA剪接,以及可由RNA参与或促进的催化活性。所述功能可被增量调节或受抑制,这取决于所需的功能。
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、可变剪接物、引物、探针和与靶核酸的至少一部分杂交的其他寡聚化合物。因此,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。
在本发明的文段中,将反义化合物靶定到特定的核酸分子可为多步过程。所述过程通常以鉴定待调节其功能的靶核酸开始。此靶核酸可为,例如其表达与特定病症或疾病状态有关的细胞基因(或从基因转录的mRNA),或来自传染剂的核酸分子。在本发明中,所述靶核酸编码胶原基因。
靶定过程通常也包括确定靶核酸内的至少一个靶区、区段或位点以用于发生反义相互作用,使得产生所需的效应,例如,表达的调节。在本发明的文段中,术语“区”定义为具有至少一个可识别结构、功能或特征的靶核酸的一部分。靶核酸区内为区段。“区段”定义为在靶核酸内区的较小或亚部分。本发明所用的“位点”定义为靶核酸内的位置。
在一个实施方案中,反义寡核苷酸结合到胶原基因的天然反义序列并调节胶原基因(SEQ ID NO:1-3)的表达和/或功能。反义序列的实例包括SEQ ID NO:4-29。
在另一个实施方案中,反义寡核苷酸结合到胶原基因多核苷酸的一个或多个区段并调节胶原基因的表达和/或功能。所述区段包含胶原基因有义或反义多核苷酸的至少五个连续的核苷酸。
在另一个实施方案中,反义寡核苷酸对胶原基因的天然反义序列而言为特异的,其中所述寡核苷酸与胶原基因的天然反义序列的结合调节胶原基因的表达和/或功能。
在另一个实施方案中,寡核苷酸化合物包括如SEQ ID NO:10-29 所述的序列、使用例如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、较短或较长的片段、经修饰的键等。经修饰的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,所述核苷酸包括磷衍生物。可连接到本发明的修饰寡核苷酸中的糖或糖类似物部分的磷衍生物(或经修饰的磷酸基),可为单磷酸酯、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,以及它们掺入到核苷酸、修饰核苷酸和寡核苷酸中本身也为已知的且无需在此描述。
由于如本领域已知,翻译起始密码子通常为5′-AUG(在转录的mRNA分子中;在相应的DNA分子中为5′-ATG),因而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”。少数基因具有翻译起始密码子,其具有RNA序列5′-GUG、5′-UUG或 5′-CUG;以及5′-AUA、5′-ACG和5′-CUG已显示在体内起作用。因此,术语“翻译起始密码子”和“起始密码子”可包括许多密码子序列,但在每个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或更多个备选起始密码子,其中的任何一个可优先地用于在特定细胞类型或组织中或在特定条件组下的翻译起始。在本发明的文段中,“起始密码子”和“翻译起始密码子”是指这样的一个或多个密码子,其在体内用于起始由编码胶原基因的基因转录的mRNA的翻译,与这类密码子的一个或多个序列无关。基因的翻译终止密码子(或“终止密码子”)可具有三个序列中的一个,即,5′-UAA、5′-UAG和5′-UGA(对应的DNA序列分别为 5′-TAA、5′-TAG和5′-TGA)。
术语“起始密码子区”和“翻译起始密码子区”是指从翻译起始密码子开始在任一方向上(即,5’或3’)包含约25-约50个连续的核苷酸的这类mRNA或基因的部分。类似地,术语“终止密码子区”和“翻译终止密码子区”是指从翻译终止密码子开始在任一方向上(即,5’或3’)包含约25-约50个连续的核苷酸的这类mRNA或基因的部分。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地靶定的区。
本领域已知的可读框(ORF)或“编码区”是指在翻译起始密码子和翻译终止密码子之间的区,也为可有效地靶定的区。在本发明的文段中,靶定的区为包含基因可读框(ORF)的翻译起始或终止密码子的基因内区。
另一种靶区包括本领域已知的5’非翻译区(5’UTR),是指在翻译起始密码子的5’方向上的mRNA的部分,因此包括在mRNA的5’加帽位点和翻译起始密码子之间的核苷酸(或基因上对应的核苷酸)。再一种靶区包括本领域已知的3’非翻译区(3′UTR),是指在翻译终止密码子3’方向上的mRNA的部分,因此包括在mRNA的翻译终止密码子和3’末端之间的核苷酸(或基因上对应的核苷酸)。mRNA的5’加帽位点包含经由5’-5’三磷酸酯键连接到mRNA的5’最末端残基的N7-甲基化鸟苷残基。认为mRNA的5’帽区包括5’帽子结构本身以及邻近该帽位点的前50个核苷酸。用于本发明的另一种靶区为5’帽区。
尽管一些真核mRNA转录物为直接翻译的,但是许多包含一个或多个称为“内含子”的区,其在翻译前被从转录物中切除。余下的(且因此翻译的)区称为“外显子”,并将其剪接在一起形成连续的mRNA序列。在一个实施方案中,靶定剪接位点(即,内含子-外显子连接处或外显子-内含子连接处)在疾病牵涉异常剪接或疾病牵涉特定剪接产物过度产生的状况中特别有用。因重排或缺失所致的异常融合连接处为靶位点的另一个实施方案。经由来自不同基因来源的两个(或更多个) mRNA的剪接过程产生的mRNA转录物称为“融合转录物”。内含子可使用靶定到例如DNA或前mRNA的反义化合物来有效地靶定。
在另一个实施方案中,反义寡核苷酸结合到靶多核苷酸的编码和 /或非编码区并调节靶分子的表达和/或功能。
在另一个实施方案中,反义寡核苷酸结合到天然反义多核苷酸并调节靶分子的表达和/或功能。
在另一个实施方案中,反义寡核苷酸结合到有义多核苷酸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。这些可变转录物一般称为“变体”。更具体地,“前mRNA变体”为产生自相同的基因组DNA的转录物,其与产生自相同的基因组DNA的其他转录物在其起始或终止位置上不同且包含内含子和外显子序列二者。
当剪接期间切除了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变体为经加工的前mRNA变体,并且由于剪接所致,每种独特的前mRNA变体必须总是产生独特的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,则前mRNA变体与mRNA 变体完全相同。
变体可通过使用可变信号启动或终止转录来产生。前mRNA和 mRNA可具有多于一个起始密码子或终止密码子。起源于使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”。使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”。可变终止变体的一个具体类型为“聚腺苷酸变体”,其中所产生的多重转录物起因于转录机构对其中一种“聚腺苷酸终止信号”的可变选择,从而产生终止在独特的聚腺苷酸位点上的转录物。在本发明的文段内,本文所述的变体类型也为靶核酸的实施方案。
将反义化合物与之杂交的靶核酸上的位置定义为活性反义化合物靶定的靶区的至少5个核甘酸长的部分。
虽然将某些示例性靶区段的具体序列列举于此,但是本领域的技术人员会认识到,这些用于说明和描述在本发明范围内的具体实施方案。根据本公开内容,其他靶区段可由本领域普通技术人员容易地鉴定。
认为以下靶区段同样适合靶定,该靶区段长度为5-100个核苷酸并包含选自说明性靶区段之内的一段至少五(5)个连续的核苷酸。
靶区段可包括DNA或RNA序列,其包含来自说明性靶区段之一的5’末端的至少5个连续核苷酸(余下的核苷酸为相同DNA或RNA 的连续段,其开始于靶区段5’末端的紧接上游且持续到该DNA或 RNA包含约5-约100个核苷酸为止)。类似的靶区段由以下DNA或 RNA序列表示,该序列包含来自说明性靶区段之一的3’末端的至少5 个连续核苷酸(余下的核苷酸为相同DNA或RNA的连续段,其开始于靶区段3’末端的紧接下游且持续到该DNA或RNA包含约5-约100 个核苷酸为止)。本领域技术人员根据本文所说明的靶区段,无需过度试验就能够鉴定另外的靶区段。
一旦鉴定一个或多个靶区、区段或位点,就选出与该靶标足够互补的反义化合物,所述足够互补即充分良好且具有足够的特异性杂交以得到所需的效果。
在本发明的实施方案中,寡核苷酸与特定靶标的反义链结合。所述寡核苷酸长度为至少5个核苷酸且可为合成的,使得每个寡核苷酸靶定重叠的序列,由此将寡核苷酸合成为覆盖靶多核苷酸的全长。靶标也包括编码区以及非编码区。
在一个实施方案中,通过反义寡核苷酸来靶定特定核酸。将反义化合物靶定到特定核酸为多步过程。该过程通常开始于鉴定其功能待调节的核酸序列。这可为,例如其表达与特定的病症或疾病状态有关的细胞基因(或从该基因转录的mRNA),或非编码多核苷酸,例如非编码RNA(ncRNA)。
可将RNA归类为(1)信使RNA(mRNA),其被翻译成蛋白,和(2) 非编码蛋白的RNA(ncRNA)。ncRNA包括微小RNA、反义转录物和包含高密度的终止密码子并缺少任何广泛的“可读框”的其他转录单元 (TU)。许多ncRNA似乎开始于蛋白编码基因座的3’非翻译区(3′UTR) 中的起始位点。ncRNA常常为罕见的且至少一半已由FANTOM协会测序的ncRNA似乎未聚腺苷酸化。大多数研究者因为明显的原因而关注经加工并输出到细胞质的聚腺苷酸化mRNA。近来,已显示非聚腺苷酸化核RNA的群体可非常巨大,且许多这类转录物产生于基因内区。ncRNA可调节基因表达的机制为通过与靶转录物的碱基配对。通过碱基配对起作用的RNA可分组成(1)顺式编码RNA,其在相同的基因位置、但在其所作用的RNA相反的链上编码,因此显示对其靶标完美的互补性,和(2)反式编码RNA,其在与其所作用的RNA不同的染色体位置上编码,一般不表现出与其靶标完美的碱基配对潜能。
不希望受到理论的约束,通过本文所述的反义寡核苷酸来扰乱反义多核苷酸,可改变相应有义信使RNA的表达。然而,此调节可为不一致的(反义敲减导致信使RNA上升)或一致的(反义敲减导致伴随的信使RNA下降)。在这些情况下,可将反义寡核苷酸靶定到反义转录物的重叠或非重叠部分,引起其敲减或隔离。编码以及非编码反义物可以相同的方式来靶定,并且任一种类别均能够调节相应有义转录物——以一致或不一致的方式。用于鉴定针对靶标使用的新寡核苷酸的策略可基于通过反义寡核苷酸或任何其他调节所需靶标的方法对反义RNA转录物的敲减。
策略1:在不一致调节的情况下,敲减所述反义转录物提升常规(有义)基因的表达。若后者基因编码已知或假定的药物靶标,则其反义配对物的敲减可预料到地模拟受体激动剂或酶刺激剂的作用。
策略2:在一致调节的情况下,可伴随地敲减反义和有义转录物两者,从而达到常规(有义)基因表达的协同下降。如果例如将反义寡核苷酸用于进行敲减,则此策略可用于应用针对有义转录物靶定的一种反义寡核苷酸和针对相应反义转录物的另一种反义寡核苷酸,或同时靶定重叠的有义和反义转录物的单个有力对称的反义寡核苷酸。
