CN101883576B - 调控纤维化的微小rna家族及其用途 - Google Patents
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Abstract
本发明涉及作为心脏组织中纤维化的关键调节物的称作miR-29a-c的微小RNA家族的鉴定。发明人显示了miR-29家族的成员在心脏组织中响应压力而下调,且在对压力和纤维化都有抗性的小鼠的心脏组织中上调。还提供了调控miR-29 miRNA家族的表达和活性的方法,作为对纤维变性疾病,包括心脏肥大、骨骼肌纤维化、其它纤维化相关疾病和胶原丢失相关疾病的治疗。
Description
对相关申请的交叉引用
本申请要求2007年7月31日提交的美国临时申请No.60/952,917;2007年10月16日提交的美国临时申请No.60/980,303;和2008年4月22日提交的美国临时申请No.61/047,014的权益,通过述及将它们都完整收入本文。
关于政府资助的声明
本发明是在来自(美国)国家卫生研究院(NIH)的拨款No.HL53351-06的资助下做出的。政府拥有本发明的某些权利。
关于电子提交的文本文件的说明
通过述及将随此电子提交的文本文件的内容完整收入本文:序列表的计算机可读格式拷贝(文件名:UTFD_2021WO.txt,记录日:2008年7月30日,文件大小5千字节)。
发明领域
一般而言,本发明涉及发育生物学和分子生物学领域。更具体的说,它关注miR-29家族对成纤维细胞中的基因调控和细胞生理。此miRNA家族在胶原沉积,特别是由成纤维细胞介导的胶原沉积中发挥重要作用。
发明背景
心脏病及其表现,包括冠心病、心肌梗死、充血性心力衰竭和心脏肥大,清楚代表了美国当今的一项重大健康风险。诊断、治疗和支持罹患这些疾病的患者的花费完全达到数十亿美元。心脏病的两项特别严重的表现是心肌梗死和心脏肥大。就心肌梗死而言,典型的是,由于动脉粥样硬化,在冠状动脉中发生急性血小板性冠状动脉闭塞,引起心肌细胞死亡。因为心肌细胞,即心脏肌肉细胞,是终末分化的且一般没有能力进行细胞分裂,所以当它们在急性心肌梗死过程期间死亡时它们一般被瘢痕组织代替。瘢痕组织没有收缩性,无助于心脏功能,而且常常通过在心脏收缩期间扩张,或通过增加心室的大小和有效半径,例如变得肥大,而在心脏功能中发挥有害作用。虽然初始的胶原沉积是梗死愈合和预防心脏破裂所需要的,但是成纤维细胞持续生成胶原在梗死缘带中的肌细胞周围和梗死心脏的远端心肌(remotemyocardium)诱发间质性纤维化。由于压力的增大,此纤维化诱发僵硬、舒张功能障碍、和心肌细胞肥大,而且还能导致心率失常(arrythmias)。
心脏肥大是心脏对实际上所有形式心脏病(包括那些源自高血压、机械负荷、心肌梗死、心脏心率失常、内分泌病症、和心脏收缩蛋白质基因中遗传突变的)的适应性应答。虽然肥大性应答最初是提高心输出量的代偿机制,但是持久的肥大能导致扩张性心肌病(DCM)、心力衰竭、和猝死。在美国,每年有大约50万人诊断出心力衰竭,死亡率接近50%。心脏肥大的前因后果已经被广泛证明,但是根本的分子机制尚未阐明。了解这些机制是心脏病的预防和治疗中的一项重大关注点,而且作为设计特异性靶向心脏肥大和心脏心力衰竭的新药物中的治疗形态会是至关重要的。
用药理学药剂进行的治疗代表了用于减轻或消除心力衰竭表现的主要机制。利尿药构成了轻度至中度心力衰竭的一线治疗。如果利尿药无效,那么可使用血管扩张药,诸如血管紧张素转化酶(ACE)抑制剂(例如enalopril和lisinopril)或肌力药疗法(即通过提高心肌肌肉收缩力量来提高心输出量的药物)。不幸的是,这些标准疗法中的许多具有众多不良反应,而且在有些患者中是禁忌的。如此,当前使用的药理学药剂在特定患者群中具有严重缺陷。新的、安全的且有效的药剂的可得性无疑会惠及不能使用目前可得的药理学形态的患者或没有自那些形态获得足够缓解的患者。
心肌细胞在正常情况中由胶原纤维的精细网络所包围。响应病理性压力,心脏成纤维细胞和细胞外基质蛋白质不成比例地且过度地积累。心肌纤维化,即所有形式病理性肥大的一项特征,导致机械僵硬,这促成收缩功能障碍(Abraham等,2002)。病理性肥大和心力衰竭的另一项标志是对一组胎儿心脏基因(包括那些编码心房利钠肽(ANP)、B-型利钠肽(BNP)和收缩蛋白质胎儿同等型诸如骨骼α-肌动蛋白和β-肌球蛋白重链(MHC))的重新激活。这些基因通常在出生后受到遏制,并被一组成人心脏基因的表达替换(McKinsey和Olson,2005)。胎儿基因表达对心脏功能和重塑的后果(例如纤维化)尚未完全了解。然而,已经提出响应压力而发生的β-MHC(一种慢速ATP酶)上调和α-MHC(一种快速收缩ATP酶)下调涉及心脏功能的降低(Bartel,2004),而且已知BNP在心脏纤维化中发挥支配性作用。
在心脏纤维化之外,有许多病症或疾患与各种组织的纤维化有关。先天性肝纤维化(一种常染色体隐性疾病)是一种影响肝和肾二者的罕见遗传病。该疾病的特征为肝异常,诸如肝大、门高血压、和遍及整个肝的纤维样结缔组织(肝纤维化)。肺纤维化(或肺瘢痕形成)源自正常肺气囊逐渐被纤维变性组织替换。当瘢痕形成时,组织变厚,引起组织运送氧进入血流的能力不可逆地丢失。最流行的想法是肺组织中的纤维变性过程是对肺微观损伤的反应(因遗传而易感)。虽然尚不知道确切的起因,但是已经得出与吸入的环境和职业污染物、吸烟、疾病(诸如硬皮病、类风湿性关节炎、狼疮和结节病)、某些药疗和治疗性辐射有关。
硬皮病是一种特征为胶原在皮肤或其它器官中过度沉积的慢性病。该疾病的局限性类型尽管使人失去能力,但不太会致命。作为心、肾、肺或肠损伤的结果,系统性类型或系统性硬化病(它是该疾病的全身性类型)会是致命的。硬皮病影响皮肤,而且在更加严重的情况中,它能影响血管和内脏器官。
骨骼肌纤维化是常常在患病或受损肌肉中发生的现象。它以纤维组织的过度生长为特征,这通常源自身体试图自损伤恢复的企图。纤维化损害肌肉功能并引起虚弱。肌肉功能丢失的程度一般随纤维化的程度而增大。肌肉营养不良(特别是贝克(Becker)肌营养不良(BMD)和更严重深入的等位基因表现,迪谢内(Duchenne)肌营养不良(DMD))的受害者随着疾病进展常常罹患日益增多的骨骼肌纤维化。已知其它病痛(诸如去神经萎缩)造成骨骼肌纤维化,以及神经肌肉疾病,诸如急性多神经炎、脊髓灰质炎、Werdig/Hoffman病、肌萎缩侧索硬化(Lou Gehrig病)、和渐进性延髓萎缩疾病。
最近提出微小RNA涉及多种生物学过程,包括对发育时机、凋亡、脂肪代谢、和造血细胞分化等的调节。微小RNA(miR)指自常常编码多种密切相关miRNA的多顺反子转录物、蛋白质编码基因的内含子、或各miRNA基因衍生的,长度为约18个至约25个核苷酸的小型、非蛋白质编码RNA。参见综述Carrington等(2003)。miR起靶物mRNA的阻抑物的作用,这通过促进它们的降解(当它们的序列优选互补时)或通过抑制翻译(当它们的序列含有错配时)来实现。
miRNA由RNA聚合酶II(pol II)或RNA聚合酶III(pol III;参见Qi等(2006)Cellular & Molecular Immunology Vol.3:411-419)转录,而且源自称作初级miRNA转录物(pri-miRNA)的初始转录物,它们一般长数千碱基。pri-miRNA在细胞核中被RNA酶Drosha加工成约70个至约100个核苷酸的发夹形前体(pre-miRNA)。转运至细胞质后,发夹pre-miRNA被Dicer进一步加工以生成双链miRNA。然后将成熟miRNA链掺入RNA诱导的沉默复合物(RISC),在那里它通过碱基对互补性与它的靶mRNA联合。在相对罕见的、miRNA与mRNA靶物完美碱基配对的情况中,它促进mRNA降解。更常见的是,miRNA与靶mRNA形成不完美的异源双链体,从而影响mRNA稳定性或抑制mRNA翻译。
跨越碱基2-8(称作“种子”区)的miRNA的5′部分对于靶物识别是尤其重要的(Krenz和Robbins,2004;Kiriazis和Kranias,2000)。种子的序列与靶序列的系统发生保守性一起构成许多当前靶物预测模型的基础。虽然可获得目益增多的用于预测miRNA及其靶物的深奥计算办法,但是靶物预测仍然是一项重大挑战,而且需要实验验证。将miRNA的功能归于对特定mRNA靶物的调节因各miRNA与数以百计的潜在的高和低亲和力mRNA靶物碱基配对的能力及使多种miRNA靶向各mRNA变得更加复杂。增强的对miRNA功能的了解无疑会揭示促成正常发育、分化、细胞间和细胞内通讯、细胞周期、血管发生、凋亡、和许多其它细胞过程的调节网络。最近,发明人报告了一种心脏特异性微小RNA,miR-208,它是由α-肌球蛋白重链(MHC)基因的内含子编码的,而且是响应心脏压力而上调β-MHC表达和遏制心脏中的快速骨骼肌基因所需要的(参见共同悬而未决的申请WO2008/016924,通过述及将其完整收入本文)。本发明详述了微小RNA在心脏以及其它组织中的参与。
发明概述
本发明基于如下的发现,即miR-29家族(其在心脏中响应压力而下调)调节胶原沉积和纤维化(包括心脏纤维化)形成。miR-29a-c表达或功能的上调导致胶原和纤维蛋白基因的表达降低,导致降低的心脏纤维化。因而,本发明提供了一种在有所需要的受试者中治疗心脏纤维化、心脏肥大、或心力衰竭的方法,包括鉴定具有心脏纤维化、心脏肥大或心力衰竭的受试者;并给所述受试者施用miR-29a-c表达或功能的激动剂。在一个实施方案中,所述miR-29a-c激动剂是包含miR-29a、miR-29b、miR-29c、或其组合的成熟序列的多核苷酸。所述miR-29a-c激动剂可以通过胃肠外施用(例如静脉内或皮下)、口服、经皮、持续释放、受控释放、延迟释放、栓剂、导管或舌下施用来施用。在另一个实施方案中,所述方法进一步包括给所述受试者施用第二疗法。所述第二疗法选自下组:β-阻滞剂、肌力药、利尿药、ACE-I、AII拮抗剂、BNP、Ca++-阻滞剂、内皮缩血管肽受体拮抗剂、和HDAC抑制剂。
本发明还提供了一种在有所需要的受试者中预防病理性肥大或心力衰竭的方法,包括鉴定有风险发生病理性心脏肥大或心力衰竭的受试者;并提升所述受试者的心脏细胞中的miR-29a-c的表达或活性。在一个实施方案中,提升miR-29a-c的表达或活性包括对所述心脏细胞递送miR-29a-c的激动剂或编码miR-29a-c的表达载体。在另一个实施方案中,所述有风险的受试者展现出一种或多种选自下组的风险因素:长期存在的不受控制的高血压、未矫正的瓣膜病、慢性心绞痛(chronic angina)、近期的心肌梗死、对心脏病的先天性素因、和病理性肥大。在另一个实施方案中,所述有风险的受试者已经诊断为具有对心脏肥大的遗传素因。在还有一个实施方案中,所述有风险的受试者具有心脏肥大的家族史。
本发明还涵盖一种转基因的非人哺乳动物,其细胞未能表达功能性miR-29a、miR29b、和/或miR29c。在另一个实施方案中,本发明提供了一种转基因的非人哺乳动物,其细胞包含在异源启动子控制下的miR-29a-c编码区,所述异源启动子在所述非人哺乳动物的细胞中有活性。所述转基因哺乳动物可以是小鼠。
在一个实施方案中,本发明提供了一种在有所需要的受试者中治疗心肌梗死的方法,包括提升所述受试者的心脏细胞中的miR-29a-c的表达或活性。在另一个实施方案中,本发明提供了一种在有所需要的受试者中预防心脏肥大和扩张性心肌病的方法,包括提升所述受试者的心脏细胞中的miR-29a-c的表达或活性。在另一个实施方案中,本发明提供了一种在有所需要的受试者中抑制心脏肥大进展的方法,包括提升所述受试者的心脏细胞中的miR-29a-c的表达或活性。
本发明还涵盖一种在受试者中治疗或预防组织纤维化的方法,包括鉴定具有组织纤维化或有组织纤维化风险的受试者;并提高所述受试者的骨骼肌或成纤维细胞细胞中的miR-29a-c的表达和/或活性。所述组织纤维化可以是心脏纤维化、硬皮病、骨骼肌纤维化、肝纤维化、肾纤维化、肺纤维化、或糖尿病纤维化。在一些实施方案中,提高miR-29a-c的表达和/或活性包括给所述受试者施用miR-29a-c的激动剂。miR-29a-c的激动剂可以是包含成熟miR-29a、miR-29b、和/或miR-29c序列之序列的多核苷酸。所述miR-29a-c激动剂还可以是编码miR-29a、miR-29b、和/或miR-29c的表达载体。在一个实施方案中,所述方法进一步包括给所述受试者施用非miR-29a-c抗纤维变性疗法。
本发明还提供了一种鉴定miR-29a-c调控物的方法,包括使细胞接触候选化合物;评估miR-29a-c活性或表达;并比较步骤(b)中的活性或表达与不存在所述候选化合物时miR-29a-c的活性或表达,其中测量得到的miR-29a-c活性或表达间的差异指示所述候选化合物是miR-29的调控物。可以在体外或在体内使所述细胞接触所述候选化合物。合适的候选化合物包括蛋白质、肽、多肽、多核苷酸、寡核苷酸或小分子。
本发明还涵盖一种药物组合物,其包含miR-29a-c的激动剂或拮抗剂。在一些实施方案中,所述药物组合物可以是为注射或局部施用而配制的。用于局部施用的配制剂可以是凝胶(gel)、乳膏(cream)、洗剂(lotion)、或软膏剂(ointment)。
本发明提供了一种在组织中诱导胶原沉积的方法,包括使所述组织接触miR-29a-c的拮抗剂。所述拮抗剂可以是miR-29a、miR-29b、或miR-29c的拮抗剂。所述拮抗剂可以是miR-29a-c的小RNA拮抗剂(antagomir)、靶向成熟miR-29a-c序列的反义寡核苷酸、或包含与成熟miR-29a-c序列相同的序列的抑制性RNA分子(诸如siRNA或shRNA)、或核酶或其它抑制性核酸。在一个实施方案中,所述方法进一步包括使所述组织接触第二药剂。所述第二药剂可以是局部维生素A、局部维生素C、或维生素E。在另一个实施方案中,所述方法进一步包括对所述组织进行第二处理,诸如化学脱皮、激光处理、皮肤整平(dermaplaning)、或皮肤磨削术。在另一个实施方案中,所述组织在罹患埃勒斯一当洛综合征(Ehler’s-Danlos syndrome)或维生素C缺乏病的受试者中。
附图简述
通过参考这些附图中的一幅或多幅并与本文所呈现的具体实施方案的详述组合,可以更好地理解本发明。
图1A-B。miR-208由α-MHC基因编码并在心脏中特异性表达。(图1A)miR-208在α-MHC基因的内含子内编码。星号指示序列保守性(SEQ IDNO:1-5)。(图1B)通过Northern分析对成年小鼠组织的miR-208转录物的检测。U6mRNA充当加载对照。
图2A-B。对α-和β-MHC的调节。(图2A)甲状腺激素和TRE对类别转变的调节。(图2B)快速向慢速的肌肉纤维收缩性转变中的压力/甲状腺功能减退症的模型。
图3。人类心脏中miR-208的检测。通过来自六名正常个体和六名具有特发性心肌病的个体的心脏组织的Northern印迹检测α-MHC和miR-208的转录物。在α-MHC与pre-miR-208的表达水平间存在密切相关性,而成熟miR-208表达在后者下调后得到维持。
图4A-B。miR-208突变小鼠的生成。(图4A)通过同源重组生成miR-208突变小鼠的策略。用侧翼为loxP位点的新霉素抗性盒替换pre-miRNA序列(在大多数转录物中位于小鼠α-MHC基因的内含子29内)。通过将杂合小鼠与携带CAG-Cre转基因的转基因小鼠育种,清除小鼠种系中的新霉素盒。(图4B)通过来自野生型和miR-208突变小鼠的心脏的Northern分析检测miR-208转录物。
图5。所示基因型的新生小鼠的心脏中α-MHC和β-MHC蛋白质水平的 Western分析。每种基因型分析两只小鼠。检测GAPDH作为加载对照。
图6。miR-208 -/- 小鼠显示出响应压力过载的心脏肥大减轻。野生型和miR-208-/-小鼠的心脏的组织学切片Masson三色染色。miR-208的缺失消除了在接受21天胸主动脉绑扎(TAB)的野生型小鼠中看到的肥大和纤维化。顶图中的标度条等于2mm,而底图中的等于20μm。