根据本发明,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),以及与靶核酸的至少一部分杂交且调节其功能的其他寡聚化合物。因此,其可为DNA、RNA、DNA样、RNA样、或其混合物,或可为这些中的一种或多种的模拟物。这些化合物可为单链、双链、环状或发夹寡聚化合物且可包含结构元件,例如内部或末端突起、错配或环。将反义化合物常规地制备为线性的,但可被连接或者另外制备成环状和/或分枝的。反义化合物可包括构建体,例如杂交以形成完全或部分双链化合物的两条链,或具有足够自我互补性以允许杂交并形成完全或部分双链化合物的单链。可将所述两条链内部连接而留下游离的3’或5’末端,或可将其连接形成连续的发夹结构或环。发夹结构可在5’或3’末端上包含突出端,产生单链特征的延伸。所述双链化合物任选可在末端上包含突出端。进一步的修饰可包括与末端之一、经挑选的核苷酸位置、糖位置或与核苷间键之一连接的缀合基团。或者,所述两条链可经由非核酸部分或连接基团来连接。当仅由一条链形成时,dsRNA可呈自我互补的发夹型分子形式,其在其自身上对折形成双链体。因此,所述dsRNA可为完全或部分双链的。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发夹来完成,然而,在一些实施方案中,基因表达或功能为增量调节的。当形成自两条链,或呈在其自身上对折形成双链体的自身互补发夹型分子形式的单链时,所述两条链(或单链的双链体形成区)为以沃森-克里克模式碱基配对的互补RNA链。
一旦引入系统,本发明的化合物可引起一种或多种酶或结构蛋白的作用以实现靶核酸的切割或其他修饰,或可经由基于占据的机制来运作。一般而言,核酸(包括寡核苷酸)可描述为“DNA样”(即,一般具有一个或多个2’脱氧糖和一般地T而不是U碱基)或“RNA样”(即,一般具有一个或多个2’羟基或2’修饰的糖和一般U而不是T碱基)。核酸螺旋可采取多于一种类型的结构,最普通地A和B型。据认为,一般而言,具有B型样结构的寡核苷酸为“DNA样”而具有A型样结构的寡核苷酸为“RNA样”。在一些(嵌合的)实施方案中,反义化合物可包含A和B型区两者。
在另一个实施方案中,所需的寡核苷酸或反义化合物,包括以下中的至少一种:反义RNA、反义DNA、嵌合反义寡核苷酸、包含经修饰的键的反义寡核苷酸、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也可激活基因表达,这是已被称为“小RNA诱导的基因激活”或RNAa的机制。靶定基因启动子的dsRNA诱导相关基因的有效转录激活。在人细胞中使用合成dsRNA(称为“小激活RNA”(saRNA)) 证实RNAa。
已发现小双链RNA(dsRNA)(例如小干扰RNA(siRNA)和微小 RNA(miRNA))是称为RNA干扰(RNAi)的进化保守机制的触发物。 RNAi总是导致基因沉默。然而,在下文实施例章节详述的例子中,显示寡核苷酸增加胶原基因多核苷酸和其编码产物的表达和/或功能。dsRNA也可充当小激活RNA(saRNA)。不希望受理论约束,通过靶定基因启动子中的序列,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”可用于筛选调节胶原基因多核苷酸表达的另外化合物。“调节剂”为以下化合物,其减少或增加编码胶原基因的核酸分子的表达并包含与靶区段互补的至少5个核苷酸的部分。筛选方法包括以下步骤:使编码胶原基因有义或天然反义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,以及选择一种或多种减少或增加编码胶原基因多核苷酸的核酸分子表达的候选调节剂(例如SEQ ID NO:10-29)。一旦显示一种或多种候选调节剂能够调节(例如减少或增加)编码胶原基因多核苷酸的核酸分子表达,则可将所述调节剂用于胶原基因多核苷酸功能的进一步调查研究,或用作依照本发明的研究、诊断或治疗剂。
靶定天然反义序列调节靶基因的功能。例如,胶原基因(例如检索号NM_000088、NM_000089、NM_000094)。在一个实施方案中,靶标为胶原基因的反义多核苷酸。在一个实施方案中,反义寡核苷酸靶定胶原基因多核苷酸(例如检索号NM_000088、NM_000089、 NM_000094)的有义和/或天然反义序列、其变体、等位基因、同种型、同源物、突变体、衍生物、片段和互补序列。优选所述寡核苷酸为反义分子且所述靶标包括反义和/或有义胶原基因多核苷酸的编码和非编码区。
本发明的靶区段也可与本发明的其各自互补的反义化合物结合,以形成稳定的双链(双链体)寡核苷酸。
本领域中已显示这类双链寡核苷酸部分经由反义机制来调节靶表达和调节翻译以及RNA加工。此外,所述双链部分可经受化学修饰。例如,已显示这类双链部分通过所述双链体的反义链与靶标的典型杂交来抑制该靶标,从而触发靶标的酶促降解。
在一个实施方案中,反义寡核苷酸靶定胶原基因多核苷酸(例如检索号NM_000088、NM_000089、NM_000094)、其变体、等位基因、同种型、同源物、突变体、衍生物、片段和互补序列。优选所述寡核苷酸为反义分子。
依照本发明的实施方案,靶核酸分子不单独限于胶原基因而是扩展到胶原基因分子的任何同种型、受体、同源物等等。
在另一个实施方案中,寡核苷酸靶定胶原基因多核苷酸的天然反义序列(例如,如SEQ ID NO:4-9所述的多核苷酸),以及其任何变体、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:10-29所述。
在一个实施方案中,所述寡核苷酸与胶原基因反义物的核酸序列互补或结合,并调节胶原基因分子的表达和/或功能,所述核酸序列包括但不限于与胶原基因多核苷酸有关的非编码有义和/或反义序列。
在另一个实施方案中,所述寡核苷酸与如SEQ ID NO:4-9所述的胶原基因天然反义物的核酸序列互补或结合,并调节胶原基因分子的表达和/或功能。
在一个实施方案中,寡核苷酸包含SEQ ID NO:10-29的至少5个连续核苷酸的序列且调节胶原基因分子的表达和/或功能。
多核苷酸靶标包括胶原基因,包括其家族成员、胶原基因的变体;胶原基因的突变体,包括SNP;胶原基因的非编码序列;胶原基因的等位基因;物种变体、片段等等。优选所述寡核苷酸为反义分子。
在另一个实施方案中,靶定胶原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,胶原基因多核苷酸(例如SEQ ID NO:4-9) 的靶定调节这些靶标的表达或功能。在一个实施方案中,表达或功能相比于对照为增量调节的。在另一个实施方案中,表达或功能相比于对照为减量调节的。
在另一个实施方案中,反义化合物包括如SEQ ID NO:10-29所述的序列。这些寡核苷酸可包含一个或多个经修饰的核苷酸、更短或更长的片段、经修饰的键等等。
在另一个实施方案中,SEQ ID NO:10-29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数个方式来进行。例如,反义寡核苷酸、siRNA等。酶促核酸分子(例如,核酶)为能够催化一种或多种不同反应(包括以核苷酸碱基序列特异的方式反复切割其他单独的核酸分子的能力)的核酸分子。这类酶促核酸分子可用于,例如,靶定几乎任何RNA转录物。
由于反式切割酶促核酸分子的序列特异性,其有望作为用于人类疾病的治疗剂。可将酶促核酸分子设计成在细胞RNA背景下切割特定的RNA靶标。这类切割事件致使mRNA无功能且终止从该RNA 的蛋白表达。以这种方式,可选择性地抑制与疾病状态有关的蛋白合成。
一般而言,带有RNA切割活性的酶促核酸通过首先与靶RNA结合来起作用。这类结合通过酶促核酸的靶结合部分来进行,该酶促核酸的靶结合部分保持紧密靠近进行切割靶RNA的分子的酶促部分。因此,所述酶促核酸首先识别而后通过互补的碱基配对与靶RNA结合,且一旦与正确的位点结合,即进行酶促地切割靶RNA。这类靶 RNA的策略性切割将破坏其指导合成编码蛋白的能力。在酶促核酸结合和切割其RNA靶标之后,其从该RNA中释放以寻找另一个靶标且可反复结合和切割新靶标。
已使用诸如体外选择(进化)策略等数种途径来进化能够催化各种反应的新核酸催化剂,所述反应为例如磷酸二酯键和酰胺键的切割和连接。
催化活性最佳的核酶的开发会显著地有助于以调节基因表达为目的而采用RNA切割核酶的任何策略。例如锤头状核酶在存在Mg2+ 辅因子的饱和(10mM)浓度下,以约1min-1的催化速率(kcat)起作用。已显示人造“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,据了解具有由DNA组成的底物结合臂的某些经修饰的锤头状核酶,以接近100min-1的倍数转换速率(multiple turn-over rate)催化RNA切割。最终,用某些核苷酸类似物置换在锤头的催化核心内的特定残基产生显示出在催化速率上多达10倍改进的修饰核酶。这些研究结果证实核酶可以以显著高于大多数天然自我切割核酶展示于体外的催化速率,促进化学转化。那么可能的是,可优化某些自我切割核酶的结构以产生最高的催化活性,或者可制备展示出显著更快的RNA磷酸二酯切割速率的全新RNA基序。
通过符合“锤头”模型的RNA催化剂来分子间切割RNA底物首先显示于1987年。将所述RNA催化剂回收并与多种RNA分子反应,证实其为真正催化性的。
基于“锤头”基序设计的催化性RNA已通过在催化性RNA中作出适当的碱基改变以维持与靶序列的必要碱基配对,来用于切割特定靶序列。这允许使用催化性RNA来切割特定靶序列,并指出根据“锤头”模型设计的催化性RNA可能在体内切割特定底物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强大工具。此方法要求使用表达质粒或病毒以及加工成siRNA的小发夹RNA的编码序列,将小干扰RNA(siRNA)作为RNA本身或作为DNA递送。此系统能够有效将前siRNA转运到它们在其中活跃的细胞质中,并允许使用经调节的和组织特异的启动子用于基因表达。
在一个实施方案中,寡核苷酸或反义化合物包括核糖核酸(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。此术语包括由天然存在核苷酸、糖和共价核苷间(骨架)键组成的寡核苷酸以及类似地起作用的具有非天然存在部分的寡核苷酸。由于所需性质,例如增强的细胞摄取、对靶核酸增强的亲和力以及在核酸酶存在时增大的稳定性,常常需要这类经修饰或取代的寡核苷酸超过天然形式。
根据本发明,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以及与靶核酸的至少一部分杂交且调节其功能的其他寡聚化合物。因此,它们可为DNA、RNA、 DNA样、RNA样、或其混合物,或可为这些中的一种或多种的模拟物。这些化合物可为单链、双链、环状或发夹寡聚化合物且可包含结构元件,例如内部或末端突起、错配或环。将反义化合物常规地制备成线性但可经连接或者另外地制备成环状和/或分枝的。反义化合物可包括构建体,例如杂交以形成完全或部分双链化合物的两条链,或带有足够自我互补性以允许杂交并形成完全或部分双链化合物的单链。可将所述两条链内部连接而留下游离的3’或5’末端或可将其连接形成连续的发夹结构或环。发夹结构可在5’或3’末端上包含突出端,产生单链特征的延伸。双链化合物任选可在末端上包含突出端。进一步的修饰可包括与末端之一、经挑选的核苷酸位置、糖位置或核苷间键之一连接的缀合基团。备选地,所述两条链可经由非核酸部分或连接基团来连接。当形成自仅一条链时,dsRNA可采取自我互补的发夹型分子形式,其在其自身上对折形成双链体。因此,所述dsRNA可为完全或部分双链的。基因表达的特异性调节可通过dsRNA发夹在转基因细胞系中的稳定表达来完成。当形成自两条链或采取在其自身上对折形成双链体的自身互补的发夹型分子形式的单链时,所述两条链(或单链的双链体形成区)为以沃森-克里克模式碱基配对的互补RNA链。