图7。miR-208 -/- 小鼠显示出响应钙依赖磷酸酶活化的心脏肥大减轻。表达钙依赖磷酸酶转基因的6周龄小鼠的心脏(CnA-Tg)和miR-208-/-;CnA-Tg的心脏的组织学切片Masson三色染色。miR-208的缺失消除在CnA-Tg小鼠中看到的肥大和纤维化。标度条=2mm(顶图)或20μm(底图)。
图8。miR-208 -/- 小鼠未能响应TAB和钙依赖磷酸酶活化而上调β-MHC。
图9。成年野生型和miR-208转基因动物中α和β-MHC蛋白质水平的 Western分析。检测GAPDH作为加载对照。
图10。miR-208 -/- 小鼠未能响应PTU处理的甲状腺功能减退而上调 β-MHC。
图11。miR-208在控制β-MHC表达中的作用的示意图。
图12。miR-208在经Thrap1调节β-MHC和快速骨骼肌基因表达中的作用 的示意图。
图13。微小RNA在心脏肥大期间的作用机制。
图14A-C。心脏肥大和重塑期间的miRNA表达。(图14A)来自假和TAB 21天后的小鼠和来自CnA Tg小鼠的代表性心脏的H&E染色切片。标度条等于2mm(图14B)下面显示了显示在每种心脏类型中的表达有变化的微小RNA的数目的Venn图。(图14C)肥大期间的表达有变化的微小RNA的Northern印迹。检测U6RNA作为加载对照。
图15。miR-29a-c表达响应心脏压力而下调。在左边显示了来自野生型小鼠(WT)和具有钙依赖磷酸酶转基因(CnA)或TAB诱发的肥大和纤维化小鼠的心脏。在右边显示了miR-29a-c在每种心脏类型中的相对表达水平。
图16。与野生型相比,来自miR-208敲除小鼠的心脏的微阵列分析。在6周龄时对自野生型和miR-208无效心脏分离的mRNA实施了微阵列分析。位居miR-208之后下调最多的miRNA是miR-499。
图17。miR-29家族在miR-208无效心脏中显著上调。
图18。miR-29家族靶向编码胶原和细胞外基质的涉及纤维化的其它成分 的mRNA。基于它们的高度序列同源性,miR29家族由4个成员组成;miR-29a、miR29b-1和-2、及miR-29c。显示了成熟miRNA的序列(SEQ ID NO:18-20)。miR-29b-1和miR-29b-2的成熟序列是相同的。此家族一起针对细胞外基质的涉及纤维化的许多成分。
图19。miR-208和miR-29家族控制心脏纤维化的模型。在正常心脏中,miR-208抑制miR-29a-c表达。在没有miR-208时,miR-29a-c表达上调,阻止响应压力而发生的纤维化和细胞外基质表达。miR-208、miR-499和miR-29的功能是连环的。通过阻止miR-499表达和上调miR-29a-c表达,由此阻断纤维化,miR-208的丢失会是心脏保护性的。
图20A-D。miR-29a-c调节细胞外基质蛋白质的表达。(图20A)关键纤维变性基因的3′UTR区中miR-29a-c的潜在结合位点。(图20B)MI后3天缘带和远端心肌层二者中预测靶基因的实时PCR分析显示了miR-29a-c的降低,与胶原(COL1A1、COL1A2和COL3A1)和微纤维蛋白(FBN1)的升高有关,而弹性蛋白(ELN1)没有显著变化。(图20C)经渐增量的编码miR-29b-1/miR-29a簇的CMV表达质粒转染的COS细胞的Northern印迹分析显示miR-29a-b的有效过表达。顶部的带对应于pre-miRNA,而下面的带对应于成熟miRNA。(图20D)使用预测靶基因的内源UTR序列进行的萤光素酶实验,显示了响应渐增量的miR-29a-c,miR-29a-c遏制萤光素酶表达,而在使用无关miR(即miR-206)时没有这种降低。
图21A-B。miR-29a-c表达响应TGFβ。(图21A)实时PCR分析指示所有三个miR-29家族成员在成纤维细胞中响应TGFβ而下调。(图21B)显示miR-29a-c表达在miR-208突变动物中上调的Northern分析,与通过实时PCR测定的BNP表达升高一致。
图22A-G。miR-29a-c抑制在体内诱导纤维化。(图22A)反miR-29a-c和错配(mm)miR-29a-c的结构。(图22B)Northern印迹分析,显示了3天后响应静脉内注射80mg/kg反miR-29a-c或mm miR-29a-c或相当体积的盐水而发生的组织特异性敲低。(图22C)肝提取物的实时PCR分析指示胶原表达响应miR-29a-c敲低的显著升高,而在注射盐水或mm后没有这种效果。(图22D)连续两天静脉内注射80mg/kg反miR-29a-c或mm miR-29a-c寡核苷酸或相当体积的盐水后三周收集的组织指示心、肝和肾中miR-29a-c的剧烈敲低,而肺中的miR-29a-c水平表现出不受影响。(图22E)心提取物的实时PCR分析指示心脏胶原表达响应miR-29a-c敲低而升高。(图22F)实时PCR分析指示miR-29b模拟物处理后两天成纤维细胞中miR-29b表达升高,而miR-29a水平没有变化,miR-29c水平只有略微升高。(图22G)成纤维细胞中的miR-29b过表达遏制胶原基因表达,如实时PCR分析所测定的。
图23。miR-29家族成员在各种组织中响应miR-29b敲低的表达。不同组织中所有miR-29成员的敲低指示miR-29b显示响应反miR-29b在心脏中降低50%,而miR-29a和-c只显示边缘性变化。然而,肝和肾中miR-29b响应反miR-29b的敲低几乎是完全的,而miR-29a和-c也表现出在这些组织中响应反miR-29b而降低。
发明详述
心肌和骨骼肌通过调控肌球蛋白的调节收缩效率的各同等型的表达来响应多种病理生理刺激,诸如工作负荷、甲状腺激素信号传导和损伤。最近,发明人报告了一种心脏特异性微小RNA,即miR-208,它是由α-肌球蛋白重链(MHC)基因的内含子编码的,而且是在心脏中响应心脏压力而上调β-MHC表达和遏制快速骨骼肌基因所需要的(参见共同悬而未决的申请WO2008/016924,通过述及而完整收入本文)。
在此,发明人延伸了他们早先的工作,并且显示了miR-208还下调一个相关miRNA家族,即miR-29a-c。由于miR-29a-c遍在表达,而且涉及对胶原沉积的调节,因此调节miR-29a-c表达的策略可应用于预防多种组织纤维化,包括心脏纤维化,以及骨骼肌、肝、肺、糖尿病和肾纤维化。对心脏细胞(诸如心脏成纤维细胞)中miR-29a-c的调节可用于在受试者中治疗或预防心脏肥大或心力衰竭。如此,本发明的一个方面是对miR-29a-c表达或活性的激动,任选与抑制miR-208联合。激动可涉及将外源miR-29a-c导入心脏或其它感兴趣组织,或是直接使用裸的核酸或递送媒介物(vehicle)(诸如脂质/脂质体/纳米颗粒),或是经由基因表达,例如通过使用腺病毒载体或其它异位表达手段,以降低纤维化。还涵盖经由药物“小分子”来激活miR-29a-c的抗纤维变性功能,正如用于鉴定此类化合物的筛选。
遏制miR-29a-c表达后,例如在心肌梗死(MI)和其它压力形式后发生的胶原增多可指示miR-29a-c的另一项作用。发明人的工作的一个焦点是心脏纤维化,而且对一个关键调节基因子集(即胶原I、III、弹性蛋白和微纤维蛋白)的检查显示了这两种胶原和微纤维蛋白响应miR-29a-c下调的惊人增多,而弹性蛋白没有增多。因此,治疗性遏制miR-29a-c来增加胶原沉积为解决以胶原丢失为特征的状况(诸如在化妆品应用和瘢痕形成)呈现了一个独特选项。
微小RNA 29(miR-29)是一个微小RNA家族,由4个已知成员组成,即miR-29a、b1和2(相同的)和c。虽然miR 29b-1和29a滋生自源自人类染色体7和小鼠染色体6的相同转录物,但是含有miR 29b-2和miR 29c的miRNA簇在这两种物种中都是自染色体1转录的。下面列出了每一个人类miR-29家族成员的成熟miRNA序列:
hsa-miR-29a uagcaccaucugaaaucgguua(SEQ ID NO:18)
hsa-miR-29b-1和b-2uagcaccauuugaaaucaguguu(SEQ ID NO:19)
hsa-miR-29c uagcaccauuugaaaucgguua(SEQ ID NO:20)
这些微小RNA基于它们的序列同源性而形成家族(Yu等;2006)。由于在家族各成员间只有微小的差异,而且各成员具有100%保守的种子区(其有助于限定靶物决定),因此它们很有可能靶向相同的mRNA靶物(图18),而且降低这些特定靶基因的基因表达。miR-29家族的靶物决定揭示了miR-29家族显示出对靶向涉及胶原形成的基因以及其它细胞外基质蛋白质(诸如诸如弹性蛋白(ELN)、微纤维蛋白1(FBN1)、胶原I型α1和α2(COL1A1,COL1A2)胶原III型α1(COL3A1)、金属肽酶、和整联蛋白)的高度偏爱。在响应病理压力时,心脏成纤维细胞和细胞外基质蛋白质不成比例地且过度地积累。心肌纤维化(所有形式的病理性肥大的一项特征)导致机械僵硬,这促成收缩功能障碍(Berk等,2007)。由于miR-29家族在此重塑过程期间下调,因此此家族有可能在对胶原沉积的调控中发挥积极作用,并由此调节心脏纤维化和心脏收缩性,这继发地能诱导肥大和病理性重塑。
正如先前所讨论的,miR-208表现出调节miR-29表达,因为miR-29在miR-208的两个拷贝都缺失的小鼠的心脏中显著上调(见实施例1)。如此,对miR-208的调控能影响miR-29的表达以及miR-29靶基因的表达。miR-208是位于α-MHC基因内含子内的内含子miRNA。精确的内含子位置取决于具体的物种和具体的转录物。例如,在人类中,miR-208是在α-MHC基因的第28内含子内编码的,而在小鼠中,它是在第29内含子内编码的。SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17中分别提供了人类、小鼠、大鼠、和犬的miR-208的pre-miRNA编码序列。SEQ ID NO:5中提供了成熟miR-208序列。像α-MHC一样,miR-208仅仅在心脏中表达(图1)。人pre-miR-208(SEQ ID NO:14)acgggcgagc ttttggcccg ggttatacct gatgctcacgtataagacga gcaaaaagct tgttggtcag a
小鼠pre-miR-208(SEQ ID NO:15)acgggtgagc ttttggcccg ggttatacct gactctcacgtataagacga gcaaaaagct tgttggtcag a
大鼠pre-miR-208(SEQ ID NO:16)acgggtgagc ttttggcccg ggttatacct gactctcacgtataagacga gcaaaaagct tgttggtcag a
犬pre-miR-208(SEQ ID NO:17)acgcatgagc ttttggctcg ggttatacct gatgctcacgtataagacga gcaaaaagct tgttggtcag a
使用用于鉴定miRNA靶物的PicTar算法(Krek等,2005),发明人鉴定出甲状腺激素受体相关蛋白质1(THRAP1)作为miR-208的预测靶物。SEQ IDNO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ IDNO:11、SEQ ID NO:12、和SEQ ID NO:13中分别提供了来自人类、黑猩猩、小鼠、大鼠、犬、鸡、河豚、和斑马鱼的THRAP1 3′UTR序列。
人THRAP1 3′UTR(SEQ ID NO:6)uucuugcuuu aaagcaauug gucuaaaauauauguaaucg ucuuaauuaa aaaguugcag uaggguugc
黑猩猩THRAP1 3′UTR(SEQ ID NO:7)uucuugcuuu aaagcaauug gucuaaaauauauguaaucg ucuuaauuaa aacguugcag uaggguugc
小鼠THRAP1 3′UTR(SEQ ID NO:8)uucuugcuuu aaagcaauug gucuaaaauauauguaaucg ucuuaauuaa aacguugcag uaggguugc
大鼠THRAP1 3′UTR(SEQ ID NO:9)uucuugcuuu aaagcaauug gucuaaaauauauguaaucg ucuuaauuaa aacguugcag uaggguugc
犬THRAP1 3′UTR(SEQ ID NO:10)uucuugcuuu aaagcaauug gucuaaaauauauguaaucg ucuuaauuaa aacguugcag uaggguugc
鸡THRAP1 3′UTR(SEQ ID NO:11)uucuugcuuu aaagcaauug gucuaaaauauauguaaucg ucuuaauuaa aacguugcag uaggguugc
河豚THRAP1 3′UTR(SEQ ID NO:12)uuccugcuuu aagcaauugg uugaaaauauauguauguaa uggucuuaau uaaaaaaaca aacuaagaca aa
斑马鱼THRAP1 3′UTR(SEQ ID NO:13)uuccugcuuu aaagcaauug gucuaaaauauauguaaucg ucuucauuac aaaaacgaac caucaaacg
本发明提供了在有所需要的受试者中治疗心脏纤维化、心脏肥大或心力衰竭的方法,包括鉴定具有心脏纤维化、心脏肥大或心力衰竭的受试者;并对所述受试者施用miR-29表达或功能的激动剂。所述miR-29激动剂可以是miR-29a、miR-29b和/或miR-29c的激动剂。
在一个实施方案中,miR-29a-c的激动剂可以是包含成熟miR-29a-c序列的多核苷酸。在一些实施方案中,所述多核苷酸包含序列SEQ ID NO:18、SEQ ID NO:19、或SEQ ID NO:20。在另一个实施方案中,所述miR-29a-c激动剂可以是包含miR-29a、miR-29b、和/或miR-29c之pri-miRNA或pre-miRNA序列的多核苷酸。所述包含成熟miR-29a-c、pre-miR-29a-c、或pri-miR-29a-c序列的多核苷酸可以是单链的或双链的。所述多核苷酸可含有一处或多处化学修饰,诸如锁定核酸、肽核酸、糖修饰(诸如2′-O-烃基(例如2′-O-甲基、2′-O-甲氧乙基)、2′-氟、和4′-硫修饰)、和主链修饰(诸如一个或多个硫代硫酸酯、吗啉代、或膦羧酸酯连接。在一个实施方案中,所述包含miR-29a-c序列的多核苷酸偶联有胆固醇。在另一个实施方案中,所述miR-29a-c激动剂可以是不同于miR-29a-c,起提高、补充、或代替miR-29a-c功能的作用的药剂。
在另一个实施方案中,可以在体内自载体表达所述miR-29a-c激动剂。“载体”指可用于将感兴趣核酸递送至细胞内部的物质组合物。本领域已知众多载体,包括但不限于线性多核苷酸、与离子的或两亲性的化合物有关的多核苷酸、质粒、和病毒。如此,术语“载体”包括自主复制的质粒或病毒。病毒载体的例子包括但不限于腺病毒载体、腺伴随病毒载体、逆转录病毒载体、等等。表达构建体能在活细胞中复制,或者它能合成制备。为了本申请,术语“表达构建体”、“表达载体”、和“载体”可互换使用,以一般性的、例示性的意义演示本发明的应用,而且并非意图限制本发明。
在一个实施方案中,用于表达miR-29a-c的表达载体包含与编码miR-29a、miR-29b、miR-29c、或其组合的多核苷酸“可操作连接”的启动子。在另一个实施方案中,所述多核苷酸可编码miR-29b-1/miR-29a簇。在另一个实施方案中,所述多核苷酸可编码miR-29b-2/miR-29c簇。如本文中所使用的,短语
“可操作连接”或“在转录控制下”意味着启动子相对于多核苷酸处于正确的定位和取向以控制RNA聚合酶进行的转录的和多核苷酸的表达的启动。编码miR-29a-c的多核苷酸可编码一级微小RNA-29a-c序列(pri-RNA-29a-c)、前体微小RNA-29a-c序列(pre-RNA-29a-c)或成熟RNA-29a-c序列。在另一个实施方案中,所述表达载体包含与启动子可操作连接的多核苷酸,其中所述多核苷酸包含序列SEQ ID NO:18。在另一个实施方案中,所述表达载体包含与启动子可操作连接的多核苷酸,其中所述多核苷酸包含序列SEQ ID NO:19。在还有一个实施方案中,所述表达载体包含与启动子可操作连接的多核苷酸,其中所述多核苷酸包含序列SEQ ID NO:20。所述包含序列SEQ ID NO:18、SEQ ID NO:19、或SEQID NO:20的多核苷酸可以是长约18个至约2000个核苷酸、长约70个至约200个核苷酸、长约20个核苷酸至约50个核苷酸、或长约18个核苷酸至约25个核苷酸。
贯穿本申请,术语“表达构建体”意图包括任何类型的遗传构建体,其包含编码基因产物的核酸,其中部分或整个核酸编码序列能够被转录。一般而言,编码基因产物的核酸在启动子的转录控制下。“启动子”指受到细胞的合成机械、或导入的合成机械识别,启动基因的特异性转录所需要的DNA序列。
术语启动子在本文中会用于指在RNA聚合酶的启动位点周围聚簇的一组转录控制模块。关于如何组织启动子的许多思考衍生自对数种病毒启动子的分析,包括HSV胸苷激酶(tk)和SV40早期转录单元的。这些研究(得到最近工作的扩充)显示了启动子是由离散功能模块构成的,其中每个模块由大约7-20bp DNA组成,且含有转录激活物或阻抑物蛋白质的一个或多个识别位点。
每种启动子中的至少一个模块发挥定位RNA合成起始位点的功能。这知道得最多的例子是TATA盒,但是在一些缺少TATA盒的启动子中,诸如哺乳动物末端脱氧核苷酸转移酶基因的启动子和SV40晚期基因的启动子,与起始位点自身交叠的一个离散元件有助于固定启动位置。
别的启动子元件调节转录起始的频率。典型的是,这些位于起始位点上游30-11Obp的区域中,尽管许多启动子最近显示出在起始位点下游也含有功能元件。各启动子元件间的间距通常是灵活的,使得当各元件彼此相对被倒置或移动时启动子功能得到保留。在tk启动子中,各启动子元件间的间距能增加至相距50bp,之后活性才开始下降。取决于启动子,各元件表现出能协同地或独立地发挥激活转录的功能。
在其它实施方案中,人巨细胞病毒(CMV)立即早期基因启动子、SV40早期启动子、劳氏肉瘤病毒长末端重复、大鼠胰岛素启动子、RNA pol III启动子、和甘油醛-3-磷酸脱氢酶启动子可用于获得感兴趣多核苷酸的高水平表达。还涵盖本领域公知的用于实现感兴趣多核苷酸表达的其它病毒或哺乳动物细胞或细菌噬菌体启动子的使用,只要表达水平对于给定目的是足够的。
通过采用具有公知特性的启动子,可优化转染或转化后感兴趣多核苷酸的表达水平和样式。另外,响应特定生理学信号而受到调节的启动子的选择能容许基因产物的诱导型表达。表1和表2列举了在本发明的背景中可采用来调节感兴趣基因表达的数种调节元件。此列表并非意图是穷尽提高基因表达所涉及的所有可能的元件,但是仅仅是它们的例示。
增强子是提高来自位于同一DNA分子上不同位置处的启动子的转录的遗传元件。增强子的组织与启动子很像。也就是说,它们由许多单独的元件构成,其中每个元件结合一种或多种转录蛋白。
增强子与启动子之间的基本区别是运作。增强子区作为整体必须能够刺激远处的转录;而启动子区或其构成元件不必如此。另一方面,启动子必须具有一种或多种指导特定位点处和特定取向的RNA合成启动的元件,而增强子缺少这些特异性。启动子和增强子常常是交叠的且毗邻的,常常表现出具有非常相似地模块组构。
下文是可以在表达构建体中与编码感兴趣基因的核酸组合使用的病毒启动子、细胞启动子/增强子和诱导型启动子/增强子的列表(表1和表2)。另外,也可以使用任何启动子/增强子组合(按照真核启动子数据库EPDB)来驱动所述基因的表达。如果提供适宜的细菌聚合酶(或是作为递送复合物的一部分或是作为另外的基因表达构建体)的话,真核细胞能支持来自某些细菌启动子的胞质转录。在一个优选的实施方案中,编码miR-29a-c或miR-29a-c拮抗剂的多核苷酸与成纤维细胞特异性启动子可操作连接。
在采用cDNA插入物的情况中,通常会希望包括聚腺苷酸化信号来实现基因转录物的正确聚腺苷酸化。认为聚腺苷酸化信号的本质对于本发明的成功实施不是至关重要的,而且可采用任何此类序列,诸如人生长激素和SV40聚腺苷酸化信号。作为表达盒元件还涵盖终止子。这些元件能用来增强信息水平和自该盒进入其它序列的通读最小化。
在本发明的某些实施方案中,含有本发明核酸构建体的细胞可以在体外或在体内通过在表达构建体中包括标志物来鉴定。此类标志物会赋予细胞以可鉴定的变化,容许容易地鉴定含有表达构建体的细胞。通常,包括药物选择标志物有助于克隆和选择转化体,例如赋予针对新霉素、嘌呤霉素、潮霉素、DHFR、GPT、zeocin和组氨醇的抗性的基因是有用的选择标志。或者,可采用酶,诸如单纯疱疹病毒胸苷激酶(tk)或氯霉素乙酰转移酶(CAT)。还能采用免疫学标志物。认为所采用的选择标志不是重要的,只要它能够与编码基因产物的核酸同时表达。选择标志的其它例子是本领域技术人员公知的。
有多种方式可将表达载体导入细胞中。在本发明的某些实施方案中,表达构建体包含病毒或自病毒基因组衍生的工程改造的构建体。某些病毒经受体介导的胞吞进入细胞、整合入宿主细胞基因组和稳定且高效表达病毒基因的能力使得它们成为将外来基因转移入哺乳动物细胞中的诱人候选(Ridgeway,1988;Nicolas和Rubinstein,1988;Baichwal和Sugden,1986;Temin,1986)。
用于体内递送的优选方法之一涉及使用腺病毒表达载体。“腺病毒表达载体”意图包括那些含有足以(a)支持构建体的包装和(b)表达其中克隆的多核苷酸的腺病毒序列的构建体。表达载体包含遗传工程形式的腺病毒。关于腺病毒(一种36kB,线性,双链DNA病毒)的遗传组构的知识容许用长达7kB的外来序列替代大段腺病毒DNA(Grunhaus和Horwitz,1992)。与逆转录病毒形成对比,宿主细胞的腺病毒感染不导致染色体整合,因为腺病毒DNA能以附加体方式复制,没有潜在的遗传毒性。而且,腺病毒在结构上是稳定的,而且广泛扩增后没有检测到基因组重排。腺病毒能感染实际上所有上皮细胞,不管它们的细胞周期阶段。
腺病毒特别适合于用作基因转移载体,因为它有中等大小的基因组、易于操作、滴度高、靶细胞范围广且感染性高。该病毒基因组的两个末端都含有100-200个碱基对的反向重复(ITR),它们是病毒DNA复制和包装所必需的顺式元件。
在腺病毒载体是复制缺陷的或至少条件性缺陷的要求之外,认为腺病毒载体的本质对于本发明的成功实施不是至关重要的。所述腺病毒可以是42种不同的已知血清型或亚群A-F中的任一种。为了获得供本发明中使用的条件性复制缺陷型腺病毒载体,亚群C的5型腺病毒是优选的起始材料。这是因为5型腺病毒是人腺病毒,关于它知道极多的生化和遗传信息,而且它在历史上用于大多数采用腺病毒作为载体的构建。
如上所述,依照本发明的典型载体是复制缺陷的,而且不会具有腺病毒E1区。如此,在消除E1编码序列的位置导入编码感兴趣基因的多核苷酸会是最方便的。然而,腺病毒序列内插入构建体的位置对于本发明不是至关重要的。也可以将编码感兴趣基因的多核苷酸插入E3置换型载体中,代替被删除的E3区,如Karlsson等(1986)所述,或者在E4区中,在这种情况中辅助细胞系或辅助病毒补足E4缺陷。
腺病毒载体已经用于真核基因表达(Levrero等,1991;Gomez-Foix等,1992)和疫苗开发(Grunhaus和Horwitz,1992;Graham和Prevec,1991)。最近,动物研究提示重组腺病毒可用于基因疗法(Stratford-Perricaudet和Perricaudet,1991;Stratford-Perricaudet等,1990;Rich等,1993)。对不同组织施用重组腺病毒的研究包括气管滴注(Rosenfeld等,1991;Rosenfeld等,1992)、肌肉注射(Ragot等,1993)、外周静脉内注射(Herz和Gerard,1993)和定向(stereotactic)接种入脑中(Le Gal La Salle等,1993)。
逆转录病毒载体也适合于在细胞中表达本发明的多核苷酸。逆转录病毒是以在受感染细胞中通过逆转录过程将它们的RNA转变成双链DNA的能力为特征的一组单链RNA病毒(Coffin,1990)。然后所得DNA稳定整合入细胞染色体中,作为原病毒,并指导病毒蛋白质的合成。所述整合导致病毒基因序列在受体细胞及其后代中的保持。逆转录病毒基因组含有分别编码壳体蛋白、聚合酶、和包膜成分的三种基因,即gag、pol、和env。在gag基因上游找到的一段序列含有将基因组包装入病毒体中的信号。在病毒基因组的5′和3′末端存在两段长末端重复(LTR)序列。这些含有强启动子和增强子序列,而且还是整合入宿主细胞基因组所需要的(Coffin,1990)。
为了构建逆转录病毒载体,将编码感兴趣基因的核酸插入病毒基因组中,代替某些病毒序到,以生成复制缺陷型病毒。为了生成病毒体,构建含有gag、pol、和env基因但没有LTR和包装构件的包装细胞系(Mann等,1983)。当含有cDNA以及逆转录病毒LTR和包装序列的重组质粒被导入此细胞系(例如通过磷酸钙沉淀)时,包装序列容许重组质粒的RNA转录物被包装入病毒颗粒中,然后分泌入培养物的培养基中(Nicolas和Rubenstein,1988;Temin,1986;Mann等,1983)。然后收集含有重组逆转录病毒的培养基,任选浓缩,并用于基因转移。逆转录病毒载体能够感染极其多种细胞类型。然而,整合和稳定表达要求宿主细胞分裂(Paskind等,1975)。
可采用其它病毒载体作为本发明中的表达构建体。可采用自诸如牛痘病毒(Ridgeway,1988;Baichwal和Sugden,1986;Coupar等,1988)、腺伴随病毒(AAV)(Ridgeway,1988;Baichwal和Sugden,1986;Hermonat和Muzycska,1984)和疱疹病毒等病毒衍生的载体。它们为各种哺乳动物细胞提供数项诱人特征(Friedmann,1989;Ridgeway,1988;Baichwal和Sugden,1986;Coupar等,1988;Horwich等,1990)。
为了实现有义或反义基因构建体的表达,必须将表达构建体递送入细胞中。此递送可以在体外(像用于转化细胞系的实验室规程中)或者在体内或回体(像某些疾病状态的治疗中)实现。一种递送机制是经病毒感染,其中将表达构建体包裹在感染性病毒颗粒的壳体中。
本发明还涵盖用于将表达构建体转移入培养的哺乳动物细胞中的数种非病毒方法。这些包括磷酸钙沉淀(Graham和Van Der Eb,1973;Chen和Okayama,1987;Rippe等,1990)、DEAE-右旋糖苷(Gopal,1985)、电穿孔、(Tur-Kaspa等,1986;Potter等,1984)、直接显微注射、(Harland和Weintraub,1985)、加载了DNA的脂质体(Nicolau and Sene,1982;Fraley等,1979)和Lipofectamine-DNA复合物、细胞超声处理(Fechheimer等,1987)、使用高速微弹进行的基因轰击(Yang等,1990)、和受体介导的转染(Wu和Wu,1987;Wu和Wu,1988)。这些技术中的一些可成功适应体内或回体使用。
一旦已经将表达构建体递送入细胞中,编码感兴趣基因的核酸可以在不同部位定位和表达。在某些实施方案中,编码基因的核酸可以稳定整合入细胞的基因组中。此整合可以经同源重组而处于相关定位和取向(基因替代),或者它可以以随机的、非特异性的位置整合(基因增强)。在还有一些实施方案中,核酸可以作为分开的、附加型的DNA区段在细胞中稳定维持。此类核酸区段“附加体”编码足以容许不依赖宿主细胞周期地或与宿主细胞周期同步地维持和复制的序列。如何将表达构建体递送至细胞和核酸在细胞中保持在何处取决于所采用的表达构建体的类型。
在本发明的还有一个实施方案中,表达构建体可以仅仅由裸的重组DNA或质粒组成。所述构建体的转移可以通过上文所述物理或化学透化细胞膜的任何方法来实施。这特别适用于体外转移,但是它也可应用于体内使用。Dubensky等(1984)成功地以磷酸钙沉淀物的形式将多瘤病毒DNA注射入成年和新生小鼠的肝和脾中,展现出活跃的病毒复制和急性感染。Benvenisty和Neshif(1986)也证明了直接腹膜内注射磷酸钙沉淀的质粒导致所转染基因的表达。也可以在体内以相似方式转移编码感兴趣基因的DNA并表达基因产物。
在本发明的还有一个实施方案中,将裸的DNA表达构建体转移入细胞中可涉及颗粒轰击。此方法依赖于将DNA包被的微弹加速至高速的能力,所述高速容许微弹穿透细胞膜并进入细胞,但不杀死它们(Klein等,1987)。已经开发了数种用于加速小颗粒的装置。一种这样的装置依赖于高压放电来产生电流,该电流继而提供原动力(Yang等,1990)。所使用的微弹由生物学惰性物质组成,诸如钨或金珠。
已经在体内轰击了大鼠和小鼠的选定器官,包括肝、皮肤、和肌肉组织(Yang等,1990;Zelenin等,1991)。这可能要求手术暴露组织或细胞,以消除枪与靶器官之间的任何居间组织,即回体处理。再次,编码特定基因的DNA可以经此方法递送,而且仍然收入本发明。
在本发明的又一个实施方案中,可以将表达构建体封装在脂质体中。脂质体是以磷脂双层膜和内部水介质为特征的囊泡结构。多层脂质体具有多个由水介质隔开的脂质层。它们在将磷脂悬浮在过量的水溶液中时自发形成。脂质成分在形成闭合的结构之前经历自我重排并在脂质双层间封装水和溶解的溶质(Ghosh和Bachhawat,1991)。还涵盖Lipofectamine-DNA复合物。
体外脂质体介导的核酸递送和外来DNA表达已经非常成功。Wong等,(1980)在培养的鸡胚、HeLa和肝瘤细胞中证明了脂质体介导的外来DNA递送和表达的可行性。Nicolau等,(1987)在大鼠中在静脉内注射后实现了成功的脂质体介导的基因转移。
在本发明的某些实施方案中,可以将脂质体与血细胞凝集病毒(HVJ)复合。这显示出促进与细胞膜的融和和提升脂质体封装的DNA进入细胞(Kaneda等,1989)。在其它实施方案中,可以将脂质体与细胞核中非组蛋白的染色体蛋白质(HMG-I)复合或联合采用(Kato等,1991)。在还有一些实施方案中,可以将脂质体与HVJ和HMG-I二者复合或联合采用。由于此类表达构建体已经成功用于体外和体内核酸转移和表达,所以它们适用于本发明。在DNA构建体中采用细菌启动子的情况中,还会希望在脂质体内包括适宜的细菌聚合酶。
其它能采用来将编码特定基因的核酸递送入细胞中的表达构建体是受体介导的递送媒介物。这些利用几乎在所有真核细胞中的受体介导的胞吞对高分子的选择性摄取。因为各种受体的细胞类型特异性分布,所以所述递送会是高度特异性的(Wu和Wu,1993)。
受体介导的基因靶向媒介物一般由两种成分组成:细胞受体特异性配体和DNA结合剂。数种配体已经用于受体介导的基因转移。最广泛表征的配体是脱唾液酸血清类粘蛋白(ASOR)(Wu和Wu,1987)和运铁蛋白(Wagner等,1990)。最近,一种合成的拟糖蛋白(neoglycoprotein)(其与ASOR识别相同受体)已经用作基因递送媒介物(Ferkol等,1993;Perales等,1994),而且表皮生长因子(EGF)也已经用于将基因递送至鳞癌细胞(Myers,EPO 0273085)。