一旦引入系统,本发明的化合物可引起一种或多种酶或结构蛋白的作用以实现靶核酸的切割或其他修饰,或可经由基于占据的机制来运作。一般而言,核酸(包括寡核苷酸)可描述为“DNA样”(即,一般具有一个或多个2’脱氧糖和,一般地,T而不是U碱基)或“RNA样”(即,一般具有一个或多个2’羟基或2’修饰的糖和,一般U而不是T碱基)。核酸螺旋可采取多于一种类型的结构,最普通地A和B型。据认为,一般而言,具有B型样结构的寡核苷酸为“DNA样”而具有A型样结构的寡核苷酸为“RNA样”。在一些(嵌合的)实施方案中,反义化合物可包含A和B型区两者。
依照本发明的反义化合物可包含约5-约80个核苷酸(即约5-约80 个连接核苷)长度的反义部分。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5-约80个核苷酸,而本发明的双链反义化合物(例如,dsRNA)包含5-约80个核苷酸长度的有义和反义链或部分。本领域普通技术人员将认识到,这包括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个核苷酸长度、或其之内任何范围的反义部分。
在一个实施方案中,本发明的反义化合物具有10-50个核苷酸长度的反义部分。本领域普通技术人员将认识到,这包括具有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个核苷酸长度、或其之内任何范围的反义部分的寡核苷酸。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,本发明的反义或寡核苷酸化合物具有12或 13-30个核苷酸长度的反义部分。本领域普通技术人员将认识到,这包括具有12、13、14、15、16、17、18、19、20、21、22、23、24、 25、26、27、28、29或30个核苷酸长度、或其之内任何范围的反义部分的反义化合物。
在另一个实施方案中,本发明的寡聚化合物也包括其中不同的碱基存在于化合物中的一个或多个核苷酸位置上的变体。例如,如果第一个核苷酸为腺苷,那么可产生在此位置包含胸苷、鸟苷或胞苷的变体。这可在反义或dsRNA化合物的任何位置上进行。然后使用本文所述的方法来检测这些化合物以确定其抑制靶核酸表达的能力。
在一些实施方案中,反义化合物与靶标之间的同源性、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:4-29中所述的核酸分子)包含一个或多个取代或修饰。在一个实施方案中,将核苷酸用锁定核酸(LNA)取代。
在另一个实施方案中,寡核苷酸靶定与胶原基因有关的编码和/ 或非编码序列以及如SEQ ID NO:1-9所述的序列有义和/或反义的核酸分子的一个或多个区。也将寡核苷酸靶定到SEQ ID NO:1-9的重叠区。
本发明的某些寡核苷酸为嵌合寡核苷酸。“嵌合寡核苷酸”或“嵌合体”,在本发明的文段中,为包含两个或更多个化学上不同区的寡核苷酸,每个区由至少一个核苷酸组成。这些寡核苷酸典型地包含赋予一种或多种有益特性(例如,对核酸酶的抗性增强、摄入细胞增强、对靶标增强的结合亲和力)的修饰核苷酸的至少一个区,以及作为能够切割 RNA:DNA或RNA:RNA杂合体的酶底物的区。作为实例,核糖核酸酶H为细胞核酸内切酶,其切割RNA:DNA双链体的RNA链。核糖核酸酶H的活化因此导致RNA靶标的切割,从而大大地增强基因表达的反义调节效率。因此,当使用嵌合寡核苷酸时,与杂交到相同靶区的硫代磷酸酯脱氧寡核苷酸相比,常常可用较短的寡核苷酸获得相当的结果。RNA靶标的切割可通过凝胶电泳和必要时本领域已知的相关核酸杂交技术,常规地检测。在一个实施方案中,嵌合寡核苷酸包含修饰成增加靶结合亲和力的至少一个区,并且通常包含充当核糖核酸酶H的底物的区。寡核苷酸对其靶标(在此情况下,编码ras的核酸) 的亲和力通过测定寡核苷酸/靶标对的Tm来常规地确定,Tm为寡核苷酸与靶标解离的温度;解离以分光光度法检测。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作为如上所述的两种或更多种寡核苷酸、修饰寡核苷酸、寡聚核苷和/或寡核苷酸模拟物的复合结构而形成。本领域亦已将这类化合物称为杂合体或gapmer。教导制备这类杂合结构的代表性美国专利包括但不限于,美国专利第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及5,700,922号,每个通过引用结合于本文中。
在另一个实施方案中,经修饰的寡核苷酸区包含在糖的2’位置上修饰的至少一个核苷酸,最优选2’-O烷基、2’-O-烷基-O-烷基或2’- 氟修饰的核苷酸。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。将这类修饰常规地掺入到寡核苷酸中,已显示这些寡核苷酸具有比2’-脱氧寡核苷酸对给定靶标更高的Tm(即,更高的靶结合亲和力)。这种增加的亲和力的作用大大地增强基因表达的RNAi寡核苷酸抑制。核糖核酸酶H为切割RNA:DNA双链体的RNA链的细胞核酸内切酶;此酶的活化因此导致RNA靶标的切割,且因此可大大地增强RNAi抑制效率。RNA靶标的切割可通过凝胶电泳来常规地证实。在另一个实施方案中,也修饰嵌合寡核苷酸以增强核酸酶抗性。细胞包含可降解核酸的各种核酸外切酶和核酸内切酶。已显示许多核苷酸和核苷修饰使掺入有它们的寡核苷酸比天然寡脱氧核苷酸对核酸酶消化更有抗性。核酸酶抗性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并测定随时间推移剩余的完好寡核苷酸的程度(通常地通过凝胶电泳)来常规地测定。已修饰成增强其核酸酶抗性的寡核苷酸比未修饰寡核苷酸保持完好持续更长时间。已证实多种寡核苷酸修饰增强或赋予核酸酶抗性。包含至少一个硫代磷酸酯修饰的寡核苷酸为目前更优选的。在一些情况下,增强靶结合亲和力的寡核苷酸修饰也能够独立地增强核酸酶抗性。一些所需的修饰可在DeMesmaeker 等,(1995)Acc.Chem.Res.,28:366-374中找到。
预想用于本发明的一些寡核苷酸的具体实例包括包含经修饰的骨架的那些,所述经修饰的骨架为例如硫代磷酸酯、磷酸三酯、甲基膦酸酯、短链烷基或环烷基糖间键或者短链杂原子或杂环的糖间键。最多的为带有硫代磷酸酯骨架和带有杂原子骨架的寡核苷酸,杂原子骨架特别地为CH2--NH--O--CH2、CH,--N(CH3)--O--CH2[称为亚甲基 (甲亚氨基)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。由De Mesmaeker等,(1995)Acc.Chem.Res.28:366-374公开的酰胺骨架也为优选的。具有吗啉代骨架结构的寡核苷酸(Summerton和Weller,美国专利第5,034,506号)亦是如此。在其他实施方案中,将寡核苷酸的例如肽核酸(PNA)骨架、磷酸二酯骨架替换为聚酰胺骨架,核苷酸直接或间接地与聚酰胺骨架的氮杂氮原子结合。寡核苷酸也可包含一个或多个取代的糖部分。寡核苷酸在2’位置上包含下列中的一种: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低级烷基、烷氧基烷氧基、取代的低级烷基、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;取代的甲硅烷基;RNA切割基团;报道基团;嵌入剂;改进寡核苷酸药代动力学特性的基团;或改进寡核苷酸药效学特性的基团以及具有类似特性的其他取代基。修饰包括2’-甲氧乙氧基[2′-O-CH2CH2OCH3,也称为 2′-O-(2-甲氧乙基)]。其他修饰包括2’-甲氧基(2′-O--CH3)、2’-丙氧基 (2′-OCH2CH2CH3)和2’-氟(2′-F)。类似的修饰也可在寡核苷酸的其他位置上进行,具体地在3’末端核苷酸上糖的3’位置和5’末端核苷酸的 5’位置。寡核苷酸也可具有糖模拟物例如取代戊呋喃糖基基团的环丁基。
寡核苷酸也可另外或备选地包含核碱基(本领域常常简称为“碱基”)修饰或取代。本文所用的“未修饰的”或“天然的”核苷酸包括腺嘌呤(A)、鸟嘌呤(G)、胸腺嘧啶(T)、胞嘧啶(C)和尿嘧啶(U)。修饰核苷酸包括在天然核酸中仅稀少或短暂地存在的核苷酸,例如,次黄嘌呤、 6-甲基腺嘌呤、5-Me嘧啶、特别地5-甲基胞嘧啶(也称为5-甲基-2’脱氧胞嘧啶且常常在本领域中称为5-Me-C)、5-羟甲基胞嘧啶(HMC)、糖基HMC和龙胆二糖基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-(氨烷基氨基)腺嘌呤或其他杂取代的烷基腺嘌呤、2-硫尿嘧啶、2-硫胸腺嘧啶、5-溴尿嘧啶、5-羟基甲基尿嘧啶、8-氮杂鸟嘌呤、7-脱氮杂鸟嘌呤、N6(6-氨基己基)腺嘌呤和2,6-二氨基嘌呤。可包括本领域已知的“通用的”碱基,例如,肌苷。已显示5-Me-C取代增强核酸双链体的稳定性达0.6-1.2℃ (Sanghvi,Y.S.,载于Crooke,S.T.和Lebleu,B.,编辑,反义研究和应用(Antisense Research and Applications),CRC Press,Boca Raton,1993, 276-278页)且为目前的碱基取代。
本发明的寡核苷酸的另一种修饰涉及以化学方法使一种或多种增强寡核苷酸的活性或细胞摄取的部分或缀合物与寡核苷酸连接。这类部分包括但不限于脂质部分,例如胆固醇部分、胆甾醇基部分、硫醚例如己基-S-三苯甲基硫醇、巯基胆固醇、脂族链例如十二烷二醇或十一烷基残基、磷脂例如二-十六烷基-消旋-甘油或1,2-二-O-十六烷基 -消旋-甘油-3-H-膦酸三乙铵、聚胺或聚乙二醇链、或金刚烷乙酸。包含亲脂性部分的寡核苷酸以及用于制备这类寡核苷酸的方法为本领域已知的,例如美国专利第5,138,045、5,218,105和5,459,255号。
无需将给定寡核苷酸中的所有位置一致地修饰,且实际上多于一种上述修饰可掺入到单个寡核苷酸中或甚至在寡核苷酸内的单个核苷内部。本发明也包括作为如上文中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另一个部分缀合,所述部分包括但不限于脱碱基核苷酸、聚醚、聚胺、聚酰胺、肽、碳水化合物、脂质或聚碳氢化合物。本领域技术人员将认识到,可将这些分子在糖、碱基或磷酸基的数个位置上连接到一个或多个构成核酸分子的任何核苷酸。
依照本发明使用的寡核苷酸可通过众所周知的固相合成技术来便利和常规地制备。用于这类合成的设备由包括Applied Biosystems 在内的数个供应商销售。也可使用用于这类合成的任何其他方法;寡核苷酸的实际合成完全在本领域普通技术人员的才能之内。亦众所周知的是使用类似技术来制备其他寡核苷酸,例如硫代磷酸酯和烷基化衍生物。还众所周知的是使用类似技术和市购经修饰的amidites和可控孔度玻璃(CPG)产品,例如生物素、荧光黄、吖啶、或补骨脂素修饰的amidites和/或CPG(可从Glen Research,Sterling VA购买),以合成荧光标记的、生物素化的或其他修饰的寡核苷酸,例如胆固醇修饰的寡核苷酸。
依照本发明,使用修饰(例如使用LNA单体)以增加寡核苷酸的效价、特异性和作用持续时间并拓宽其施用途径,所述寡核苷酸由诸如 MOE、ANA、FANA、PS等当前的化学物质组成。这可通过用LNA 单体取代当前寡核苷酸中的一些单体来完成。LNA修饰的寡核苷酸可具有类似于母体化合物的大小或可更大或优选更小。这类LNA修饰寡核苷酸包含少于约70%、更优选少于约60%、最优选少于约50%的 LNA单体且其大小在约5-25个核苷酸之间,更优选在约12-20个核苷酸之间。