在其它实施方案中,递送媒介物可包含配体和脂质体。例如,Nicolau等(1987)采用掺入脂质体中的乳糖基-神经酰胺(一种末端为半乳糖的脱唾液酸的神经节苷脂),并观察到肝细胞对胰岛素基因的摄取增加。如此,可行的是也可以通过多种受体-配体系统在有或无脂质体的情况中将编码特定基因的核酸特异性递送入某细胞类型中。例如,表皮生长因子(EGF)可用作受体,用于介导将核酸递送入展现出EGF受体上调的细胞中。甘露糖可用于靶向肝细胞上的甘露糖受体。而且,针对CD5(CLL)、CD22(淋巴瘤)、CD25(T细胞白血病)和MAA(黑素瘤)的抗体能类似地用作靶向模块。
在一个具体的例子中,可以与阳离子脂质组合地施用寡核苷酸。阳离子脂质的例子包括但不限于Lipofectin、DOTMA、DOPE、和DOTAP。WO/0071096(通过述及明确收入本文)的公开文本记载了不同配制剂,诸如能有效用于基因疗法的DOTAP:胆固醇或胆固醇衍生物配制剂。其它公开文本也讨论了不同脂质或脂质体配制剂,包括纳米颗粒和施用方法;这些包括但不限于美国专利公开文本20030203865,20020150626,20030032615,和20040048787,通过述及明确收入本文,其程度为它们公开了施用和递送核酸的配制剂和其它相关方面。用于形成颗粒的方法还记载于美国专利5,844,107,5,877,302,6,008,336,6,077,835,5,972,901,6,200,801,和5,972,900,那些方面通过述及而收入本文。
在某些实施方案中,可以在回体(ex vivo)条件下更容易地实施基因转移。回体基因疗法指自动物分离细胞,在体外将核酸递送入细胞中,然后将经修饰的细胞返还入动物中。这可涉及自动物手术取出组织/器官或细胞和组织的原代培养。
在本发明的一些实施方案中,希望抑制miR-29a-c的表达或活性以提高胶原沉积。例如,在一个实施方案中,本发明提供了诱导组织中的胶原沉积的方法,包括使所述组织接触miR-29a-c的拮抗剂。miR-29a-c功能的拮抗剂或抑制剂可以是针对miR-29a、miR-29b和/或miR-29c。
miRNA的功能可通过小RNA拮抗剂的施用来抑制。最初由Krutzfeldt及其同事(Krützfeldt等,2005)记载,“小RNA拮抗剂”指单链的、经化学修饰的、至少部分与miRNA序列互补的核糖核苷酸。小RNA拮抗剂会含有一个或多个经修饰的核苷酸,诸如2′-O-甲基-糖修饰。在一些实施方案中,小RNA拮抗剂仅包含经修饰的核苷酸。小RNA拮抗剂也可包含一个或多个硫代磷酸酯连接,导致部分或完全是硫代磷酸酯的主链。为了促进体内递送和稳定性,可以在其3′端将小RNA拮抗剂连接至胆固醇模块。适合于抑制miRNA的小RNA拮抗剂可以长约15个至约50个核苷酸,更优选长约18个至约30个核苷酸,且最优选长约20个至约25个核苷酸。“部分互补”指某序列与靶多核苷酸序列至少约75%、80%、85%、90%、95%、96%、97%、98%、或99%互补。小RNA拮抗剂可以与成熟miRNA序列至少约75%、80%、85%、90%、95%、96%、97%、98%、或99%互补。在一些实施方案中,小RNA拮抗剂可以与成熟miRNA序列基本上互补,也就是与靶多核苷酸序列至少约95%、96%、97%、98%、或99%互补。在其它实施方案中,小RNA拮抗剂与成熟miRNA序列100%互补。
在一个实施方案中,miR-29a-c拮抗剂是小RNA拮抗剂。小RNA拮抗剂可包含与miR-29a、miR-29b、或miR-29c的成熟miRNA序列至少部分互补的序列。在另一个实施方案中,小RNA拮抗剂包含与序列SEQ ID NO:18、SEQID NO:19、或SEQ ID NO:20至少部分互补的序列。在另一个实施方案中,小RNA拮抗剂包含与SEQ ID NO:18、SEQ ID No:19、或SEQ ID NO:20100%互补的序列。
对微小RNA功能的抑制也可以通过施用靶向成熟miR-29a、miR-29b、或miR-29c序列的反义寡核苷酸来实现。所述反义寡核苷酸可以是核糖核苷酸或脱氧核糖核苷酸。优选的是,所述反义寡核苷酸具有至少一处化学修饰。反义寡核苷酸可以包含一个或多个“锁定核酸(locked nucleic acid)”。“锁定核酸”(LNA)指经修饰核糖核苷酸,它在核糖糖模块的2′和4′碳之间含有额外桥接,导致赋予含有LNA的寡核苷酸以增强的热稳定性的“锁定”构象。或者,所述反义寡核苷酸可包含肽核酸(PNA),其含有基于肽的主链,而非糖-磷酸酯主链。反义寡核苷酸可含有的其它化学修饰包括但不限于糖修饰,诸如2′-O-烃基(alkyl)(例如2′-O-甲基、2′-O-甲氧乙基)、2′-氟、和4′-硫修饰,及主链修饰,诸如一个或多个硫代磷酸酯、吗啉代、或膦羧酸酯(phosphonocarboxylate)连接(参加例如美国专利No.6,693,187和7,067,641,通过述及而完整收入本文)。在一些实施方案中,合适的反义寡核苷酸是2′-O-甲氧乙基“缺口聚物”(gapmer),其在5′和3′端都含有2′-O-甲氧乙基修饰的核糖核苷酸,且中央有至少十个脱氧核糖核苷酸。这些“缺口聚物”能够触发RNA酶H依赖性的对RNA靶物的降解机制。增强稳定性和提高功效的对反义寡核苷酸的其它修饰(诸如美国专利No.6,838,283中记载的那些,通过述及而完整收入本文)是本领域已知的,而且适合于在本发明的方法中使用。对抑制微小RNA的活性有用的优选反义寡核苷酸长约19个至约25个核苷酸。反义寡核苷酸可包含至少部分与成熟miRNA序列互补的序列,例如与成熟miRNA序列至少约75%、80%、85%、90%、95%、96%、97%、98%、或99%互补。在一些实施方案中,所述反义寡核苷酸可以与成熟miRNA序列基本上互补,也就是与靶多核苷酸序列至少约95%、96%、97%、98%、或99%互补。在一个实施方案中,所述反义寡核苷酸包含与成熟miRNA序列100%互补的序列。
在本发明的另一个实施方案中,miR-29a-c拮抗剂是经化学修饰的反义寡核苷酸。所述经化学修饰的反义寡核苷酸可包含与miR-29a、miR-29b、或miR-29c的成熟miRNA序列至少部分互补的序列。在又一个实施方案中,所述经化学修饰的反义寡核苷酸包含与序列SEQ ID NO:18、SEQ ID NO:19、或SEQ ID NO:20至少部分互补的序列。在另一个实施方案中,所述经化学修饰的反义寡核苷酸包含与SEQ ID NO:18、SEQ ID NO:19、或SEQ ID NO:20 100%互补的序列。
反义寡核苷酸可包含与miR-29a-c的前体miRNA序列(pre-miRNA)基本上互补的序列。在一些实施方案中,所述反义寡核苷酸包含与位于pre-miR-29a、pre-miR-29b、或pre-miR-29c序列的茎环区以外的序列基本上互补的序列。
用于抑制miR-29a-c的功能的另一种办法是施用与成熟miR-29a、miR-29b和miR-29c序列具有至少部分序列同一性的抑制性RNA分子。所述抑制性RNA分子可以是双链小干扰RNA(siRNA)或包含茎环结构的短发夹RNA分子(shRNA)。所述抑制性RNA分子的双链区可包含与成熟miRNA序列至少部分相同,例如约75%、80%、85%、90%、95%、96%、97%、98%、或99%相同的序列。在一些实施方案中,所述抑制性RNA的双链区包含与成熟miRNA序列至少基本上相同的序列。“基本上相同”指某序列与靶多核苷酸序列至少约95%、96%、97%、98%、或99%相同。在其它实施方案中,所述抑制性RNA分子的双链区可以与靶miRNA序列100%相同。
在一个实施方案中,miR-29a-c的拮抗剂是包含双链区的抑制性RNA分子,其中所述双链区包含与成熟miR-29a(SEQ ID NO:18)、miR-29b(SEQ IDNO:19)、或miR-29c(SEQ ID NO:20)序列具有100%同一性的序列。在一些实施方案中,miR-29a-c的拮抗剂是包含双链区的抑制性RNA分子,其中所述双链区包含与成熟miR-29a、miR-29b、或miR-29c序列具有至少约75%、80%、85%、90%、95%、96%、97%、98%、或99%同一性的序列。
在另一个实施方案中,抑制性RNA分子可以是核酶。核酶指水解RNA分子之磷酸二酯键的催化性RNA。核酶可以设计成靶向miR-29a、miR-29b、和miR-29c中的一种或多种,导致它们的水解。
在某些实施方案中,采用表达载体来表达miR-29a-c的拮抗剂(例如小RNA拮抗剂、反义寡核苷酸、和抑制性RNA分子)。在一个实施方案中,用于表达miR-29a-c拮抗剂的表达载体包含与编码反义寡核苷酸的多核苷酸可操作连接的启动子,其中所表达的反义寡核苷酸的序列与成熟miR-29a、miR-29b、或miR-29c序列至少部分互补。在又一个实施方案中,用于表达miR-29a-c抑制剂的表达载体包含与编码shRNA或siRNA的多核苷酸可操作连接的一个或多个启动子,其中所表达的shRNA或siRNA包含与成熟miR-29a、miR-29b、或miR-29c序列相同、部分相同、或基本上相同的序列。“部分相同”指某序列与靶多核苷酸序列至少约75%、80%、85%、90%、95%、96%、97%、98%、或99%相同。“基本上相同”指某序列与靶多核苷酸序列至少约95%、96%、97%、98%、或99%相同。
心血管病症背景中的心脏肥大的当前医学管理包括使用至少两种类型的药物:肾素-血管紧张素系统的抑制剂,和β-肾上腺素能阻断剂(Bristow,1999)。用于治疗心力衰竭背景中的病理性肥大的治疗剂包括血管紧张素II转化酶(ACE)抑制剂和β-肾上腺素能受体阻断剂(Eichhom和Bristow,1996)。已经公开的用于治疗心脏肥大的其它药剂包括血管紧张素II受体拮抗剂(美国专利5,604,251)和神经肽Y拮抗剂(WO 98/33791)。不管当前可得的药用化合物,对心脏肥大和后续心力衰竭的预防和治疗继续呈现治疗考验。
非药理学治疗主要作为药理学治疗的辅助方法使用。非药理学治疗的一种手段涉及减少饮食中的钠。另外,非药理学治疗还需要消除某些沉淀性药物,包括负性肌力药(例如某些钙通道阻滞剂和抗心率不齐药像丙吡胺(disopyramide))、心脏毒素(例如安非他明(amphetamine)、和血容量扩充药(plasma volume expander)(例如非类固醇抗炎药和糖皮质激素)。
本发明提供了在有所需要的受试者中治疗心脏纤维化、心脏肥大或心力衰竭的方法,包括鉴定具有心脏纤维化、心脏肥大或心力衰竭的受试者;并对所述受试者施用miR-29表达或功能的激动剂。优选的是,miR-29激动剂的施用导致受试者中病理性心脏纤维化、肥大或心力衰竭的一种或多种症状的改善,或心脏肥大转变成心力衰竭延迟。所述一种或多种得到改善的症状可以是提高的运动能力、升高的心脏射血体积、降低的左心室舒张末期压、降低的肺毛细血管楔压、升高的心输出量或心指数、降低的肺动脉压、降低的左心室收缩和舒张末期内径、降低的心脏纤维化、降低的胶原在心脏肌肉中的沉积、降低的左和右心室壁压、降低的壁张力、提高的生命质量、和降低的疾病相关发病率或死亡率。另外,miR-29a-c激动剂的使用可直接或间接预防心脏肥大及其相关症状发生。
在另一个实施方案中,提供了在有所需要的受试者中预防病理性肥大或心力衰竭的方法,包括鉴定有风险发生病理性心脏肥大或心力衰竭的受试者;并提高所述受试者的心脏细胞中miR-29a-c的表达或活性。心脏细胞包括心脏肌细胞、成纤维细胞、平滑肌细胞、内皮细胞、和任何其它在正常情况中在心脏组织中找到的细胞类型。miR-29a-c激动剂可以是miR-29a、miR-29b和/或miR-29c的激动剂。有风险的受试者可展现出风险因素列表中的一种或多种,包括心脏纤维化、低miR-29表达、长期存在的不受控制的高血压、未矫正的瓣膜病、慢性心绞痛、近期的心肌梗死、对心脏病的先天性素因和/或病理性肥大、和/或可以诊断为具有对心脏肥大的遗传素因和/或可具有心脏肥大的家族史。
在另一个实施方案中,提供了在有所需要的受试者中治疗心肌梗死的方法,包括提高所述受试者心脏细胞中miR-29a-c的表达或活性。在另一个实施方案中,本发明提供了在有所需要的受试者中预防心脏肥大和扩张性心肌病的方法,包括提高所述受试者的心脏细胞中miR-29a-c的表达或活性。在另一个实施方案中,本发明提供了在有所需要的受试者中抑制心脏肥大进展的方法,包括提高所述受试者的心脏细胞中miR-29a-c的表达或活性。另一个实施方案是在具有心力衰竭或心脏肥大的受试者中提高运动耐量的方法,包括提高所述受试者的心脏细胞中miR-29a-c的表达或活性。另一个实施方案是在具有心力衰竭或心脏肥大的受试者中减少住院治疗的方法,包括提高所述受试者的心脏细胞中miR-29a-c的表达或活性。在一些实施方案中,本发明提供了在具有心力衰竭或心脏肥大的受试者中提高生命质量和降低发病率或死亡率的方法,包括提高所述受试者的心脏细胞中miR-29a-c的表达或活性。
治疗方案会随临床情形而变化。然而,长期维持在大多数情形中会是适宜的。可能还希望间歇地用miR-29a-c的激动剂治疗肥大,诸如在疾病进展期间的短暂窗口内。
另外,miR-29家族涉及对心脏纤维化的调节。由于此miR家族在成纤维细胞中与在肌细胞中相比更富集,因此有可能的是肌细胞分泌一种因子,可能是BNP,其上调成纤维细胞中的miR-29家族,并如此针对心脏纤维化的形成提供保护。此因子在miR-208KO小鼠中很高,与miR-29a-c的上调和纤维化的遏制有关联。miR-29a-c水平在普通心脏病中升高,这有可能是限制胶原沉积的一种保护效应。如此,涵盖miR-29a-c及其激动剂在遏制心脏纤维化和心脏组织中的胶原沉积中的具体用途。同样,激活miR-29家族的相应机制可应用于骨骼肌纤维化。miR-29a-c调节多种细胞外基质基因的表达,诸如微纤维蛋白1(FBN1)、胶原I型α1(COL1A1)、胶原I型α2(COL1A2)、和胶原III型α1(COL3A1)(见实施例4)。因而,本发明还提供了调节细胞中的一种或多种细胞外基质基因的方法。
在一个实施方案中,所述方法包括使细胞接触miR-29a-c的激动剂。在另一个实施方案中,所述方法包括使细胞接触miR-29a-c的拮抗剂。在还有一个实施方案中,所述一种或多种细胞外基质基因包括微纤维蛋白1(FBN1)、胶原I型α1(COL1A1)、胶原I型α2(COL1A2)、和胶原III型α1(COL3A1)。在一些实施方案中,所述一种或多种细胞外基质基因在细胞接触miR-29a-c拮抗剂后上调。在其它实施方案中,所述一种或多种细胞外基质基因在细胞接触miR-29a-c激动剂后下调。
发明人证明了miR-29a-c表达在暴露于TGFβ的心脏成纤维细胞中降低,提示心肌梗死后的miR-29a-c降低可能受TGFβ调节(实施例5)。有趣的是,利钠肽(像B型利钠肽(BNP))显示出抑制与纤维化和肌成纤维细胞转变有关的受TGFβ调节的基因表达(Kapoun等,2004)。在这点上,发明人先前报告了心脏特异性miRNA miR-208缺失的小鼠对心脏纤维化和重塑有抗性且在基线时展现出升高的BNP表达(van Rooij等,2007)。由于已知BNP拮抗TGFβ的效果,因此发明人提出这些小鼠中升高的BNP水平可能增强miR-29a-c的表达。确实,在消除miR-208后观察到miR-29a-c表达的剂量依赖性升高,与BNP表达水平升高一致(实施例5)。这些数据指示TGFβ诱导成纤维细胞中胶原相关基因的表达,这至少部分经由降低miR-29a-c水平来进行,而miR-29a-c能通过由心肌细胞分泌的BNP来抑制。如此,本发明提供了通过施用至少一种TGFβ抑制剂在受试者中提高miR-29a-c表达和/或活性的方法。TGFβ抑制剂可包括抑制TGFβ活性的抗TGFβ抗体、TGFβ反义分子、和小分子,如美国专利No.6,509,318中所记载的,通过述及完整收入本文。TGFβ抑制剂还可与miR-29a-c激动剂联合使用,作为组合疗法用于在受试者中治疗心脏纤维化、心脏肥大、或心力衰竭。TGFβ抑制剂还可与miR-29a-c激动剂共施用,用以在受试者中治疗或预防组织纤维化。
除了在控制心脏中的纤维化中发挥重要作用之外,miR-29家族的遍在表达提示它还可能在其它纤维变性适应症中发挥作用,诸如那些涉及肾、肝和肺的。还观察到糖尿病继发的纤维化。1型和2型糖尿病患者处于升高的心肌病风险。糖尿病中的心肌病与一簇特征有关,包括降低的舒张顺应(diastoliccompliance)、间质纤维化、和肌细胞肥大。
本发明还提供了在受试者治疗或预防组织纤维化的方法。在一个实施方案中,所述方法包括鉴定具有组织纤维化或有组织纤维化风险的受试者;并提高所述受试者的骨骼肌细胞或成纤维细胞中的miR-29a-c的表达和/或活性。在另一个实施方案中,所述组织纤维化是心脏纤维化、硬皮病(局限性的或系统性的)、骨骼肌纤维化、肝纤维化、肾纤维化、肺纤维化、或糖尿病纤维化。在一些实施方案中,提高miR-29a-c的表达和/或活性包括给所述受试者施用miR-29a-c的激动剂。在其它实施方案中,提高miR-29a-c的表达和/或活性包括给所述受试者施用编码miR-29a-c的表达载体。在另一个实施方案中,所述方法进一步包括给所述受试者施用非miR-29a-c纤维变性疗法。
本发明涵盖在有所需要的受试者中治疗与一种或多种疾患或病症有关的组织纤维化的方法。在一个实施方案中,所述方法包括给所述受试者施用miR-29a-c的激动剂。在另一个实施方案中,所述方法包括给所述受试者施用编码miR-29a-c的表达载体。所述与组织纤维化有关的一种或多种疾患或病症可包括但不限于先天性肝纤维化(CHF);肾小管间质性纤维化;与自身免疫性病症(例如类风湿性关节炎、狼疮和结节病)有关的肺纤维化;与糖尿病心肌病有关的间质纤维化;与肌肉营养不良(例如贝克肌营养不良和迪谢内肌营养不良)有关的骨骼肌纤维化、去神经萎缩、和神经肌肉疾病(例如急性多神经炎、脊髓灰质炎、Werdig/Hoffman病、肌萎缩侧索硬化、和进行性延髓萎缩疾病)。
本发明还涵盖治疗以胶原流失、缺失、或生成不足为特征的病理/缺陷的方法。使用miR-29a-c的拮抗剂,能提高胶原的表达用以在有需要的部位替换流失的胶原或补充现有的胶原。如此,本发明提供了诱导组织中的胶原沉积的方法,包括使所述组织接触miR-29a-c的拮抗剂。所述拮抗剂可以针对miR-29a、miR-29b和/或miR-29c。在一个实施方案中,所述拮抗剂包含与SEQID NO:18互补的序列。在另一个实施方案中,所述拮抗剂包含与SEQ ID NO:19互补的序列。在另一个实施方案中,所述拮抗剂包含与SEQ ID NO:20互补的序列。所述拮抗剂可以是miR-29a-c的小RNA拮抗剂、靶向成熟miR-29a-c序列的反义寡核苷酸、或包含与成熟miR-29a-c序列相同的序列的抑制性RNA分子(诸如siRNA或shRNA)、核酶或任何其它抑制性核酸。所述拮抗剂可以连接或偶联有促进所述拮抗剂进入细胞或组织的药剂。提高胶原沉积会是有益的且能通过施用miR-29a-c拮抗剂来治疗的各种疾患和病症包括但不限于埃勒斯-当洛综合征(EDS);维生素C缺乏病(也称作坏血病);皮肤老化(例如自然老化和由于晒伤的光老化);和拉伸纹(stretch mark)(细沟(striae))。
埃勒斯-当洛综合征(EDS)是一组由胶原合成缺陷引起的、影响人类和家畜的罕见遗传病症。根据个体突变,疾病的严重程度可以自轻度至危及生命而变化。ADAMTS2、COL1A1、COL1A2、COL3A1、COL5A1、COL5A2、PLOD1和TNXB基因中的突变引起EDS。这些基因中的突变通常改变胶原的或与胶原相互作用的蛋白质的结构、生成、或加工。胶原缺陷能削弱皮肤、骨骼、血管、和器官中的结缔组织,导致病症的特征。如此,由本发明的miR-29a-c拮抗剂诱导的胶原沉积会起补充EDS患者中的正常胶原水平和减轻疾病症状的作用。类似地,施用miR-29a-c的拮抗剂会有益于罹患维生素C缺乏病或坏血病的受试者。维生素C缺乏病是一种源自维生素C摄取不足的疾病,而维生素C是人类中正常胶原合成所需要的。
组织中源自miR-29a-c拮抗剂施用的胶原沉积还会在各种化妆品应用中有用。由自然老化过程或过度暴露于阳光所致光损伤产生的皮肤老化的效果能通过给有所需要的受试者施用miR-29a-c拮抗剂来降低。施用miR-29a-c拮抗剂还可促进拉伸纹的消失。拉伸纹是皮肤上由真皮撕裂引起的一种瘢痕形成形式。拉伸纹是与快速生长(青春期常见)或体重增加(例如妊娠)有关的皮肤快速拉伸的结果。
本发明的方法可应用的组织包括面部组织,诸如额组织、唇、颊、颏、眉、眼睑、眼下、或口附近、手组织、颈组织、臂组织、腿组织、胃组织或乳房组织。在一些实施方案中,所述组织可包含伤口、皮肤移植物、瘢痕组织、皱纹、皮肤松垂、晒伤、化学损伤、烫伤、冻伤、和/或拉伸纹。
在本发明的另一个实施方案中,使组织接触miR-29a-c拮抗剂包括注射入所述组织中、注射入供应所述组织的脉管系统中、或局部应用。局部应用可以是软膏剂、乳膏、凝胶、油膏剂、或香膏。在另一个实施方案中,所述方法进一步包括使用压迫绷带或裹覆物(dressing)。可以使miR-29a-c拮抗剂接触所述组织超过一次。在一些实施方案中,拮抗剂接触所述组织2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、60、70、80、90或100次。在其它实施方案中,拮抗剂接触所述组织超过2、3、4、5、或6天,1、2、3、或4周,1、2、3、4、5、6、7、8、9、10或11个月,或1、2、3、3、4、5、6、7、8、9、10、15、20、或25年。
在还有一个实施方案中,所述方法进一步包括使所述组织接触第二药剂。所述第二药剂可包括但不限于局部维生素A、局部维生素C、或维生素E。在另一个实施方案中,所述方法进一步包括对所述组织进行第二处理。所述第二处理可包括化学脱皮、激光处理、皮肤整平、或皮肤磨削术。在另一个实施方案中,所述组织在罹患埃勒斯-当洛综合征或维生素C缺乏病的受试者中。
本发明还涵盖miR-29a-c拮抗剂作为促纤维变性剂用于将脉管系统中的软斑转变成纤维变性组织以预防心肌梗死的用途。软斑是位于动脉壁的内皮衬里下面、主要含有胆固醇的脂质的构造。最近,认识到这些软斑倾向于破裂,导致血凝块的形成,其能潜在地阻断通过该动脉的血流并引起心脏病发作(即心肌梗死)。正是这些软斑常常负责引起没有症状的健康受试者遭受表面上出乎意料的心脏病发作。软斑破裂后,血管壁愈合而软斑变成硬斑,这罕见地引起进一步的问题。如此,使软斑转变成纤维变性组织的策略会预防软斑破裂且可能诱发的心肌梗死。
正如上文详细描述的,对miR-29a-c的抑制导致胶原沉积的和纤维变性组织形成的增加。因而,本发明提供了用于增加血管壁中的纤维变性组织形成的方法,包括将miR-29a-c的拮抗剂递送至血管壁中的一个或多个软斑部位,其中在递送所述miR-29a-c拮抗剂后,所述软斑转变成纤维变性组织。软斑可以通过本领域已知方法来鉴定,包括但不限于血管内超声和计算机断层照相术(Sahara等(2004)European Heart Journal,Vol.25:2026-2033;Budhoff(2006)J.Am.Coll.Cardiol,Vol.48:319-321;Hausleiter等(2006)J.Am.Coll.Cardiol,Vol.48:312-318)。本文所述任何miR-29a-c拮抗剂适合于在所述方法中使用。
可以通过直接注射或通过使用导管或分离冠状循环的装置将miR-29a-c拮抗剂递送至一个或多个软斑部位。在一个实施方案中,通过血管手术中使用的医学装置(诸如支架或球囊)将miR-29a-c拮抗剂递送至一个或多个软斑部位。可以将miR-29拮抗剂包被在金属支架上以形成药物洗脱支架。药物洗脱支架是保持变窄的或患病的动脉开放并释放化合物以预防细胞增殖和/或炎症的支架。可以将miR-29a-c拮抗剂应用至埋藏在薄聚合物中的金属支架以随时间释放miR-29a-c。用治疗性化合物包被支架的方法是本领域已知的。参加例如美国专利No.7,144,422;美国专利No.7,055,237;和WO 2004/004602,通过述及完整收入本文。在一些实施方案中,miR-29a-c可以与其它抗再狭窄化合物组合使用以生成用于掺入药物洗脱支架和球囊中的配制剂。适合与miR-29a-c拮抗剂组合使用的化合物包括但不限于帕利他塞(paclitaxel)、雷帕霉素(rapamycin)(西罗莫司(sirolimus))、他克莫司(tacrolimus)、唑他莫司(zotarolimus)、依维莫司(everolimus)、多西他塞(docetaxel)、吡美莫司(pimecrolimus)、及其衍生物。
本发明还涵盖用于在治疗后清除或消除miR-29a-c激动剂的方法。在一个实施方案中,所述方法包括使用成纤维细胞特异性启动子在成纤维细胞中过表达miR-29a-c的结合位点区。所述结合位点区优选含有miR-29a-c的种子区的序列。在一些实施方案中,所述结合位点可含有来自miR-29a-c的一种或多种靶物3′UTR的序列,诸如COL1A1、COL1A2、COL1A3和/或FBN1。在另一个实施方案中,可以在miR-29a-c激动剂之后施用miR-29a-c拮抗剂以削弱或终止微小RNA的功能。在另一个实施方案中,本发明提供了用于在治疗后清除或消除miR-29a-c拮抗剂的方法。所述方法可包括在施用了miR-29a-c拮抗剂的成纤维细胞或其它组织中过表达miR-20a-c拮抗剂的结合位点。
组合疗法
在另一个实施方案中,与其它用于治疗心脏肥大、心力衰竭和心肌梗死的治疗形态组合地使用miR-29a-c的激动剂。如此,还可以给受试者提供与miR-29a-c激动剂组合的更多“标准”制药学心脏疗法。其它疗法的例子包括但不限于所谓的“β-阻滞剂”、抗高血压药、强心药、抗血栓药、血管扩张药、激素拮抗剂、肌力药(iontrope)、利尿药、内皮缩血管肽受体拮抗剂、钙通道阻滞剂、磷酸二酯酶抑制剂、ACE抑制剂、血管紧张素2型拮抗剂和细胞因子阻滞剂/抑制剂、和HDAC抑制剂。
可以如下实现组合,即使心脏细胞接触包括miR-29a-c的激动剂和标准药剂的单一组合物或药理学配制剂,或者使细胞同时接触两种不同组合物或配制剂,其中一种组合物包括miR-29a-c的激动剂,而另一种包括标准药剂。或者,所述使用miR-29a-c激动剂的疗法可以在另一药剂的施用之前或之后,间隔范围为数分钟至数周。在分开对细胞应用标准药剂和miR-29a-c激动剂的实施方案中,一般会确保每次递送的时间之间没有经过显著的一段时间,使得所述药剂和miR-29a-c激动剂会仍然能够有利地对细胞发挥组合效应。在此类情况中,通常会使细胞在相距约12-24小时、更优选在相距约6-12小时内接触两种形态,延迟时间最优选只有约12小时。然而,在一些情况中,可能希望显著延长治疗时间段,其中各施用间经过数天(2、3、4、5、6或7)至数周(1、2、3、4、5、6、7或8)。
也想得到的是会希望超过一次地施用miR-29a-c激动剂、或另一药剂。在这点上,可以采用各种组合。举例而言,在miR-29a-c激动剂为“A”而另一药剂为“B”的情况中,下列基于总共3次和4次施用的排列是例示性的:
A/B/A B/A/B B/B/A A/A/B B/A/A A/B/B B/B/B/A B/B/A/B
A/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B B/B/B/A
A/A/A/B B/A/A/A A/B/A/A A/A/B/A A/B/B/B B/A/B/B B/B/A/B同样涵盖其它组合。
药理学治疗剂和施用方法、剂量、等是本领域技术人员公知的(参加例如《Physicians Desk Reference》、Klaassen的《The Pharmacological Basis ofTherapeutics》、《Remington′s Pharmaceutical Sciences》、和《The Merck Index》第11版,通过述及将相关部分收入本文),而且可以根据本文中的公开内容与本发明组合。取决于所治疗的受试者的状况,剂量必然会发生一些变化。在任何情况中负责施用的人会为各受试者决定适宜的剂量,而且此类个体决定在本领域普通技术人员的技术范围内。
可以在本发明中使用的药理学治疗剂的非限制性例子包括抗高脂蛋白药、抗动脉硬化药、抗血栓药/溶纤维蛋白药、凝血药、抗心率不齐药、抗高血压药、血管加压药、用于充血性心力衰竭的治疗剂、抗心绞痛药、抗菌剂或其组合。
另外,应当注意,可以使用任何下述各项来开发心脏疗法靶基因的新集合,正如本例中使用β-阻滞剂(见下文)。虽然预期这些基因中许多可能有交叠,但是有可能能开发出新的基因靶。
在某些实施方案中,可以将降低一种或多种血脂和/或脂蛋白的浓度的药剂(在本文中称作“抗高脂蛋白药”)的施用与依照本发明的心血管疗法组合,特别是在动脉粥样硬化和血管组织的增厚或阻断的治疗中。在某些实施方案中,抗高脂蛋白药可包含芳氧链烷酸/纤维酸衍生物、树脂/胆汁酸隐蔽剂(sequesterant)、HMG CoA还原酶抑制剂、烟酸衍生物、甲状腺激素或甲状腺激素类似物、混杂剂或其组合。
芳氧链烷酸/纤维酸衍生物的非限制性例子包括苄氯贝特(beclobrate)、enzafibrate、比尼贝特(binifibrate)、环丙贝特(ciprofibrate)、克利贝特(clinofibrate)、氯贝特(clofibrate)(安妥明(atromide)-S)、氯贝酸(clofibric acid)、依托贝特(etofibrate)、非诺贝特(fenofibrate)、吉非贝齐(gemfibrozil)(lobid)、尼可贝特(nicofibrate)、吡贝特(pirifibrate)、氯烟贝特(ronifibrate)、双贝特(simfibrate)和益多酯(theofibrate)。
树脂/胆汁酸隐蔽剂的非限制性例子包括考来烯胺(cholestyramine)(cholybar、questran)、考来替泊(colestipol)(colestid)和降胆葡胺(polidexide)。
HMG CoA还原酶抑制剂的非限制性例子包括洛伐他汀(lovastatin)(美降脂(mevacor))、普伐他汀(pravastatin)(pravochol)或辛伐他汀(simvastatin)(zocor)。
烟酸衍生物的非限制性例子包括烟酸、acepimox、戊四烟酯(niceritrol)、尼可氯酯(nicoclonate)、尼可莫尔(nicomol)和氧烟酸(oxiniacic acid)。
甲状腺激素及其类似物的非限制性例子包括etoroxate、甲状丙酸和甲状腺素。
混杂抗高脂蛋白药的非限制性例子包括阿昔呋喃(acifran)、阿扎胆醇(azacosterol)、苯氟雷司(benfluorex)、β-苄丁酰胺(β-benzalbutyramide)、卡尼汀(carnitine)、硫酸软骨素(chondroitin sulfate)、氯雌酮甲醚(clomestrone)、detaxtran、右旋糖苷硫酸钠(dextran sulfate sodium)、5,8,11,14,17-二十碳五烯酸、赤酮嘌啉(eritadenine)、夫拉扎勃(furazabol)、美格鲁托(meglutol)、甲亚油酰胺(melinamide)、双甲雌三醇(mytatrienediol)、鸟氨酸(ornithine)、γ-谷维素(γ-oryzanol)、泛硫乙胺(pantethine)、四乙酸季戊四醇酯(pentaerythritoltetraacetate)、α-苯基丁酰胺(α-phenylbutyramide)、吡扎地尔(pirozadil)、普罗布考(probucol)(lorelco)、β-谷甾醇(β-sitosterol)、磺托酸-哌嗪盐(sultosilicacid-piperazine salt)、硫地醇(tiadenol)、曲帕拉醇(triparanol)和联苯丁酸(xenbucin)。抗动脉硬化药的非限制性例子包括氨基甲酸吡啶酚酯(pyridinolcarbamate)。