修饰的寡核苷酸骨架包括但不限于硫代磷酸酯、手性硫代磷酸酯、二硫代磷酸酯、磷酸三酯、氨烷基磷酸三酯、甲基和其他烷基膦酸酯包括3’烯基膦酸酯和手性膦酸酯、次磷酸酯、氨基磷酸酯包括3’- 氨基氨基磷酸酯和氨烷基氨基磷酸酯、硫羰基氨基磷酸酯、硫羰基烷基膦酸酯、硫羰基烷基磷酸三酯,以及具有正常3’-5’键合的硼烷磷酸酯(boranophosphates)、这些的2’-5’连接类似物,以及具有反极性的那些,其中核苷单元的相邻对为3’-5’与5’-3’或2’-5’与5’-2’连接的。也包括各种盐、混合盐和游离酸形式。
教导制备上述含磷键的代表性的美国专利包括但不限于,美国专利第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号,每个通过引用结合于本文中。
修饰的寡核苷酸骨架(其中不包含磷原子),具有由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、或一种或多种短链杂原子或杂环核苷间键形成的骨架。这些包括具有吗啉代键的骨架(部分由核苷的糖部分形成);硅氧烷骨架;硫化物、亚砜和砜骨架;甲乙酰基(formacetyl)和硫代甲乙酰基(thioformacetyl)骨架;亚甲基甲乙酰基和硫代甲乙酰基骨架;含烯骨架;氨基磺酸酯骨架;亚甲基亚氨基和亚甲基肼基骨架;磺酸酯和氨磺酰骨架;酰胺骨架;以及具有混合N、O、S和CH2组分部分的其他骨架。
教导制备上述寡聚核苷的代表性的美国专利包括但不限于,美国专利第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号,每个通过引用结合于本文中。
在其他寡核苷酸模拟物中,将核苷酸单元的糖和核苷间键(即骨架),均用新基团置换。维持碱基单元用于与适当的核酸靶化合物杂交。一种这类寡聚化合物,即已显示具有优秀的杂交特性的寡核苷酸模拟物,称为肽核酸(PNA)。在PNA化合物中,寡核苷酸的糖骨架替换为含酰胺的骨架,具体地氨乙基氨基乙酸骨架。将核碱基保留并直接或间接地与骨架的酰胺部分的氮杂氮原子结合。教导制备PNA化合物的代表性的美国专利包括但不限于,美国专利第5,539,082、5,714,331 和5,719,262号,每个通过引用结合于本文中。PNA化合物的进一步教导可在Nielsen等,(1991)Science 254,1497-1500中找到。
在本发明的另一个实施方案中,带有硫代磷酸酯骨架的寡核苷酸和带有杂原子骨架的寡聚核苷,杂原子骨架具体地为 -CH2-NH-O-CH2-、-CH2-N(CH3)-O-CH2-(称为亚甲基(甲亚氨基)或 MMI骨架)、-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第5,489,677号的-O-P-O-CH2-,以及上文引用的美国专利第 5,602,240号的酰胺骨架。具有上文引用的美国专利第5,034,506号的吗啉代骨架结构的寡核苷酸亦是如此。
修饰寡核苷酸也可包含一个或多个经取代的糖部分。寡核苷酸在 2’位置上包含下列中的一种:OH;F;O-、S-或N-烷基;O-、S-或 N-烯基;O-、S-或N-炔基;或O烷基-O-烷基,其中所述烷基、烯基和炔基可为取代或未取代的C到CO烷基或C2到CO烯基和炔基。特别是O(CH2)nOmCH3、O(CH2)n,OCH3、O(CH2)nNH2、 O(CH2)nCH3、O(CH2)nONH2及O(CH2nON(CH2)nCH3)2,其中n和m可为1-约10。其他的寡核苷酸在2’位置上包含下列中的一种:C到 CO、低级烷基、取代的低级烷基、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、氨烷基氨基、聚烷基氨基、取代的甲硅烷基、RNA切割基团、报道基团、嵌入剂、用于改进寡核苷酸药代动力学特性的基团、或用于改进寡核苷酸药效学特性的基团,以及具有类似特性的其他取代基。修饰包括2’- 甲氧乙氧基(2′-O-CH2CH2OCH3,也称为2’-O-(2-甲氧乙基)或 2′-MOE),即,烷氧基烷氧基基团。另外的修饰包括2’-二甲基氨基氧基乙氧基,即O(CH2)2ON(CH3)2基团,也称为2′-DMAOE(如下文实施例中所述),以及2’-二甲基氨基乙氧基乙氧基(本领域也称为2’-O- 二甲基氨基乙氧基乙基或2′-DMAEOE),即 2′-O-CH2-O-CH2-N(CH2)2。
其他修饰包括2’-甲氧基(2′-OCH3)、2’-氨基丙氧基 (2′-OCH2CH2CH2NH2)和2’-氟(2′-F)。类似的修饰也可在寡核苷酸的其他位置上进行,具体地在3’末端核苷酸上或2’-5’连接的寡核苷酸中糖的3’位置以及5’末端核苷酸的5’位置。寡核苷酸也可具有糖模拟物例如取代戊呋喃糖基糖的环丁基部分。教导制备这类经修饰的糖结构的代表性的美国专利包括但不限于,美国专利第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号,每个通过引用结合于本文中。
寡核苷酸也可包含核碱基(本领域常常简称为“碱基”)修饰或取代。本文所用的“未修饰的”或“天然的”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)。修饰核苷酸包括其他合成和天然核苷酸,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-甲基和其他烷基衍生物、腺嘌呤和鸟嘌呤的2-丙基和其他烷基衍生物、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-偶氮尿嘧啶、胞嘧啶和胸腺嘧啶、5-尿嘧啶(假尿嘧啶)、4-硫尿嘧啶、8-卤代、8-氨基、8-巯基、8- 硫烷基、8-羟基和其他8-取代的腺嘌呤和鸟嘌呤、5-卤代具体地5-溴、 5-三氟甲基和其他5-取代的尿嘧啶和胞嘧啶、7-甲基鸟嘌呤 (methylquanine)和7-甲基腺嘌呤、8-氮杂鸟嘌呤和8-氮杂腺嘌呤、7- 脱氮杂鸟嘌呤和7-脱氮杂腺嘌呤以及3-脱氮杂鸟嘌呤和3-脱氮杂腺嘌呤。
此外,核苷酸包括公开于以下文献中的核苷酸:美国专利第 3,687,808号、“高分子科学和工程的简明百科全书(The Concise Encyclopedia of Polymer Science AndEngineering)”,858-859页, Kroschwitz,J.I.,编辑,John Wiley&Sons,1990、Englisch等,′Angewandle Chemie,International Edition′,1991,30,613页及Sanghvi, Y.S.,第15章,“反义研究和应用(Antisense Research and Applications)”, 289-302页,Crooke,S.T.和Lebleu,B.ea.,CRC Press,1993。这些核苷酸中的某些对于增加本发明的寡聚化合物的结合亲和力特别地有用。这些包括5-取代嘧啶、6-氮杂嘧啶和N-2、N-6和0-6取代的嘌呤,包括2-氨丙基腺嘌呤、5-丙炔基尿嘧啶和5-丙炔基胞嘧啶。已显示5-甲基胞嘧啶取代增加核酸双链体的稳定性达0.6-1.2℃(Sanghvi,Y.S., Crooke,S.T.和Lebleu,B.,编辑,“反义研究和应用”,CRC Press,Boca Raton,1993,276-278页)且为目前的碱基取代,更特别地当与2’-O甲氧基乙基糖修饰组合时。
教导制备上述修饰核苷酸以及其他修饰核苷酸的代表性的美国专利包括但不限于,美国专利第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号,每个通过引用结合于本文中。
本发明的寡核苷酸的另一种修饰涉及使所述寡核苷酸与一种或多种部分或缀合物化学连接,该部分或缀合物增强所述寡核苷酸的活性、细胞分布或细胞摄取。
这类部分包括但不限于,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)、硫代胆固醇、脂族链(例如,十二烷二醇或十一烷基残基)、磷脂(例如,二-十六烷基-消旋-甘油或1,2-二-O- 十六烷基-消旋-甘油-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、或十八胺或己基氨基-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的美国专利包括但不限于,美国专利第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 号,每个通过引用结合于本文中。
药物开发:本发明的化合物也可应用于药物开发和靶标验证的领域。本发明包括本文所鉴定的化合物和靶区段在阐明存在于胶原基因多核苷酸和疾病状态、表型或病况之间的关系的药物开发努力中的应用。这些方法包括检测或调节胶原基因多核苷酸,包括使本发明的化合物与样品、组织、细胞或生物体接触;在处理后的某个时间测定胶原基因多核苷酸的核酸或蛋白水平和/或相关的表型或化学终末点,以及任选将该测定值与未处理样品或与用本发明的另一种化合物处理的样品比较。这些方法也可与其他试验平行或组合进行以确定未知基因的功能用于靶标验证过程,或确定特定基因产物作为用于治疗或预防特定疾病、病况或表型的靶标的有效性。
评价基因表达的增量调节或抑制:
外源核酸到宿主细胞或生物体中的转移可通过直接检测细胞或生物体中核酸的存在情况来评价。这类检测可通过本领域众所周知的数种方法来完成。例如,外源核酸的存在情况可通过DNA印迹或通过聚合酶链式反应(PCR)技术使用以下引物来检测,该引物特异地扩增与所述核酸相关的核苷酸序列。外源核酸的表达也可使用包括基因表达分析在内的常规方法来测定。例如,由外源核酸产生的mRNA可使用RNA印迹和反转录PCR(RT-PCR)来检测和定量。
来自外源核酸的RNA表达也可通过测定酶活性或报道蛋白活性来检测。例如,反义调节活性可根据靶核酸表达的减少或增加间接地测定,靶核酸表达的减少或增加作为外源核酸正在产生效应物RNA 的指示。基于序列保守性,可设计和使用引物来扩增靶基因的编码区。最初,可使用来自每个基因的最高表达的编码区来建立模型对照基因,但任何编码或非编码区均可使用。每个对照基因通过将每个编码区插入报道基因编码区和其聚腺苷酸信号之间来装配。这些质粒可产生在基因的上游部分具有报道基因以及在3’非编码区中具有潜在 RNAi靶标的mRNA。各个反义寡核苷酸的有效性可通过调节报道基因来测定。可用于本发明的方法中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葡糖醛酸酶(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)、胭脂碱合酶(NOS)、章鱼碱合酶(OCS)以及其衍生物。多重选择标记为可利用的,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、草丁膦(phosphinothricin)、嘌呤霉素和四环素的抗性。确定报道基因调节的方法为本领域众所周知的,包括但不限于,荧光法(例如荧光光谱法、荧光激活细胞分选术(FACS)、荧光显微法)、抗生素抗性测定。
COL1A1、COL1A2、COL7A1蛋白和mRNA表达可使用本领域技术人员已知和本文别处所描述的方法测定。例如,免疫测定法(例如 ELISA)可用来测定蛋白水平。用于ELISA的胶原基因抗体可市购,例如,从R&D Systems(Minneapolis,MN),Abcam,Cambridge,MA。
在实施方案中,使用本发明反义寡核苷酸处理的样品(例如,体内或体外细胞或组织)中的COL1A1、COL1A2、COL7A1表达(例如, mRNA或蛋白)通过与对照样品中的胶原基因表达相比较来评价。例如,蛋白或核酸表达可使用本领域技术人员已知的方法,与模拟处理或未处理样品中的蛋白或核酸表达相比较。或者,与用对照反义寡核苷酸(例如,具有已改变或不同序列的反义寡核苷酸)处理的样品的比较可根据所需信息来进行。在另一个实施方案中,可将已处理样品对比未处理样品在胶原基因蛋白或核酸表达方面的差异,与已处理样品对比未处理样品在不同核酸(包括研究者认为适当的任何标准,例如,持家基因)表达方面的差异相比较。
可将观察到的差异根据需要例如以比例或分数的形式表达,用于与对照比较。在实施方案中,胶原基因mRNA或蛋白水平,在用本发明反义寡核苷酸处理的样品中,相对于未处理样品或用对照核酸处理的样品增加至约1.25倍-约10倍或更多或者减少至约1/1.25-约1/10 或更少。在实施方案中,胶原基因mRNA或蛋白水平增加或减少至至少约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、诊断和治疗
本发明的化合物可用于诊断、治疗和预防,并作为研究试剂和试剂盒的组分。此外,能够灵敏特异地抑制基因表达的反义寡核苷酸,常常被普通技术人员用于阐明特定基因的功能或区分生物途径的各个成员的功能。
对于用于试剂盒和诊断和各种生物系统,本发明的化合物(单独的或与其他化合物或治疗剂组合)可用作在差异和/或组合分析中的工具,以阐明在细胞和组织内表达的基因的一部分或全部互补序列的表达模式。
本文所用的术语“生物系统”或“系统”定义为表达或使得能够表达胶原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、移植物及其组合。
作为一个非限制性实例,将在用一种或多种反义化合物处理的细胞或组织内的表达模式与未用反义化合物处理的对照细胞或组织相比较,并针对基因表达的差异水平分析产生的模式,因为它们有关于,例如,所检测基因的疾病相关、信号传导途径、细胞定位、表达水平、大小、结构或功能。这些分析可对受刺激或未受刺激的细胞以及在影响表达模式的其他化合物存在或不存在时进行。
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(基因表达的系列分析)(Madden等,(2000)Drug Discov.Today,5,415-425)、READS(已消化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)、已表达序列标志 (EST)测序(Celis等,FEBS Lett.,2000,480,2-16;Larsson等,J. Biotechnol.,2000,80,143-57)、消减RNA指纹法(subtractive RNAfingerprinting,SuRF)(Fuchs等,(2000)Anal.Biochem.286,91-98;Larson等,(2000)Cytometry 41,203-208)、消减克隆(subtractive cloning)、差异显示(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)和质谱分析法(To,Comb. (2000)Chem.HighThroughput Screen,3,235-41)。
本发明的化合物对于研究和诊断而言为有用的,因为这些化合物与编码胶原基因的核酸杂交。例如,作为有效的胶原基因调节剂以本文公开的这类效率和这类条件下杂交的寡核苷酸,在有利于基因扩增或检测的条件下分别为有效的引物或探针。这些引物和探针可用于需要对编码胶原基因的核酸分子特异检测的方法中,和可用于扩增所述核酸分子,以用于检测或用于进一步研究胶原基因。本发明的反义寡核苷酸(具体地,引物和探针)与编码胶原基因的核酸的杂交,可通过本领域已知的方法来检测。这类方法可包括使酶与所述寡核苷酸缀合、放射性标记所述寡核苷酸或任何其他适当的检测方法。也可制备使用这类检测方法来检测样品中胶原基因水平的试剂盒。
反义物的特异性和灵敏性也由本领域技术人员掌握用于治疗用途。已将反义化合物在动物(包括人)的疾病状态的治疗中用作治疗部分。反义寡核苷酸药物已安全和有效地施用给人且许多临床试验目前正在进行。因此确立的是,反义化合物可为有用的治疗形式,可将其经配置以在用于治疗细胞、组织和动物、尤其是人的治疗方案中有用。
对于治疗而言,将怀疑具有可通过调节胶原基因多核苷酸的表达来治疗的疾病或病症的动物(优选人),通过施用依照本发明的反义化合物来治疗。例如,在一个非限制性实施方案中,所述方法包括给需要治疗的动物施用治疗上有效量的胶原基因调节剂的步骤。本发明的胶原基因调节剂有效地调节胶原基因的活性或调节胶原基因蛋白的表达。在一个实施方案中,动物中胶原基因的活性或表达与对照相比抑制了约10%。优选地,将动物中胶原基因的活性或表达抑制约30%。更优选地,将动物中胶原基因的活性或表达抑制50%或更多。因此,与对照相比,寡聚化合物将胶原基因mRNA的表达调节至少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,与对照相比,在动物中胶原基因的活性或表达增加约10%。优选地,在动物中胶原基因的活性或表达增加约30%。更优选地,在动物中胶原基因的活性或表达增加50%或更多。因此,与对照比较,寡聚化合物使胶原基因mRNA的表达调节至少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,胶原基因表达的下降可在动物的血清、血液、脂肪组织、肝脏或任何其他体液、组织或器官中测定。优选地,包含于待分析的所述液体、组织或器官之内的细胞包含编码胶原基因肽的核酸分子和 /或胶原基因蛋白本身。
本发明的化合物可通过向合适的药学上可接受的稀释剂或载体中添加有效量的化合物来用于药物组合物。本发明的化合物和方法的应用也可为预防上有用的。
缀合物:本发明的寡核苷酸的另一种修饰涉及以化学方法将一种或多种增强寡核苷酸的活性、细胞分布或细胞摄取的部分或缀合物与寡核苷酸连接。这些部分或缀合物可包含与官能团(例如伯羟基或仲羟基)共价结合的缀合基团。本发明的缀合基团包括嵌入剂、报道分子、聚胺、聚酰胺、聚乙二醇、聚醚、增强寡聚体药效学特性的基团,以及增强寡聚体药代动力学特性的基团。典型的缀合基团包括胆固醇、脂质、磷脂、生物素、吩嗪、叶酸、菲啶、蒽醌、吖啶、荧光黄、罗丹明、香豆素和染料。增强药效学特性的基团,在本发明的文段中,包括改善摄取、增强对降解的抗性和/或加强与靶核酸的序列特异性杂交的基团。增强药代动力学特性的基团,在本发明的文段中,包括改善本发明的化合物的摄取、分布、代谢或分泌的基团。代表性的缀合基团在提交于1992年10月23日的国际专利申请号PCT/US92/09196 和美国专利第6,287,860号中公开,所述文献通过引用结合于本文中。缀合部分包括但不限于,脂质部分(例如胆固醇部分)、胆酸、硫醚(例如,己基-5-三苯甲基硫醇)、硫代胆固醇、脂族链(例如,十二烷二醇或十一烷基残基)、磷脂(例如,二-十六烷基-消旋-甘油或1,2-二-O-十六烷基-消旋-甘油-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、或十八胺或己基氨基-羰基-羟胆固醇部分。也可将本发明的寡核苷酸与活性药物物质缀合,例如,阿司匹林、华法林、保泰松、布洛芬、舒洛芬、芬布芬、酮洛芬、(S)-(+)普拉洛芬、卡洛芬、丹酰肌氨酸、2,3,5-三碘苯甲酸、氟芬那酸、亚叶酸、苯并噻二嗪、氯噻嗪、二氮杂吲哚美辛(indomethicin)、巴比妥酸盐、头孢菌素、磺胺类药物、抗糖尿病药、抗菌剂或抗生素。
教导制备这类寡核苷酸缀合物的代表性的美国专利包括但不限于,美国专利第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 号。
制剂:本发明的化合物也可与其他分子、分子结构或化合物的混合物混合、封装、缀合或以其他方式缔合,作为例如,脂质体、受体靶向分子、口服的、直肠的、局部的或其他制剂,用于有助于摄取、分布和/或吸收。教导制备这类摄取、分布和/或吸收辅助制剂的代表性的美国专利包括但不限于,美国专利第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号,每个通过引用结合于本文中。
尽管,反义寡核苷酸不需要在载体的情况中施用以便调节靶表达和/或功能,但是本发明的实施方案涉及用于反义寡核苷酸表达的表达载体构建体,包括启动子、杂合启动子基因序列并且拥有强组成型启动子活性,或可在所需情况下诱导的启动子活性。
在一个实施方案中,本发明实施涉及用适合的核酸递送系统施用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可操作连接的非病毒载体。这类非病毒载体的实例包括单独的寡核苷酸(例如,SEQ ID NO:10-29中的任一个或多个)或与适合的蛋白、多糖或脂质制剂组合的寡核苷酸。
其他适合的核酸递送系统包括病毒载体,典型地来自腺病毒、腺病毒伴随病毒(AAV)、依赖辅助病毒的腺病毒、逆转录病毒或仙台病毒-脂质体(HVJ)复合体中的至少一种的序列。优选地,所述病毒载体包含与多核苷酸可操作连接的强真核启动子,例如,巨细胞病毒(CMV) 启动子。
另外的载体包括病毒载体、融合蛋白和化学缀合物。逆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的病毒载体包括至少两种载体,其中gag基因和pol基因来自HIV基因组而env基因来自另一种病毒。DNA病毒载体为优选的。这些载体包括痘病毒载体(例如正痘病毒或禽痘病毒载体)、疱疹病毒载体(例如单纯疱疹I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、或这类酯的盐、或任何其他化合物,其在施用给动物包括人后,能够提供(直接地或间接地)生物学活性的代谢物或其残留物。
术语“药学上可接受的盐”是指本发明化合物的生理上和药学上可接受的盐:即,保留母体化合物的所需生物活性且不对其赋予非所需的毒理学作用的盐。对于寡核苷酸而言,药学上可接受的盐的实例和其使用进一步描述于美国专利第6,287,860号中,其通过引用结合于本文中。
本发明也包括包含本发明的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以若干方式来施用,这取决于是否需要局部或全身治疗以及待治疗的区域。施用可为局部的(包括眼的和至黏膜包括阴道和直肠递送)、肺的(例如,通过吸入或吹入散剂或气雾剂,包括通过喷雾器)、气管内的、鼻内的、表皮的和经皮的、口服的或胃肠外的。胃肠外施用包括静脉内、动脉内、皮下、腹膜内或肌肉注射或输注;或颅内例如鞘内或心室内施用。
对于治疗中枢神经系统中的组织而言,可通过例如注射或输注进入脑脊液进行施用。施用反义RNA进入脑脊液已在例如美国专利申请公开第2007/0117772号,“Methods forslowing familial ALS disease progression(减缓家族性ALS疾病进展的方法)”中描述,该申请通过引用以其整体结合于本文中。