在某些实施方案中,可以将有助于消除或预防血液凝块的药剂的施用与调控物的施用组合,特别是在动脉粥样硬化和脉管系统(例如动脉)阻断的治疗中。抗血栓药和/或溶纤维蛋白药的非限制性例子包括抗凝血药、抗凝血药拮抗剂、抗血小板药、溶血栓药、溶血栓药拮抗剂或其组合。
在某些实施方案中,优选口服施用的抗血栓药,诸如例如阿司匹林(aspirin)和华法林(wafarin)(Coumadin)。
抗凝血药的非限制性例子包括醋硝香豆素(acenocoumarol)、安克洛酶(ancrod)、茴茚二酮(anisindione)、溴茚二酮(bromindione)、氯茚二酮(clorindione)、库美香豆素(coumetarol)、环香豆素(cyclocumarol)、右旋糖苷硫酸钠(dextran sulfate sodium)、双香豆素(dicumarol)、二苯茚酮(diphenadione)、双香豆素乙酯(ethyl biscoumacetate)、乙撑双香豆素(ethylidenedicoumarol)、氟茚二酮(fluindione)、肝素(heparin)、水蛭素(hirudin)、阿朴酸钠(lyapolate sodium)、奥沙二酮(oxazidione)、戊聚糖多硫酸(pentosanpolysulfate)、苯茚二酮(phenindione)、苯丙香豆醇(phenprocoumon)、卵黄高磷蛋白(phosvitin)、吡考他胺(picotamide)、噻氯香豆素(tioclomarol)和华法林(warfarin)。
抗血小板药的非限制性例子包括阿司匹林(aspirin)、右旋糖苷(dextran)、双嘧达莫(dipyridamole)(潘生丁(persantin))、肝素(heparin)、磺吡酮(sulfmpyranone)(安特灵(anturane))和噻氯匹定(ticlopidine)(力抗栓(ticlid))。
溶血栓药的非限制性例子包括组织纤溶酶原激活物(activase)、纤溶酶、尿激酶原、尿激酶(abbokinase)链激酶(streptase)、阿尼普酶(anistreplase)/APSAC(依米那酶(eminase))。
在其中受试者罹患出血或出血可能性升高的某些实施方案中,可以使用可增强血液凝结的药剂。血液凝结促进剂的非限制性例子包括溶血栓药拮抗剂和抗凝血药拮抗剂。
抗凝血药拮抗剂的非限制性例子包括精蛋白(protamine)和维生素K1。
溶血栓药拮抗剂的非限制性例子包括氨基己酸(amiocaproic acid)(amicar)和氨甲环酸(tranexamic acid)(amstat)。抗血栓药的非限制性例子包括阿那格雷(anagrelide)、阿加曲班(argatroban)、西鲁唑啉(cilstazol)、达曲班(daltroban)、去纤苷(defibrotide)、依诺肝素(enoxaparin)、速避凝(fraxiparine)、吲哚布芬(indobufen)、lamoparan、奥扎格雷(ozagrel)、吡考他胺(picotamide)、普拉贝脲(plafibride)、替地肝素(tedelparin)、噻氯匹定(ticlopidine)和三氟柳(triflusal)。
抗心率不齐药的非限制性例子包括I类抗心率不齐药(钠通道阻滞剂)、II类抗心率不齐药(β-肾上腺素能阻滞剂)、III类抗心率不齐药(复极化延长药)、IV类抗心率不齐药(钙通道阻滞剂)和混杂型抗心率不齐药。
钠通道阻滞剂的非限制性例子包括IA类、IB类和IC类抗心率不齐药。IA类抗心率不齐药的非限制性例子包括丙吡胺(disppyramide)(norpace)、普鲁卡因胺(procainamide)(pronestyl)和奎尼丁(quinidine)(quinidex)。IB类抗心率不齐药的非限制性例子包括利多卡因(lidocaine)(xylocaine)、妥卡尼(tocainide)(tonocard)和美西律(mexiletine)(mexitil)。IC类抗心率不齐药的非限制性例子包括恩卡尼(encainide)(enkaid)和氟卡尼(flecainide)(tambocor)。
β-阻滞剂(也称作β-肾上腺素能阻滞剂、β-肾上腺素能拮抗剂或II类抗心率不齐药)的非限制性例子包括醋丁洛尔(acebutolol)(sectral)、阿普洛尔(alprenolol)、氨磺洛尔(amosulalol)、阿罗洛尔(arotinolol)、阿替洛尔(atenolol)、苯呋洛尔(befunolol)、倍他洛尔(betaxolol)、贝凡洛尔(bevantolol)、比索洛尔(bisoprolol)、波吲洛尔(bopindolol)、布库洛尔(bucumolol)、布非洛尔(bufetolol)、丁呋洛尔(bufuralol)、布尼洛尔(bunitrolol)、布拉洛尔(bupranolol)、盐酸布替君(butidrine hydrochloride)、丁非洛尔(butofilolol)、卡拉洛尔(carazolol)、卡替洛尔(carteolol)、卡维地洛(carvedilol)、塞利洛尔(celiprolol)、塞他洛尔(cetamolol)、氯拉洛尔(cloranolol)、地来洛尔(dilevalol)、依泮洛尔(epanolol)、艾司洛尔(esmolol)(brevibloc)、茚诺洛尔(indenolol)、拉贝洛尔(labetalol)、左布诺洛尔(levobunolol)、甲吲洛尔(mepindolol)、美替洛尔(metipranolol)、美托洛尔(metoprolol)、莫普洛尔(moprolol)、纳多洛尔(nadolol)、萘肟洛尔(nadoxolol)、硝苯洛尔(nifenalol)、尼普地洛(nipradilol)、氧烯洛尔(oxprenolol)、喷布洛尔(penbutolol)、吲哚洛尔(pindolol)、普拉洛尔(practolol)、丙萘洛尔(pronethalol)、普萘洛尔(propanolol)(inderal)、索他洛尔(sotalol)(betapace)、硫氧洛尔(sulfinalol)、他林洛尔(talinolol)、特他洛尔(tertatolol)、噻吗洛尔(timolol)、托利洛尔(toliprolol)和希波酚(xibinolol)。在某些实施方案中,β-阻滞剂包含芳氧丙醇胺衍生物。芳氧丙醇胺衍生物的非限制性例子包括醋丁洛尔(acebutolol)、阿普洛尔(alprenolol)、阿罗洛尔(arotinolol)、阿替洛尔(atenolol)、倍他洛尔(betaxolol)、贝凡洛尔(bevantolol)、比索洛尔(bisoprolol)、波吲洛尔(bopindolol)、布尼洛尔(bunitrolol)、丁非洛尔(butofilolol)、卡拉洛尔(carazolol)、卡替洛尔(carteolol)、卡维地洛(carvedilol)、塞利洛尔(celiprolol)、塞他洛尔(cetamolol)、依泮洛尔(epanolol)、茚诺洛尔(indenolol)、甲吲洛尔(mepindolol)、美替洛尔(metipranolol)、美托洛尔(metoprolol)、莫普洛尔(moprolol)、纳多洛尔(nadolol)、尼普地洛(nipradilol)、氧烯洛尔(oxprenolol)、喷布洛尔(penbutolol)、吲哚洛尔(pindolol)、普萘洛尔(propanolol)、他林洛尔(talinolol)、特他洛尔(tertatolol)、噻吗洛尔(timolol)和托利洛尔(toliprolol)。
延长复极化的药剂(也称作III类抗心率不齐药)的非限制性例子包括胺碘酮(amiodarone)(可达龙(cordarone))和索他洛尔(sotalol)(betapace)。
钙通道阻滞剂(也称作IV类抗心率不齐药)的非限制性例子包括芳基烃基胺(例如bepridile、地尔硫卓(diltiazem)、芬地林(fendiline)、戈洛帕米(gallopamil)、普尼拉明(prenylamine)、特罗地林(terodiline)、维拉帕米(verapamil))、二氢吡啶衍生物(非洛地平(felodipine)、伊拉地平(isradipine)、尼卡地平(nicardipine)、硝苯地平(nifedipine)、尼莫地平(nimodipine)、尼索地平(nisoldipine)、尼群地平(nitrendipine))、哌嗪衍生物(例如桂利嗪(cinnarizine)、氟桂利嗪(flunarizine)、利多氟嗪(lidoflazine))或混杂型钙通道阻滞剂(诸如苄环烷(bencyclane)、依他苯酮(etafenone)、镁(magnesium)、米贝拉地尔(mibefradil)或哌克昔林(perhexiline))。在某些实施方案中,钙通道阻滞剂包含长效二氢吡啶(硝苯地平型)钙拮抗剂。
混杂型抗心率不齐药的非限制性例子包括阿糖腺苷(adenosine)(adenocard)、地高辛(digoxin)(拉诺辛(lanoxin))、乙酰卡尼(acecainide)、阿义马林(ajmaline)、克冠吗啉(amoproxan)、阿普林定(aprindine)、甲苯磺酸溴苄胺(bretylium tosylate)、丁萘夫汀(bunaftine)、布托苯定(butobendine)、卡泊酸(capobenic acid)、西苯唑啉(cifenline)、吡二丙胺(disopyranide)、二氢奎尼丁(hydroquinidine)、英地卡尼(indecainide)、异丙托溴胺(ipatropium bromide)、利多卡因(lidocaine)、劳拉义明(lorajmine)、劳卡尼(lorcainide)、甲氧苯汀(meobentine)、莫雷西嗪(moricizine)、吡美诺(pirmenol)、丙缓脉灵(prajmaline)、普罗帕酮(propafenone)、吡诺林(pyrinoline)、聚半乳糖醛酸奎尼丁(quinidinepolygalacturonate)、硫酸奎尼丁(quinidine sulfae)和维喹地尔(viquidil)。
抗高血压药的非限制性例子包括抗交感神经药、α/β阻滞剂、α阻滞剂、抗血管紧张素II药、β阻滞剂、钙通道阻滞剂、血管扩张药和混杂型抗高血压药。
α阻滞剂(也称作α-肾上腺素能阻滞剂或α-肾上腺素能拮抗剂)的非限制性例子包括氨磺洛尔(amosulalol)、阿罗洛尔(arotinolol)、达哌唑(dapiprazole)、多沙唑嗪(doxazosin)、甲磺酸双氢麦角碱(ergoloid mesylate)、芬司匹利(fenspiride)、吲哚拉明(indoramin)、拉贝洛尔(labetalol)、麦角溴烟酯(nicergoline)、哌唑嗪(prazosin)、特拉唑嗪(terazosin)、妥拉唑林(tolazoline)、曲马唑嗪(trimazosin)和育亨宾(yohimbine)。在某些实施方案中,α阻滞剂可以包含喹唑啉衍生物。喹唑啉衍生物的非限制性例子包括阿夫唑嗪(alfuzosin)、布那唑嗪(bunazosin)、多沙唑嗪(doxazosin)、哌唑嗪(prazosin)、特拉唑嗪(terazosin)和曲马唑嗪(trimazosin)。
在某些实施方案中,抗高血压药既是α肾上腺素能拮抗剂又是β肾上腺素能拮抗剂。α/β阻滞剂的非限制性例子包含拉贝洛尔(labetalol)(normodyne、trandate)。
抗血管紧张素II药的非限制性例子包括血管紧张素转化酶抑制剂和血管紧张素II受体拮抗剂。血管紧张素转化酶抑制剂(ACE抑制剂)的非限制性例子包括阿拉普利(alacepril)、依那普利(enalapril)(vasotec)、卡托普利(captopril)、西拉普利(cilazapril)、地拉普利(delapril)、依那普拉利(enalaprilat)、福辛普利(fosinopril)、赖诺普利(lisinopril)、moveltopril、培哚普利(perindopril)、喹那普利(quinapril)和雷米普利(ramipril)。血管紧张素II受体阻滞剂(也称作血管紧张素II受体拮抗剂、ANG受体阻滞剂或ANG-II 1型受体阻滞剂(ARBS))的非限制性例子包括血管坎地沙坦(angiocandesartan)、依普罗沙坦(eprosartan)、厄贝沙坦(irbesartan)、氯沙坦(losartan)和缬沙坦(valsartan)。
抗交感神经药的非限制性例子包括作用于中枢的抗交感神经药或作用于周围的抗交感神经药。作用于中枢的抗交感神经药(也称作中枢神经系统(CNS)抗交感神经药)的非限制性例子包括可乐定(clonidine)(catapres)、胍那苄(guanabenz)(wytensin)胍法辛(guanfacine)(tenex)和甲基多巴(methyldopa)(aldomet)。作用于周围的抗交感神经药的非限制性例子包括神经节阻断剂、肾上腺素能神经元阻断剂、β-肾上腺素能阻断剂或α1-肾上腺素能阻断剂。神经节阻断剂的非限制性例子包括美卡拉明(mecamylamine)(inversine)和曲美芬(trimethaphan)(arfonad)。肾上腺素能神经元阻断剂的非限制性例子包括胍乙啶(guanethidine)(ismelin)和利舍平(reserpine)(serpasil)。β-肾上腺素能阻滞剂的非限制性例子包括醋丁洛尔(acenitolol)(sectral)、阿替洛尔(atenolol)(天诺敏(tenormin))、倍他洛尔(betaxolol)(卡尔仑(kerlone))、卡替洛尔(carteolol)(cartrol)、拉贝洛尔(labetalol)(normodyne、trandate)、美托洛尔(metoprolol)(lopressor)、纳多洛尔(nadanol)(corgard)、喷布洛尔(penbutolol)(levatol)、吲哚洛尔(pindolol)(心得静(visken))、普萘洛尔(propranolol)(心得安(inderal))和噻吗洛尔(timolol)(blocadren)。α1-肾上腺素能阻滞剂的非限制性例子包括哌唑嗪(prazosin)(脉宁平(minipress))、多沙唑嗪(doxazocin)(卡杜雷(cardura))和特拉唑嗪(terazosin)(高特灵(hytrin))。
在某些实施方案中,心血管治疗剂可以包含血管扩张药(例如脑血管扩张药、冠状动脉血管扩张药或外周血管扩张药)。在某些优选的实施方案中,血管扩张药包含冠状动脉血管扩张药。冠状动脉血管扩张药的非限制性例子包括胺氧三苯(amotriphene)、地巴唑(bendazol)、半琥珀酸琥珀呋酮(benfurodilhemisuccinate)、苯碘达隆(benziodarone)、氯酚嗪(chloracizine)、乙胺香豆素(chromonar)、氯苯呋醇(clobenfurol)、氯硝甘油(clonitrate)、地拉卓(dilazep)、双嘧达莫(dipyridamole)、氢普拉明(droprenilamine)、乙氧黄酮(efloxate)、戊四硝酯(erythrityl tetranitrane)、依他苯酮(etafenone)、芬地林(fendiline)、夫洛地尔(floredil)、更利芬(ganglefene)、己烷雌酚二(β-二乙基氨基乙基醚)(herestrol bis(β-diethylaminoethyl ether))、海索苯定(hexobendine)、甲苯磺酸硝乙醇胺(itramin tosylate)、凯林(khellin)、利多氟嗪(lidoflanine)、六硝酸甘露醇酯(mannitol hexanitrane)、美地巴嗪(medibazine)、nicorglycerin、四硝酸季戊四醇酯(pentaerythritol tetranitrate)、戊硝醇(pentrinitrol)、哌克昔林(perhexiline)、匹美茶碱(pimefylline)、曲匹地尔(trapidil)、3-甲色酮(tricromyl)、曲美他嗪(trimetazidine)、磷酸三乙硝胺(trolnitrate phosphate)和维斯那定(visnadine)。