如果意图将本发明的反义寡核苷酸施用给中枢神经系统中的细胞,可与一种或多种能够促进主题反义寡核苷酸渗透穿过血脑屏障的物质一起施用。注射可在例如内嗅皮质或海马中进行。通过施用腺病毒载体递送神经营养因子至肌肉组织中的运动神经元描述于,例如,美国专利第6,632,427号,“Adenoviral-vector-mediated gene transfer intomedullary motor neurons(腺病毒载体介导基因转移进入髓质运动神经元)”,其通过引用结合于本文中。直接递送载体至脑(例如,纹状体、丘脑、海马或黑质)为本领域已知且描述于例如美国专利第6,756,523 号,“Adenovirus vectors for the transfer of foreigngenes into cells of the central nervous system particularly in brain(用于转移外源基因进入中枢神经系统细胞(具体地脑中)的腺病毒载体)”,其通过引用结合于本文中。施用可快速,如通过注射,或在一段时间内进行,如通过缓慢输注或施用缓释制剂。
主题反义寡核苷酸也可与提供所需药学或药效学特性的物质连接或缀合。例如,反义寡核苷酸可与本领域已知的促进渗透或转运穿过血脑屏障的任何物质(例如转铁蛋白受体的抗体)偶联,并通过静脉注射施用。反义化合物可与例如使反义化合物更有效和/或增加反义化合物转运穿过血脑屏障的病毒载体连接。渗透性血脑屏障破坏也可通过例如输注糖或氨基酸来完成,所述糖包括但不限于,内消旋赤藓醇、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(+)蜜三糖、L(+)鼠李糖、D(+)蜜二糖、D(-)核糖、侧金盏糖醇、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。用于增强血脑屏障渗透的方法和材料描述于,例如,美国专利第4,866,042号,“Method for the delivery of genetic material across the bloodbrain barrier(用于递送遗传物质穿过血脑屏障的方法)”,第6,294,520号,“Materialfor passage through the blood-brain barrier(用于通过血脑屏障的材料)”,和第6,936,589号,“Parenteral delivery systems(胃肠外递送系统)”,全部通过引用以其整体结合于本文中。
主题反义化合物可与其他分子、分子结构或化合物的混合物混合、封装、缀合或以其他方式缔合,作为例如脂质体、受体靶向分子、口服的、直肠的、局部的或其他制剂,用于有助于摄取、分布和/或吸收。例如,阳离子脂质可包含在制剂中以促进寡核苷酸摄取。一种显示出促进摄取的这类组合物为LIPOFECTIN(可从GIBCO-BRL, Bethesda,MD获得)。
认为带有至少一个2’-O-甲氧基乙基修饰的寡核苷酸对于口服施用而言为特别有用的。用于局部施用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。常规药物载体、水性、粉末或油性基质、增稠剂等可为必要的或所需的。包被的避孕套、手套等也可为有用的。
可适宜地以单位剂型存在的本发明药物制剂,可根据药学工业中众所周知的常规技术来制备。这类技术包括使活性成分与药物载体或赋形剂组合的步骤。一般而言,制剂如下制备:通过使活性成分与液体载体或细碎的固体载体或两者均匀和紧密地组合,随后在需要时使产物成形。
可将本发明的组合物制成任何许多可能剂型,例如但不限于,片剂、胶囊剂、凝胶胶囊、液体糖浆、软凝胶、栓剂和灌肠剂。也可将本发明的组合物在水性、非水性或混合介质中制成混悬剂。水性混悬剂可进一步包含增加混悬剂粘度的物质,包括例如羧甲基纤维素钠、山梨醇和/或葡聚糖。所述混悬剂也可包含稳定剂。
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、赋形剂或其他活性或非活性成分。
乳剂典型地为一种液体以通常直径超过0.1μm的液滴形式分散在另一种液体中的非均质体系。乳剂可包含除分散相之外的其他组分,以及可作为在水相、油相中的溶液或其本身作为单独相存在的活性药物。将微乳剂包括为本发明的一个实施方案。乳剂及其使用为本领域众所周知的且进一步描述于美国专利第6,287,860号中。
本发明的制剂包括脂质体制剂。本发明所用的术语“脂质体”意为由排列在一个或多个球形双层中的两亲脂质组成的囊泡。脂质体为具有由亲脂材料形成的膜和包含待递送组合物的水性内部的单层或多层囊泡。阳离子脂质体为带正电的脂质体,认为其与带负电的DNA 分子相互作用以形成稳定的复合体。认为pH敏感的或带负电的脂质体诱捕DNA而不是与其复合。阳离子和非阳离子脂质体均已用来递送DNA到细胞。
脂质体也包括“空间上稳定的”脂质体,该术语如本文所用是指包含一种或多种特化脂质的脂质体。当掺入到脂质体中时,这些特化脂质给脂质体带来相对于缺乏这类特化脂质的脂质体增长的循环生命期。空间上稳定的脂质体的实例为以下脂质体,其中脂质体形成囊泡的脂质部分的部分包含一种或多种糖脂或衍生有一种或多种亲水聚合物,例如聚乙二醇(PEG)部分。脂质体及其使用进一步描述于美国专利第6,287,860号中。
本发明的药物制剂和组合物也可包含表面活性剂。表面活性剂在药物产品、制剂和乳剂中的使用为本领域众所周知的。表面活性剂及其使用进一步描述于美国专利第6,287,860号中,其通过引用结合于本文中。
在一个实施方案中,本发明使用各种渗透促进剂来实现核酸特别是寡核苷酸的有效递送。除了有助于非亲脂性药物穿过细胞膜的扩散之外,渗透促进剂还增加亲脂性药物的渗透性。可将渗透促进剂归类为属于五大类的一种,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。渗透促进剂及其使用进一步描述于美国专利第6,287,860号,其通过引用结合于本文中。
本领域的技术人员将认识到,根据其预期用途(即给药途径)来常规地设计制剂。
用于局部给药的制剂包括以下制剂,其中本发明寡核苷酸与局部递送剂(例如,脂质、脂质体、脂肪酸、脂肪酸酯、甾类化合物、螯合剂和表面活性剂)混合。脂质和脂质体包括中性的(例如二油酰基-磷脂酰DOPE乙醇胺、二肉豆蔻酰基磷脂酰胆碱DMPC、二硬脂酰基磷脂酰胆碱)、阴性的(例如二肉豆蔻酰基磷脂酰甘油DMPG)和阳离子的(例如二油酰基四甲基氨丙基DOTAP和二油酰基-磷脂酰基乙醇胺 DOTMA)。
对于局部或其他给药而言,可将本发明的寡核苷酸封装在脂质体内或可与其(特别是与阳离子脂质体)形成复合体。或者,可将寡核苷酸与脂质(特别是阳离子脂质)复合。脂肪酸和酯类、其药学上可接受的盐以及它们的使用进一步描述于美国专利第6,287,860号中。
用于口服给药的组合物和制剂包括散剂或颗粒剂、微粒、纳米粒子、在水或非水性介质中的混悬剂或溶液剂、胶囊剂、凝胶胶囊、小药囊、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为所需的。口服制剂为以下制剂,其中将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协同施用。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/盐和脂肪酸及其使用进一步描述于美国专利第6,287,860号中,其通过引用结合于本文中。渗透促进剂的组合亦是如此,例如脂肪酸/盐与胆汁酸/盐的组合。具体地组合为月桂酸的钠盐、癸酸和UDCA。另外的渗透促进剂包括聚氧化乙烯-9-月桂醚、聚氧化乙烯-20-鲸蜡醚。本发明的寡核苷酸可以以包括喷雾干燥颗粒的颗粒形式口服地递送,或络合以形成微米或纳米粒子。寡核苷酸络合剂及其使用进一步描述于美国专利第6,287,860号中,其通过引用结合于本文中。
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性溶液剂,其也可含有缓冲液、稀释剂和其他适合的添加剂,例如但不限于,渗透促进剂、载体化合物和其他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药物组合物,所述药物组合物包含一种或多种寡聚化合物和一种或多种其他通过非反义机制来起作用的化学治疗剂。这类化学治疗剂的实例包括但不限于癌症化学治疗药物,例如柔红霉素、道诺霉素、更生霉素、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、胞嘧啶阿拉伯糖苷、双氯乙基-亚硝基脲、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、五甲蜜胺、米托蒽醌、安吖啶、苯丁酸氮芥、甲基环己基亚硝基脲、氮芥、美法仑、环磷酰胺、6-巯基嘌呤、6-巯鸟嘌呤、阿糖胞苷、5-氮杂胞苷、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、长春新碱、长春碱、依托泊苷(VP-16)、三甲曲沙、伊立替康、拓泊替康、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,这类化学治疗剂可单独地(例如,5-FU 和寡核苷酸)、序贯地(例如,5-FU和寡核苷酸持续一段时间,接着 MTX和寡核苷酸)、或与一种或多种其他的这类化学治疗剂组合(例如,5-FU、MTX和寡核苷酸,或5-FU、放射疗法和寡核苷酸)使用。抗炎药(包括但不限于非甾体抗炎药和皮质类固醇)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)也可组合到本发明的组合物中。反义化合物和其他非反义药物的组合也在本发明的范围之内。两种或更多种组合的化合物可一起或序贯使用。
在另一个相关的实施方案中,本发明的组合物可包含靶定到第一核酸的一种或多种反义化合物(特别是寡核苷酸),以及靶定到第二核酸靶标的一种或多种其他反义化合物。例如,第一靶标可为胶原基因的特定反义序列,第二靶标可为来自另一个核苷酸序列的区域。或者,本发明的组合物可包含靶定到相同胶原基因核酸靶标的不同区域的两种或更多种反义化合物。本文举例说明了许多反义化合物的实例而其他的可选自本领域已知的适合化合物。两种或更多种组合化合物可一起或序贯使用。
给药:
认为治疗组合物的制剂和其随后的施用(给药)在本领域技术人员的技术之内。给药取决于要治疗的疾病状态的严重性和应答性,而疗程从数天持续到数月,或直到完成治愈或达到疾病状态的减轻。最佳给药方案可根据患者体内药物蓄积的测定来计算。普通技术人员可容易地确定最适剂量、给药方法和重复率。最适剂量可根据单独寡核苷酸的相对功效而不同,一般可基于发现在体外和体内动物模型中有效的EC50来评价。一般而言,剂量为0.01μg-100g/kg体重,且可每天、每周、每月或每年给药一次或多次,或甚至每2-20年一次。本领域普通技术人员可基于测定体液或组织中药物的停留时间和浓度来容易地评价给药的重复率。成功治疗之后,可能需要使患者进行维持疗法以预防疾病状态的复发,其中所述寡核苷酸以维持剂量来施用,范围为0.01μg-100g/kg体重,每天一次或多次到每20年一次。
在实施方案中,使用下列剂量的药物治疗患者,所述剂量为至少约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描述于,例如,美国专利第7,563,884 号,“Antisense modulation of PTP1B expression(PTP1B表达的反义调节)”通过引用以其整体结合于本文中。
虽然上文已描述了本发明的各种实施方案,但是应理解的是,其仅以实例的方式提供,而并非限制。对公开的实施方案的许多改变可依照本文的公开内容来进行,而不会背离本发明的精神或范围。因此,本发明的广度和范围不应受到任何上述的实施方案所限制。
本文提及的所有文件都通过引用结合到本文中。本申请引用的所有出版物和专利文件都为所有目的而通过引用结合,引用程度如同单独地指出各个出版物或专利文件一样。至于申请人在本文件中对不同参考文献的引用,申请人并不承认任何具体参考文献对其发明而言为“现有技术”。本发明的组合物和方法的实施方案举例说明于下列实施例中。