在某些实施方案中,血管扩张药可包含长期疗法血管扩张药或高血压突发血管扩张药。长期疗法血管扩张药的非限制性例子包括肼屈嗪(hydralazine)(apresoline)和米诺地尔(minoxidil)(loniten)。高血压突发血管扩张药的非限制性例子包括硝普盐(nitroprusside)(nipride)、二氮嗪(diazoxide)(hyperstat IV)、肼屈嗪(hydralazine)(apresoline)、米诺地尔(minoxidil)(loniten)和维拉帕米(verapamil)。
混杂型抗高血压药的非限制性例子包括阿义马林(ajmaline)、γ-氨基丁酸(γ-aminobutyric acid)、丁苯碘氨(bufeniode)、西氯他宁(cicletainine)、环西多明(ciclosidomine)、鞣酸绿藜胺(cryptenamine tannate)、非诺多泮(fenoldopam)、氟司喹南(flosequinan)、酮色林(ketanserin)、美布氨酯(mebutamate)、美卡拉明(mecamylamine)、甲基多巴(methyldopa)、甲基4-吡啶基酮氨硫脲(methyl4-pyridyl ketone thiosemicarbazone)、莫唑胺(muzolimine)、帕吉林(pargyline)、潘必啶(pempidine)、吡那地尔(pinacidil)、哌罗克生(piperoxan)、普立哌隆(primaperone)、原藜芦碱(protoveratrine)、罗巴新(raubasine)、瑞西美托(rescimetol)、利美尼定(rilmenidene)、沙拉新(saralasin)、硝普钠(sodiumnitrorusside)、替尼酸(ticrynafen)、樟脑磺酸曲美芬(trimethaphan camsylate)、酪氨酸酶(tyrosinase)和乌拉地尔(urapidil)。
在某些实施方案中,抗高血压药可包含芳基乙醇胺衍生物、苯并噻二嗪衍生物、N-羧基烃基(肽/内酰胺)衍生物、二氢吡啶衍生物、胍衍生物、肼/酞嗪、咪唑衍生物、季铵化合物、利舍平衍生物或磺磷酰胺衍生物。
芳基乙醇胺的非限制性例子包括氨磺洛尔(amosulalol)、丁呋洛尔(bufuralol)、地来洛尔(dilevalol)、拉贝洛尔(labetalol)、丙萘洛尔(pronethalol)、索他洛尔(sotalol)和硫氧洛尔(sulfinalol)。
苯并噻二嗪衍生物的非限制性例子包括阿尔噻嗪(althizide)、苄氟噻嗪(bendroflumethiazide)、苄噻嗪(benzthiazide)、苄氢氯噻嗪(benzylhydrochlorothiazide)、布噻嗪(buthiazide)、氯噻嗪(chlorothiazide)、氯噻酮(chlorthalidone)、环戊噻嗪(cyclopenthiazide)、环噻嗪(cyclothiazide)、二氮嗪(diazoxide)、依匹噻嗪(epithiazide)、乙噻嗪(ethiazide)、芬噻嗪(fenquizone)、氢氯噻嗪(hydrochlorothizide)、氢氟噻嗪(hydroflumethizide)、甲氯噻嗪(methyclothiazide)、美替克仑(meticrane)、美托拉宗(metolazone)、对氟噻嗪(paraflutizide)、泊利噻嗪(polythizide)、四氯噻嗪(tetrachlormethiazide)和三氯噻嗪(trichlormethiazide)。
N-羧基烃基(肽/内酰胺)衍生物的非限制性例子包括阿拉普利(alacepril)、卡托普利(captopril)、西拉普利(cilazapril)、地拉普利(delapril)、依那普利(enalapril)、依那普利拉(enalaprilat)、福辛普利(fosinopril)、赖诺普利(lisinopril)、莫维普利(moveltipril)、培哚普利(perindopril)、喹那普利(quinapril)和雷米普利(ramipril)。
二氢吡啶衍生物的非限制性例子包括氨氯地平(amlodipine)、非洛地平(felodipine)、伊拉地平(isradipine)、尼卡地平(nicardipine)、硝苯地平(nifedipine)、尼伐地平(nilvadipine)、尼索地平(nisoldipine)和尼群地平(nitrendipine)。
胍衍生物的非限制性例子包括倍他尼定(bethanidine)、异喹胍(debrisoquin)、胍那苄(guanabenz)、胍那克林(guanacline)、胍那决尔(guanadrel)、胍那佐定(guanazodine)、胍乙啶(guanethidine)、胍法辛(guanfacine)、胍氯酚(guanochlor)、胍诺沙苄(guanoxabenz)和胍生(guanoxan)。
肼/酞嗪的非限制性例子包括布屈嗪(budralazine)、卡屈嗪(cadralazine)、双肼屈嗪(dihydralazine)、恩屈嗪(endralazine)、肼卡巴嗪(hydracarbazine)、肼屈嗪(hydralazine)、苯异丙肼(pheniprazine)、匹尔屈嗪(pildralazine)和托屈嗪(todralazine)。
咪唑衍生物的非限制性例子包括可乐定(clonidine)、洛非西定(lofexidine)、酚妥拉明(phentolamine)、噻美尼定(tiamenidine)和托洛尼定(tolonidine)。
季铵化合物的非限制性例子包括溴化氮戊铵(azamethonium bromide)、松达氯铵(chlorisondamine chloride)、六甲季铵(hexamethonium)、二甲硫酸氰戊吗啉(pentacynium bis(methylsulfate))、五甲溴铵(pentamethonium bromide)、酒石酸喷托铵(pentolinium tartrate)、芬托氯铵(phenactropinium chloride)和甲硫曲美替定(trimethidinium methosulfate)。
利舍平衍生物的非限制性例子包括比他舍平(bietaserpine)、地舍平(deserpidine)、瑞西那明(rescinnamine)、利舍平(reserpine)和昔洛舍平(syrosingopine)。
磺胺衍生物的非限制性例子包括安布赛特(ambuside)、氯帕胺(clopamide)、呋塞米(furosemide)、吲达帕胺(indapamide)、喹乙宗(quinethazone)、曲帕胺(tripamide)和希帕胺(xipamide)。
血管加压药一般用来在手术期间可能发生的休克期间提高血压。血管加压药(也称作抗低血压药)的非限制性例子包括氨甲氧苯嗪甲基硫酸盐(amezinium methyl sulfate)、血管紧张素酰胺(angiotensin amide)、二甲福林(dimetofrine)、多巴胺(dopamine)、依替非明(etifelmin)、依替福林(etilefrin)、吉培福林(gepefrine)、间羟胺(metaraminol)、米多君(midodrine)、去甲肾上腺素(norepinephrine)、福来君(pholedrine)和昔奈福林(synephrine)。
用于治疗充血性心力衰竭的药剂的非限制性例子包括抗血管紧张素II药、后负荷-前负荷减轻处理(afterload-preload reduction treatment)、利尿药和肌力药(inotropic agent)。
在某些实施方案中,可以用组合疗法来治疗不能耐受血管紧张素拮抗剂的动物受试者。此类疗法可组合肼屈嗪(hydralazine)(阿比西林(apresoline))和二硝酸异山梨醇(isosorbide dinitrate)(isordil、sorbitrate)的施用。
利尿药的非限制性例子包括噻嗪或苯并噻二嗪衍生物(例如阿尔噻嗪(althiazide)、苄氟噻嗪(bendroflumethazide)、苄噻嗪(benzthiazide)、苄氢氯噻嗪(benzylhydrochlorothiazide)、布噻嗪(buthiazide)、氯噻嗪(chlorothiazide)、氯噻嗪(chlorothiazide)、氯噻酮(chlorthalidone)、环戊噻嗪(cyclopenthiazide)、依匹噻嗪(epithiazide)、乙噻嗪(ethiazide)、乙噻嗪(ethiazide)、芬喹唑(fenquizone)、氢氯噻嗪(hydrochlorothiazide)、氢氟噻嗪(hydroflumethiazide)、甲氯噻嗪(methyclothiazide)、美替克仑(meticrane)、美托拉宗(metolazone)、对氟噻嗪(paraflutizide)、泊利噻嗪(polythizide)、四氯噻嗪(tetrachloromethiazide)、三氯噻嗪(trichlormethiazide))、有机汞(例如氯汞君(chlormerodrin)、美拉鲁利(meralluride)、汞罗茶碱(mercamphamide)、硫汞林钠(mercaptomerin sodium)、汞香豆酸(mercumallylic acid)、汞香豆林钠(mercumatilin dodium)、氯化亚汞(mercurous chloride)、汞撒利(mersalyl))、蝶啶(例如呋氨蝶啶(furterene)、氨苯蝶啶(triamterene))、嘌呤(例如acefylline、7-吗啉甲茶碱(7-morpholinomethyltheophylline)、pamobrom、丙可可碱(protheobromine)、可可碱(theobromine))、类固醇包括醛甾酮拮抗剂(例如坎利酮(canrenone)、夹竹桃苷(oleandrin)、螺内酯(spironolactone))、磺胺衍生物(例如乙酰唑胺(acetazolamide)、安布赛特(ambuside)、阿佐塞米(azosemide)、布美他尼(bumetanide)、布他唑胺(butazolamide)、氯米非那胺(chloraminophenamide)、氯非那胺(clofenamide)、氯帕胺(clopamide)、氯索隆(clorexolone)、二苯甲烷-4,4′-二磺胺(diphenylmethane-4,4′-disulfonamide)、二磺法胺(disulfamide)、依索唑胺(ethoxzolamide)、呋塞米(furosemide)、吲达帕胺(indapamide)、美夫西特(mefruside)、醋甲唑胺(methazolamide)、吡咯他尼(piretanide)、喹乙宗(quinethazone)、托拉塞米(torasemide)、曲帕胺(tripamide)、希帕胺(xipamide))、尿嘧啶(例如氨美啶(aminometradine)、阿米美啶(amisometradine))、保钾拮抗剂(potassium sparing antagonist)(例如阿米洛利(amiloride)、氨苯蝶啶(triamterene))或混杂利尿药(诸如aminozine、熊果苷(arbutin)、氯拉扎尼(chlorazanil)、依地尼酸(ethacrynic acid)、依托唑啉(etozolin)、肼卡巴嗪(hydracarbazine)、异山梨醇(isosorbide)、甘露醇(mannitol)、美托查酮(metochalcone)、莫唑胺(muzolimine)、哌克昔林(perhexiline)、替尼酸(ticrnafen)和尿素)。
正性肌力药(也称作强心剂)的非限制性例子包括acefylline、醋洋地黄毒苷(acetyldigitoxin)、2-氨基-4-皮考啉(2-amino-4-picoline)、氨力农(amrinone)、琥珀苯呋地尔(benfurodil hemisuccinate)、布拉地新(bucladesine)、cerberosine、樟吡他胺(camphotamide)、铃兰毒苷(convallatoxin)、磁麻苷(cymarin)、地诺帕明(denopamine)、去乙酰毛花苷(deslanoside)、吉他林(digitalin)、洋地黄(digitalis)、洋地黄毒苷(digitoxin)、地高辛(digoxin)、多巴酚丁胺(dobutamine)、多巴胺(dopamine)、多培沙明(dopexamine)、依诺昔酮(enoximone)、红皮索(erythrophleine)、非那可明(fenalcomine)、吉他林(gitalin)、芰毒素(gitoxin)、胍基乙酸(glycocyamine)、辛胺醇(heptaminol)、白毛茛分碱(hydrastinine)、异波帕胺(ibopamine)、毛花苷(lanatoside)、甲氧酚酰胺(metamivam)、米力农(milrinone)、黄花夹竹桃次苷B(nerifolin)、夹竹桃苷(oleandrin)、乌巴音(ouabain)、奥昔非君(oxyfedrine)、普瑞特罗(prenalterol)、proscillaridine、残余蟾蜍配基(resibufogenin)、海葱苷(scillaren)、海葱苷(scillarenin)、strphanthin、硫马唑(sulmazole)、可可碱(theobromine)和扎莫特罗(xamoterol)。
在具体的实施方案中,肌力药是心脏糖苷、β-肾上腺素能激动剂或磷酸二酯酶抑制剂。心脏糖苷的非限制性例子包括地高辛(digoxin)(拉诺辛(lanoxin))和洋地黄毒苷(digitoxin)(crystodigin)。β-肾上腺素能激动剂的非限制性例子包括沙丁胺醇(albuterol)、班布特罗(bambuterol)、比托特罗(bitolterol)、卡布特罗(carbuterol)、克仑特罗(clenbuterol)、氯丙那林(clorprenaline)、地诺帕明(denopamine)、双羟乙麻黄碱(dioxethedrine)、多巴酚丁胺(dobutamine)(独步催(dobutrex))、多巴胺(dopamine)(intropin)、多培沙明(dopexamine)、麻黄碱(ephedrine)、乙非君(etafedrine)、乙基去甲肾上腺素(ethylnorepinephrine)、非诺特罗(fenoterol)、福莫特罗(formoterol)、海索那林(hexoprenaline)、异波帕胺(ibopamine)、乙基异丙肾上腺素(isoetharine)、异丙肾上腺素(isoproterenol)、马布特罗(mabuterol)、奥西那林(metaproterenol)、甲氧那明(methoxyphenamine)、奥昔非君(oxyfedrine)、吡布特罗(pirbuterol)、丙卡特罗(procaterol)、普罗托醇(protokylol)、瑞普特罗(reproterol)、利米特罗(rimiterol)、利托君(ritodrine)、索特瑞醇(soterenol)、特布他林(terbutaline)、曲托喹酚(tretoquinol)、妥洛特罗(tulobuterol)和扎莫特罗(xamoterol)。磷酸二酯酶抑制剂的非限制性例子包括氨力农(amrinone)(inocor)。
抗心绞痛药可包括有机硝酸盐(organonitrate)、钙通道阻滞剂、β-阻滞剂及其组合。
有机硝酸盐(也称作硝酸血管扩张药)的非限制性例子包括硝酸甘油(nitro-bid、nitrostat)、二硝酸异山梨醇(isordil、sorbitrate)和亚硝酸异戊酯(amylnitrate)(aspirol、vaporole)。