实施例
下列非限制性的实施例用于举例说明本发明的经挑选的实施方案。应理解的是,所示组分的比例变化和要素备选对本领域的技术人员而言为显而易见的且在本发明的实施方案的范围之内。
实施例1:对胶原基因的反义核酸分子和/或胶原基因多核苷酸有义链特异的反义寡核苷酸的设计
如上指出的术语“对......特异的寡核苷酸”或“靶定......的寡核苷酸”是指具有以下序列的寡核苷酸,该序列(i)能够与靶定基因的一部分形成稳定的复合体,或(ii)能够与靶定基因mRNA转录物的一部分形成稳定的双链体。
适当寡核苷酸的挑选通过使用计算机程序来促进,该计算机程序自动比对核酸序列并指出同一性或同源性区域。这类程序用于比较例如通过搜索诸如GenBank等数据库或通过测序PCR产物而获得的核酸序列。来自一系列物种的核酸序列的比较允许挑选显示出物种之间适当同一性程度的核酸序列。在未测序基因的情况下,进行DNA印迹来确定在靶物种和其他物种的基因之间的同一性程度。通过在各种严格程度下进行DNA印迹,如本领域众所周知的,可获得同一性的近似测量。这些程序允许挑选这样的寡核苷酸,其对在待控制的受试者中的靶核酸序列表现高度的互补性而对在其他物种中的相应核酸序列表现较低程度的互补性。本领域技术人员将认识到,在挑选用于本发明的适当的基因区域上具有相当大的自由。
反义化合物为“可特异杂交的”,如果所述化合物与靶核酸的结合干扰靶核酸的正常功能,导致功能和/或活性的调节,并且在需要特异性结合的条件下具有足够程度的互补性以避免所述反义化合物与非靶核酸序列的非特异性结合,所述条件即在体内测定或治疗处理情况中的生理条件下,以及在体外测定情况中进行测定的条件下。
本文所述的寡核苷酸的杂交特性可通过本领域已知的一种或多种体外测定法来确定。例如,本文所述的寡核苷酸的特性可通过使用解链曲线测定法确定靶天然反义物和潜在药物分子之间的结合强度来获得。
靶天然反义物和潜在药物分子(Molecule)之间的结合强度,可使用任何已建立的测定分子间相互作用强度的方法例如解链曲线测定法来评价。
解链曲线测定法确定这样的温度,在该温度下天然反义物 /Molecule复合体发生从双链构象到单链构象的迅速转变。此温度被广泛认可为两个分子之间相互作用强度的可靠衡量。
解链曲线测定法可使用实际的天然反义RNA分子的cDNA拷贝或对应Molecule的结合位点的合成DNA或RNA核苷酸来进行。包含进行此测定的所有必需试剂的多种试剂盒为可得的(例如Applied Biosystems Inc.MeltDoctor试剂盒)。这些试剂盒包含含有双链 DNA(dsDNA)结合染料(例如ABI HRM染料、SYBR Green、SYTO等) 之一的适宜的缓冲溶液。dsDNA染料的特性为,其在游离形式几乎不发出荧光,但当与dsDNA结合时为高度荧光的。
为进行所述测定,将所述cDNA或相应寡核苷酸以由具体制造商的方案限定的浓度与Molecule混合。将所述混合物加热到95℃以解离所有预先形成的dsDNA复合体,然后缓慢冷却到室温或由试剂盒制造商确定的其他较低的温度以使DNA分子退火。随后将新形成的复合体缓慢加热到95℃,同时连续地收集由反应产生的荧光量的数据。荧光强度反比于反应中存在的dsDNA量。数据可使用与所述试剂盒相配的实时PCR仪器(例如ABI’s StepOnePlus Real Time PCR System或LightTyper仪器,Roche Diagnostics,Lewes,UK)来收集。
解链峰通过使用适当软件(例如LightTyper(Roche)或SDS Dissociation Curve,ABI)对温度(x-轴)绘制荧光关于温度的负导数(在 y-轴上的-d(荧光)/dT)的图形来构建。分析数据以确定从dsDNA复合体迅速转变到单链分子的温度。此温度称为Tm且正比于两个分子之间的相互作用强度。典型地,Tm将超过40℃。
实施例2:胶原基因多核苷酸的调节
用反义寡核苷酸处理HepG2细胞
使来自ATCC的HepG2细胞(目录号HB-8065)在37℃和5%CO2下生长于生长培养基(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))。试验的前一天将所述细胞以密度1.5×105/ml再接种到6孔板,并在37℃和5%CO2下培养。在试验当天将6孔板中的培养基换成新鲜的生长培养基。将所有反义寡核苷酸稀释到20μM的浓度。将2μl此溶液与 400μl Opti-MEM培养基(Gibco目录号31985-070)和4μl Lipofectamine2000(Invitrogen目录号11668019)在室温下孵育20min,然后施用到具有HepG2细胞的6孔板的每个孔。含有2μl水代替所述寡核苷酸溶液的类似混合物用于模拟转染的对照。在37℃和5%CO2下培养3-18 h后,将培养基换成新鲜的生长培养基。添加反义寡核苷酸48h后,将培养基移出,并遵循制造商的说明书使用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)从细胞中提取RNA。向如制造商的方案中所述使用Thermo Scientific的Verso cDNA试剂盒(目录号AB1453B)或High Capacity cDNA Reverse Transcription Kit(目录号 4368813)进行的反转录反应中,添加600ng RNA。将来自此反转录反应的cDNA用于通过使用ABI TaqmanGene Expression Mix(目录号 4369510)和由ABI(Applied Biosystems Taqman GeneExpression Assay:Hs00164004_m1、Hs00164310_m1,Applied Biosystems Inc., FosterCity CA)设计的引物/探针的实时PCR,来监控基因表达。使用下面的PCR循环:50℃,2min;95℃,10min;40个循环的(95℃, 15秒;60℃,1min),使用Mx4000热循环仪(Stratagene)。
用反义寡核苷酸处理后基因表达的倍数变化基于处理和模拟转染的样品之间18S-标准化的dCt值的不同来计算。
结果:
实时PCR结果显示,HepG2细胞中Col1a1 mRNA的水平在用针对Col1a1反义物DW440457设计的寡核苷酸之一处理后48h显著增加(图1)。
实时PCR结果显示,HepG2细胞中Col7a1 mRNA的水平在用针对Col7a1设计为be142537和bg998538的两种寡核苷酸处理后48h 显著增加(图4)。
用反义寡核苷酸处理HUVEC细胞
使来自ATCC的HUVEC细胞(Promo Cell目录号C-12253)在37℃和5%CO2下生长于上皮生长培养基(Epithelial Growth Media)(Promo Cell目录号C-22010)。试验的前一天使用Promo Cell Detach Kit(目录号C-41200)将所述细胞以密度1.5×105/ml再接种到6孔板,并在37℃和5%CO2下培养。在试验当天将6孔板中的培养基换成新鲜的上皮生长培养基。将所有反义寡核苷酸稀释到20μM的浓度。将2μl此溶液与400μl Opti-MEM培养基(Gibco目录号31985-070)和4μl Lipofectamine 2000(Invitrogen目录号11668019)在室温下孵育20min,然后施用到具有HUVEC细胞的6孔板的每个孔。含有2μl水代替所述寡核苷酸溶液的类似混合物用于模拟转染的对照。在37℃和5% CO2下培养3-18h后,将培养基换成新鲜的生长培养基。添加反义寡核苷酸48h后,将培养基移出,并遵循制造商的说明书使用Promega 的SV Total RNA Isolation System(目录号Z3105)或Qiagen的RNeasy TotalRNA Isolation试剂盒(目录号74181)从细胞中提取RNA。向如制造商的方案中所述使用Thermo Scientific的Verso cDNA试剂盒(目录号AB1453B)进行的反转录反应中,添加600ng RNA。将来自此反转录反应的cDNA用于通过使用ABI Taqman Gene Expression Mix(目录号4369510)和由ABI(Applied Biosystems Taqman Gene Expression Assay:Hs01028970_m1和Hs00164310_m1,Applied Biosystems Inc., Foster City CA)设计的引物/探针的实时PCR,来监控基因表达。使用下面的PCR循环:50℃,2min;95℃,10min;40个循环的(95℃, 15秒;60℃,1min),使用StepOne Plus Real Time PCR Machine (AppliedBiosystems Inc.)或Mx4000热循环仪(Stratagene)。
用反义寡核苷酸处理后基因表达的倍数变化基于处理和模拟转染的样品之间18S-标准化的dCt值的不同来计算。
结果:
实时PCR结果显示,HUVEC细胞中Col1a2 mRNA的水平在用针对Col1a2反义物Hs.571263设计的寡核苷酸之一处理后48h显著增加(图2)。
实时PCR结果显示,HUVEC细胞中Col7a1 mRNA的水平在用针对Col7a1设计为CV425857(CV425857.1_1、CV425857.1_2)的 siRNA之一和针对BU615800.1(BU615800.1_1)的一种siRNA处理后 48h显著增加(图3)。
尽管已就一个或多个实现举例说明并描述本发明,但在阅读和理解本说明书和附图后,本领域技术人员将想到等价改变和修饰。此外,虽然本发明的具体特征可能已就几个实现中的唯一一个公开,但这类特征可与其他实现的一个或多个其他特征组合,因为对于任何给定或具体应用而言可为所需和有利的。
本公开内容的摘要将允许读者快速确定本技术公开内容的性质。在理解以下的情况下将其提出:其将不用于解释或限制随附权利要求的范围或含义。
Claims (45)
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在体内或体外增量调节患者细胞或组织中选自SEQ ID NO: 1-3的胶原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对具有SEQ ID NO: 4-9的胶原基因的天然反义多核苷酸有特异性且与以下多核苷酸的反向互补序列具有100%序列同一性,所述多核苷酸包含在SEQ ID NO: 4-9之内的12-30个连续核苷酸,其中所述至少一种寡核苷酸包含如SEQ IDNO: 12、14、15、16、18、20、21、22、24、25、26、27和28所述的寡核苷酸序列。
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在体内或体外增量调节患者细胞或组织中选自SEQ ID NO: 1-3的胶原基因多核苷酸的功能和/或表达的药物中的用途,其中所述至少一种反义寡核苷酸特异性靶定胶原基因多核苷酸的天然反义寡核苷酸的互补区并与之具有100%序列同一性,其中所述至少一种反义寡核苷酸靶定具有SEQ IDNO: 4-9的胶原基因多核苷酸的天然反义序列,其中所述至少一种寡核苷酸包含如SEQ IDNO: 12、14、15、16、18、20、21、22、24、25、26、27和28所述的寡核苷酸序列。
3.权利要求2的用途,其中胶原基因的功能和/或表达在体内或体外相对于对照增加。
4.权利要求2的用途,其中所述至少一种反义寡核苷酸靶定与胶原基因RNA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。
5.权利要求2的用途,其中所述至少一种反义寡核苷酸靶定与胶原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。
6.权利要求2的用途,其中所述至少一种反义寡核苷酸包含一种或多种选自以下的修饰:至少一种经修饰的糖部分、至少一种经修饰的核苷间键、至少一种经修饰的核苷酸及其组合。
7.权利要求6的用途,其中所述一种或多种修饰包括至少一种选自以下的经修饰糖部分:2’-O-甲氧基乙基修饰的糖部分、2’-甲氧基修饰的糖部分、2’-O-烷基修饰的糖部分、二环糖部分及其组合。
8.权利要求6的用途,其中所述一种或多种修饰包括至少一种选自以下的经修饰核苷间键:硫代磷酸酯、烷基膦酸酯、二硫代磷酸酯、烷基硫代膦酸酯、氨基磷酸酯、氨基甲酸酯、碳酸酯、磷酸三酯、氨基乙酸酯、羧甲基酯及其组合。
9.权利要求6的用途,其中所述一种或多种修饰包括至少一种选自以下的经修饰核苷酸:肽核酸(PNA)、锁定核酸(LNA)、阿糖核酸(FANA)、及其组合。
10.权利要求1或2的用途,其中所述至少一种寡核苷酸由如SEQ ID NO: 12、14、15、16、18、20、21、22、24、25、26、27和28所述的寡核苷酸序列组成。
11.至少一种长度为19-30个核苷酸的短干扰RNA (siRNA)寡核苷酸在制备用于在体内或体外增量调节哺乳动物细胞或组织中选自SEQ ID NO: 1-3的胶原基因的功能和/或表达的药物中的用途,所述至少一种siRNA寡核苷酸对所述胶原基因多核苷酸的天然反义多核苷酸有特异性,其中所述至少一种siRNA寡核苷酸与转录自胶原基因多核苷酸的RNA多核苷酸的至少约19个连续核酸具有100%序列同一性,其中所述至少一种siRNA寡核苷酸包含如SEQ ID NO: 12、14、15、16、18、20、21、22、24、25、26、27和28所述的寡核苷酸序列。
12.至少一种长度为约12-30个核苷酸的反义寡核苷酸在制备用于在体内或体外增量调节哺乳动物细胞或组织中选自SEQ ID NO: 1-3的胶原基因的功能和/或表达的药物中的用途,所述反义寡核苷酸对所述胶原基因多核苷酸的天然反义链特异,其中所述至少一种反义寡核苷酸与至少一个如SEQ ID NO: 1-3所述的核酸序列或转录自胶原基因的RNA多核苷酸具有100%序列同一性,其中所述至少一种反义寡核苷酸包含如SEQ ID NO: 12、14、15、16、18、20、21、22、24、25、26、27和28所述的寡核苷酸序列。
13.一种长度为12-30个核苷酸的合成的、经修饰的寡核苷酸,所述寡核苷酸包含至少一种修饰并与包含在SEQ ID NO: 4-9的之内的12-30个连续核苷酸的多核苷酸的反向互补序列具有100%序列同一性,其中所述至少一种修饰选自:至少一种经修饰的糖部分;至少一种经修饰的核苷酸间键;至少一种经修饰的核苷酸及其组合;其中所述寡核苷酸为与正常对照相比在体内或体外与选自SEQ ID NO: 1-3的胶原基因特异地杂交并增量调节所述基因的功能和/或表达的反义化合物,其中所述寡核苷酸包含如SEQ ID NO: 12、14、15、16、18、20、21、22、24、25、26、27和28所述的寡核苷酸序列。
14.权利要求13的寡核苷酸,其中所述至少一种修饰包括选自以下的核苷酸间键:硫代磷酸酯、烷基膦酸酯、二硫代磷酸酯、烷基硫代膦酸酯、氨基磷酸酯、氨基甲酸酯、碳酸酯、磷酸三酯、氨基乙酸酯、羧甲基酯及其组合。
15.权利要求13的寡核苷酸,其中所述寡核苷酸包含至少一种硫代磷酸酯核苷酸间键。
16.权利要求13的寡核苷酸,其中所述寡核苷酸包含硫代磷酸酯核苷酸间键的骨架。
17.权利要求13的寡核苷酸,其中所述寡核苷酸包含至少一种经修饰的核苷酸,所述经修饰的核苷酸选自:肽核酸、锁定核酸(LNA)、及其组合。
18.权利要求13的寡核苷酸,其中所述寡核苷酸包含多种修饰,其中所述修饰包括选自以下的经修饰的核苷酸:硫代磷酸酯、烷基膦酸酯、二硫代磷酸酯、烷基硫代膦酸酯、氨基磷酸酯、氨基甲酸酯、碳酸酯、磷酸三酯、氨基乙酸酯、羧甲基酯及其组合。
19.权利要求13的寡核苷酸,其中所述寡核苷酸包含多种修饰,其中所述修饰包括选自以下的经修饰的核苷酸:肽核酸、锁定核酸(LNA)、及其组合。
20.权利要求13的寡核苷酸,其中所述寡核苷酸包含至少一种选自以下的经修饰的糖部分:2’-O-甲氧基乙基修饰的糖部分、2’-甲氧基修饰的糖部分、2’-O-烷基修饰的糖部分、二环糖部分及其组合。
21.权利要求13的寡核苷酸,其中所述寡核苷酸包含多种修饰,其中所述修饰包括选自以下的经修饰的糖部分:2’-O-甲氧基乙基修饰的糖部分、2’-甲氧基修饰的糖部分、2’-O-烷基修饰的糖部分、二环糖部分及其组合。
22.权利要求13的寡核苷酸,其中所述寡核苷酸长度为至少约12-30个核苷酸且与胶原基因多核苷酸的天然反义多核苷酸杂交,其中所述寡核苷酸与转录自胶原基因多核苷酸的RNA的至少约12个连续核酸具有100%序列同一性。
23.权利要求13的寡核苷酸,其中所述寡核苷酸与正常对照相比在体内或体外与至少一种胶原基因多核苷酸杂交并增量调节所述多核苷酸的表达和/或功能。
24.权利要求13的寡核苷酸,其中所述寡核苷酸由如SEQ ID NO: 12、14、15、16、18、20、21、22、24、25、26、27和28所述的序列组成。
25.一种组合物,所述组合物包含对一种或多种选自SEQ ID NO: 4-9的胶原基因天然反义多核苷酸特异的一种或多种长度为12-30个核苷酸的寡核苷酸,所述多核苷酸由与包含在SEQ ID NO: 4-9之内的12-30个连续核苷酸的多核苷酸的反向互补序列具有100%序列同一性的寡核苷酸组成,其中所述寡核苷酸包含如SEQ ID NO: 12、14、15、16、18、20、21、22、24、25、26、27和28所述的寡核苷酸序列。
26.权利要求25的组合物,其中所述寡核苷酸选自SEQ ID NO: 12、14、15、16、18、20、21、22、24、25、26、27和28。
27.权利要求26的组合物,其中如SEQ ID NO: 10所述的寡核苷酸包含一种或多种修饰或取代。
28.权利要求26的组合物,其中所述一种或多种修饰选自:硫代磷酸酯、甲基膦酸酯、肽核酸、锁定核酸(LNA)分子及其组合。
29.治疗有效剂量的至少一种反义寡核苷酸在制备用于预防或治疗与至少一种选自SEQ ID NO: 1-3的胶原基因多核苷酸和/或至少一种其编码产物有关的疾病的药物中的用途,所述反义寡核苷酸与所述至少一种胶原基因多核苷酸的天然反义序列结合,并增量调节所述至少一种胶原基因多核苷酸的表达,其中所述至少一种反义寡核苷酸包含如SEQ IDNO: 12、14、15、16、18、20、21、22、24、25、26、27和28所述的寡核苷酸序列。
30.权利要求29的用途,其中与至少一种胶原基因多核苷酸有关的疾病选自:胶原障碍、年龄相关的胶原降解、成骨不全、耳硬化、骨质疏松、骨关节炎、食管鳞状上皮细胞癌、软骨发育不全、非典型马方综合征、埃-当综合征、营养不良性大疱性表皮松解症、卡菲病、动脉瘤、特发性肺纤维化、肝硬化、肾纤维化、肝纤维化、心脏纤维化、硬皮病、肥厚性瘢痕和瘢痕疙瘩。
31.权利要求30的用途,其中所述动脉瘤为颅内动脉瘤。
32.权利要求29的用途,其中与至少一种胶原基因多核苷酸有关的疾病选自:癌症、炎症、遗传性疾病、神经疾病或病症、代谢病、自身免疫性疾病或病症、创伤、缺血,以及其它血管、心脏、皮肤疾病或病症。
33.权利要求32的用途,其中所述遗传性疾病为杜兴肌营养不良。
34.权利要求32的用途,其中所述神经疾病或病症为帕金森病、阿尔茨海默氏病、亨廷顿舞蹈病或戈谢病。
35.权利要求32的用途,其中所述代谢病为I型糖尿病。
36.权利要求32的用途,其中所述创伤为脊髓损伤或烧伤。
37.权利要求29的用途,其中与至少一种胶原基因多核苷酸有关的疾病选自:皮肤老化、需要皮肤工程的皮肤疾病或病症或病况、需要移植的肝脏或肾脏疾病;腱、骨或组织再生;骨骼修复、软骨和骨修复。
38.治疗有效剂量的至少一种反义寡核苷酸在制备用于预防或治疗与至少一种选自SEQ ID NO: 1-3的胶原基因多核苷酸和/或至少一种其编码产物有关的皮肤病况的药物中的用途,其中所述反义寡核苷酸与所述至少一种胶原基因多核苷酸的天然反义序列结合并增量调节所述至少一种胶原基因多核苷酸的表达,其中所述至少一种反义寡核苷酸包含如SEQ ID NO: 12、14、15、16、18、20、21、22、24、25、26、27和28所述的寡核苷酸序列。
39.权利要求38的用途,其中所述皮肤病况由炎症、光损伤或老化引发。
40.权利要求39的用途,其中所述皮肤病况为形成皱纹、接触性皮炎、特应性皮炎、光化性角化病、角质化病症、大疱性表皮松解症、剥脱性皮炎、脂溢性皮炎、红斑、盘状红斑狼疮、皮肌炎、皮肤癌或自然老化的作用。
41.一种基于胶原基因的基质组合物,所述组合物包含由胶原原纤维组成的三维纯化胶原基质,其中通过使胶原原纤维细胞或组织与特异地靶定选自SEQ ID NO: 4-9的胶原基因多核苷酸的天然反义寡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接触,在体内或体外增量调节胶原原纤维细胞中选自SEQ ID NO: 1-3的胶原基因多核苷酸的功能和/或表达,其中所述至少一种反义寡核苷酸包含如SEQ ID NO: 12、14、15、16、18、20、21、22、24、25、26、27和28所述的寡核苷酸序列。
42.权利要求41的组合物,其中所述寡核苷酸与如SEQ ID NO: 12、14、15、16、18、20、21、22、24、25、26、27和28所述核苷酸序列相比,具有100%序列同一性。
43.权利要求41的组合物,其中所述寡核苷酸包含如SEQ ID NO: 12所述的核苷酸序列。
44.权利要求43的组合物,其中所述组合物支持干细胞。
45.如权利要求43所定义的胞外基质组合物在制备用于体外、离体或体内伤口愈合或组织再生或组织工程的药物中的用途。
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US20190309295A1 (en) | 2019-10-10 |
JP5944311B2 (ja) | 2016-07-05 |
CN102695797A (zh) | 2012-09-26 |
WO2010148050A3 (en) | 2011-06-23 |
KR101801404B1 (ko) | 2017-12-20 |
JP2012529915A (ja) | 2012-11-29 |
ES2620960T3 (es) | 2017-06-30 |
US20170073680A1 (en) | 2017-03-16 |
US10370657B2 (en) | 2019-08-06 |
US11339394B2 (en) | 2022-05-24 |
WO2010148050A2 (en) | 2010-12-23 |
EP2443237A4 (en) | 2013-06-05 |
EP2443237B1 (en) | 2017-02-22 |
EP2443237A2 (en) | 2012-04-25 |
CA2765700A1 (en) | 2010-12-23 |
CA2765700C (en) | 2021-01-05 |
US20120171170A1 (en) | 2012-07-05 |
KR20120026622A (ko) | 2012-03-19 |
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