内皮缩血管肽(ET)是一种21个氨基酸的肽,其具有有力的生理学和病理生理学效应,它们似乎涉及心力衰竭的形成。ET的效果经由与两类细胞表面受体的相互作用来介导。A型受体(ET-A)与血管收缩和细胞生长有关,而B型受体(ET-B)与内皮细胞介导的血管舒张和其它神经激素(诸如醛甾酮)的释放有关。能抑制ET的生成或其刺激有关细胞的能力的药理学药剂是本领域已知的。抑制ET的生成涉及使用阻断称作内皮缩血管肽转化酶的酶的药剂,内皮缩血管肽转化酶涉及自前体加工有活性的肽。抑制ET刺激细胞的能力涉及使用阻断ET与其受体相互作用的药剂。内皮缩血管肽受体拮抗剂(ERA)的非限制性例子包括波生坦(Bosentan)、恩拉生坦(Enrasentan)、Ambrisentan、达卢生坦(Darusentan)、替唑生坦(Tezosentan)、阿曲生坦(Atrasentan)、Avosentan、Clazosentan、Edonentan、sitaxsentan、TBC 3711、BQ 123、和BQ 788。
在某些实施方案中,第二治疗剂可包括一些类型的手术,这包括例如预防性的、诊断性的或分期的、治疗性的(curative)和治标性的手术。手术(特别是治疗性手术)可以与其它疗法(诸如本发明和一种或多种其它药剂)联合。
此类用于血管和心血管疾病和病症的手术治疗剂是本领域技术人员公知的,而且可以包括但不限于对生物体实施手术、提供心血管机械假体、血管成形术、冠状动脉再灌注、导管消融、给受试者提供埋藏式复率除颤器、机械循环支持或其组合。本发明中可使用的机械循环支持的非限制性例子包括主动脉内球囊反搏、左心室辅助装置或其组合。
用于对受试者施用的药物配制剂和路径
本发明还提供了包含miR-29a-c激动剂或拮抗剂的药物组合物。激动剂可以是包含编码miR-29a-c的核酸区段的表达载体、或包含成熟miR-29a-c序列或其有效部分的多核苷酸。激动剂可以包含在脂质递送媒介物中。拮抗剂可以是与miR-29a-c或其靶物杂交的多核苷酸。
在临床应用的情况中,药物组合物会以对于预定应用适宜的形式制备。一般而言,这会需要制备基本上不含热原以及其它对人类或动物会有害的杂质的组合物。
可以使用胶状分散系统(诸如大分子复合物、纳米胶囊、微球体、珠、和基于脂质的系统,包括水包油乳剂、胶束(micelle)、混合胶束、和脂质体)作为微小RNA功能的寡核苷酸抑制剂(例如拮抗剂)或表达特定微小RNA的构建体的递送媒介物。对于将本发明的核酸递送至心肌和骨骼肌组织合适地商品化脂肪乳剂包括II、III、Nutrilipid、和其它类似的脂质乳剂。一种作为体内递送媒介物使用的优选的胶状系统是脂质体(即人工膜囊泡)。此类系统的制备和使用是本领域公知的。例示性的配制剂还披露于US 5,981,505;US 6,217,900;US 6,383,512;US5,783,565;US 7,202,227;US 6,379,965;US 6,127,170;US 5,837,533;US6,747,014;和WO03/093449,通过述及完整收入本文。
一般会希望采用适宜的盐和缓冲剂来使得递送媒介物稳定且容许被靶细胞摄取。当将重组细胞导入受试者中时,也会采用缓冲液。本发明的水性组合物包含有效量的递送媒介物,其包含溶解或分散在药学可接受载体或水性介质中的抑制剂多核苷酸或miRNA多核苷酸序列(例如脂质体或其它复合物或表达载体)或细胞。短语“药学可接受的”或“药理学可接受的”指在对动物或人类施用时不产生不利的、变应性的、或其它不想要的反应的分子实体和组合物。如本文中所使用的,“药学可接受载体”包括溶剂、缓冲剂、溶液、分散介质、涂层、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等等可接受用于配制药物(诸如适合对人施用的药物)的。此类介质和试剂用于药学活性物质的使用是本领域公知的。除非任何常规介质或试剂与本发明的活性成分不相容,否则就涵盖它在治疗性组合物中的使用。还可以将补充性活性成分掺入组合物中,只要它们不灭活所述组合物的载体或细胞。
本发明的活性组合物可包括经典的药学制备物。依照本发明的这些组合物的施用可以经由任何常用路径,只要靶组织经由该路径可及。这包括口服、鼻、或含服。或者,施用可以是经过皮内、皮下、肌肉内、腹膜内或静脉内注射,或者通过直接注射入心脏组织。包含miRNA拮抗剂的药物组合物或包含miRNA序列的表达构建体也可以通过导管系统或为将治疗剂递送至心脏而分离冠状循环的系统来施用。本领域知道用于将治疗剂递送至心脏和冠状脉管系统的多种导管系统。美国专利No.6,416,510;美国专利No.6,716,196;美国专利No.6,953,466;WO 2005/082440;WO 2006/089340;美国专利公开文本No.2007/0203445;美国专利公开文本No.2006/0148742;和美国专利公开文本No.2007/0060907(通过述及完整收入本文)中披露了适用于本发明的基于导管的递送方法或冠状动脉分离方法的一些非限制性例子。此类组合物通常会作为如上所述的药学可接受组合物来施用。
活性化合物也可以胃肠外或腹膜内施用。举例而言,可以在与表面活性剂(诸如羟丙基纤维素)适当混合的水中制备游离碱或药理学可接受盐形式的活性化合物的溶液。也可以在甘油、液体聚乙二醇、及其混合物中及在油中制备分散体。在普通贮存和使用条件下,这些制备物一般含有防腐剂以防止微生物生长。
对于注射使用或导管递送合适的药物形式包括例如无菌水溶液或分散体及用于临场制备无菌注射液或分散体的无菌粉剂。一般而言,这些制备物是无菌的,而且以存在易于注射性的程度流动。制备物在制造和贮存条件下应当是稳定的,而且应当针对微生物(诸如细菌和真菌)的污染作用进行防腐。适宜的溶剂或分散介质可含有例如水、乙醇、多元醇(例如甘油、丙二醇、和液体聚乙二醇、等等)、它们的合适混合物、及植物油。可以通过例如使用涂层(诸如卵磷脂)、通过维持所需粒度(在分散体的情况中)和通过使用表面活性剂来维持适当的流动性。可以通过各种抗细菌剂和抗真菌剂来实现对微生物作用的预防,例如paraben、氯丁醇、酚、山梨酸、硫柳汞、等等。在许多情况中,会优选包括等渗剂,例如糖或氯化钠。可以通过在组合物中使用延迟吸收的药剂来实现可注射组合物的吸收的延长,例如单硬脂酸铝和明胶。
可如下制备无菌注射液,即以适宜的量将活性化合物掺入根据需要含有任何其它成分(例如上文所列)的溶剂中,接着过滤除菌。一般而言,如下制备分散体,即将各种经灭菌的活性成分掺入含有基本分散介质和想要的其它成分(例如上文所列)的无菌媒介物中。在用于制备无菌注射液的无菌粉剂的情况中,优选的制备方法包括真空干燥和冷冻干燥技术,它们自先前无菌过滤的溶液产生其活性成分加任何别的想要的成分的粉末。
本发明的组合物一般可配制成中性或盐形式。药学可接受盐包括例如自无机酸(例如盐酸或磷酸)或自有机酸(例如乙酸、草酸、酒石酸、扁桃酸、等等)衍生的酸加成盐(与蛋白质的游离氨基形成的)。也可以自无机碱(例如氢氧化钠、钾、铵、钙、或铁)或自有机碱(例如异丙胺、三甲胺、组氨酸、普鲁卡因等等)衍生与蛋白质的游离羧基形成的盐。
配制后,优选以与剂型相容的方式和以治疗上有效的量施用溶液。所述配制剂可以容易地以多种剂量形式来施用,诸如注射液、药物释放胶囊等等。例如,为了以水溶液形式胃肠外施用,一般将溶液适当缓冲,并且首先例如用足够的盐或葡萄糖使得液体稀释剂等渗。此类水溶液可用于例如静脉内、肌肉内、皮下和腹膜内施用。优选的是,采用无菌水介质,正如本领域技术人员知道的,特别是根据本公开内容。举例而言,可以将单个剂量溶解在1ml等渗NaCl溶液中,并且或是添加至1000ml皮下输液或是在建议的输注部位注射(参加例如《Remington′s Pharmaceutical Sciences》第15版,第1035-1038页和第1570-1580页)。取决于所治疗的受试者的状况,剂量必然会发生一些变化。在任何情况中,负责施用的人会为各受试者决定适宜的剂量。此外,对于人类施用,制备物应当达到FDA生物制剂标准室要求的无菌度、热原度、一般安全和纯度标准。
用于提高组织中的胶原沉积的化妆品配制剂可包含至少一种miR-29a-c拮抗剂。所述拮抗剂可以是miR-29a、miR-29b、miR-29c、或其组合的拮抗剂。在一些实施方案中,所述miR-29a-c拮抗剂是小RNA拮抗剂。所述拮抗剂可以连接或偶联有促进所述拮抗剂进入细胞或组织的药剂。此类药剂可包括细胞内化转运物,诸如穿膜肽(antennapedia)、TAT、Buforin II、Transportan、模型两亲性肽、K-FGF、Ku70、Prion、pVEC、Pep-1、SynB1、SynB3、SynB5、Pep-7、HN-I、双-胍盐-亚精胺-胆固醇、双-胍盐-Tren-胆固醇、和聚精氨酸。所述药剂可以连接至miR-29a-c拮抗剂的氨基或羧基端。在一个实施方案中,所述药剂通过在进入细胞后受到切割的序列连接至拮抗剂。此类序列通常包含本领域已知的蛋白酶的共有序列。
化妆品组合物可配制到所有类型的媒介物中。合适的媒介物的非限制性例子包括乳液(例如油包水、水包油包水、水包油、油包水包油、硅酮包水包油乳液)、乳膏、洗剂、溶液(水的和含水酒精的二者)、无水基质(诸如唇膏(lipstick)和粉)、凝胶、和软膏剂或通过本领域普通技术人员会知道的其它方法或上述任何组合(Remington′s,1990)。各种和其它适宜的媒介物对熟练技术人员会是显而易见的,而且适宜在本发明中使用。在某些实施方案中,各组分的浓度和组合是以所述组合化学相容且不形成自成品沉淀的复合物的方式而选择的。
还涵盖可以封装芳香的皮肤活性组分和贯穿本说明书鉴定的别的组分来递送至靶区域,诸如皮肤。封装技术的非限制性例子包括能作为递送媒介物用于将此类组分递送至皮肤的脂质体、媒介物、和/或纳米颗粒(例如生物可降解的和非生物可降解的胶状颗粒,其包含其中包裹、封装、和/或吸收有所述组分的聚合材料,例子包括纳米球体和纳米胶囊)的使用(参加例如美国专利6,387,398;美国专利6,203,802;美国专利5,411,744;及Kreuter 1998,通过述及完整收入本文)。
还涵盖药学可接受的或药理学可接受的组合物。短语“药学可接受的”或“药理学可接受的”包括在对人类施用时不产生变应性的或相似的不利反应的组合物。通常,此类组合物制备成局部组合物、液体溶液或悬浮液,也可以制备适合在使用前在液体中溶解或悬浮的固体形式。施用路径可以随要治疗的疾患的位置和性质而变化,而且包括例如局部、吸入、皮内、经皮(transdermal)、胃肠外、静脉内、肌肉内、鼻内、皮下、经皮(percutaneous)、气管内、腹膜内、肿瘤内、灌注、灌洗、直接注射、和口服施用和配制。
可以将本发明的组合物掺入产品中。产品的非限制性例子包括包括化妆品产品、基于食品的产品、药物产品等。仅仅是举例而言,非限制性的化妆品产品包括遮光剂产品(sunscreen products)、无日照皮肤晒黑产品(sunlessskin tanning products)、美发产品(hair products)、美甲产品(fingernail products)、增湿霜(moisturizing creams)、皮肤护理霜和皮肤护理液(skin benefit creamsand lotions)、柔软剂(softeners)、日霜(day lotions)、凝胶、软膏剂、粉底(foundations)、晚霜(night creams)、唇膏(lipsticks)、睫毛膏(mascaras)、眼影(eyeshadows)、眼线(eyeliners)、颊彩(cheek colors)、清洁剂(cleansers)、调色剂(toners)、面膜(masks)、或其它已知的化妆品产品或应用。另外,化妆品产品可以配制成保留着的(leave-on)或冲洗掉的(rinse-off)的产品。
本发明的组合物可包括别的组分。别的组分的非限制性例子包括化妆品组分(有活性和无活性的二者)和药物组分(有活性的和无活性的二者)。CTFA国际化妆品组分字典和手册(2004)记载了极其多种能在本发明的背景中使用的非限制性化妆品组分。这些组分类别的例子包括:香料(人造的和天然的)、染料和颜色组分(例如蓝1、湖蓝1、红40、二氧化钛、D&C 4号蓝、D&C 5号绿、D&C 4号橙、D&C 17号红、D&C 33号红、D&C 2号紫罗兰、D&C 10号黄、和D&C 11号黄)、吸附剂、乳化剂、稳定剂、润滑剂、溶剂、增湿剂(包括例如润肤剂、保温剂、成膜剂、吸留剂、和影响皮肤天然增湿机制的药剂)、防水剂、UV吸收剂(物理的和化学的吸收剂,诸如对氨基苯甲酸(PABA)和相应的PABA衍生物、二氧化钛、氧化锌、等)、精油(essential oil)、维生素(例如A、B、C、D、E、和K)、痕量金属(例如锌、钙和硒)、抗刺激剂(例如类固醇和非类固醇抗炎药)、植物提取物(例如真芦荟、甘菊、黄瓜提取物、白果、人参、和迷迭香)、抗微生物剂、抗氧化剂(例如BHT和生育酚)、螯合剂(例如EDTA二钠和EDTA四钠)、防腐剂(例如对羟基苯甲酸甲酯和对羟基苯甲酸丙酯)、pH调节剂(例如氢氧化钠和柠檬酸)、吸收剂(例如铝淀粉辛烯基琥珀酸酯、高岭土、玉米淀粉、燕麦淀粉、环式糊精、滑石、和沸石)、皮肤漂白和提亮剂(lightening agent)(例如氢醌和烟酰胺乳酸酯)、保湿剂(例如甘油、丙二醇、丁二醇、戊二醇、山梨醇、尿素、和甘露醇)、去角质剂(exfoliant)(例如α-羟基酸和β-羟基酸诸如乳酸、乙醇酸、和水杨酸;及其盐)防水剂(例如氢氧化镁/铝硬脂酸盐)、皮肤调理剂(例如芦荟提取物、尿囊素、甜没药醇、神经酰胺、二甲基硅油、透明质酸、和甘草酸二钾)、增稠剂(例如能提高组合物的粘度的物质,诸如羧酸聚合物、交联聚丙烯酸酯聚合物、聚丙烯酰胺聚合物、多糖、和胶质)、和含硅酮的化合物(例如硅油和聚有机硅氧烷)。
还涵盖对本发明的乳剂组合物有用的药学组分。药学组分的非限制性例子包括抗痤疮药、用于治疗酒糟鼻的药剂、镇痛药、麻醉药、肛门直肠药、抗组胺药、抗炎药(包括非类固醇抗炎药)、抗生素、抗真菌药、抗病毒药、抗微生物药、抗癌活性剂、杀芥螨药、灭虱药、抗肿瘤药、止汗药、止痒药、抗银屑病药、抗脂溢药、生物学活性蛋白质和肽、烧伤处理药、烧灼剂、脱色剂、脱毛药、尿布湿疹处理药、酶、毛发生长刺激剂、毛发生长延缓剂(包括DFMO及其盐和类似物)、止血药、角质层分离剂(kerotolytics)、口疮处理药、感冒疮处理药、牙齿和牙周处理药、光敏化活性剂、保护剂/屏障剂、类固醇(包括激素和皮质类固醇)、晒伤处理药、遮光剂、经皮活性剂、鼻活性剂、阴道活性剂、疣处理药、伤口处理药、伤口愈合药等。
本文所述任何成分可以包含在试剂盒中。在一个非限制性的例子中,各miRNA包括在试剂盒中。所述试剂盒可进一步包括水和杂交缓冲液以便于所述miRNA的两条链的杂交。在一些实施方案中,所述试剂盒可包括一种或多种用于抑制靶miRNA功能的寡核苷酸。所述试剂盒还可包括一种或多种转染试剂以便于将miRNA或miRNA拮抗剂递送至细胞。
试剂盒的成分可以在水介质中或以冻于形式包装。试剂盒的容器手段一般包括至少一个管形瓶、试管、烧瓶、瓶、注射器或其它容器手段,其中装有(优选合适地分配)成分。在试剂盒中有超过一种成分的情况中(标记用试剂和标记物可以包装在一起),试剂盒一般还会包含第二、第三或其它别的容器,其中可以分开装纳别的成分。然而,可以在管形瓶中装纳各种成分组合。本发明的试剂盒一般还会包括为了销售而牢固地安置核酸,和任何其它试剂容器的手段。此类容器可包括用于安放所需管形瓶的注射或吹塑成形的塑料容器。
当所述试剂盒的成分在一种和/或多种液体溶液中提供时,所述液体溶液是水溶液,特别优选无菌的水溶液。
然而,试剂盒的成分可以以干粉形式提供。当试剂和/或成分以干粉形式提供时,可以通过添加合适的溶剂来将所述粉剂重建。所述溶剂也可以在另一容器手段中提供。
容器手段一般会包括至少一个管形瓶、试管、烧瓶、瓶、注射器和/或其它容器手段,其中装有(优选合适地分配)核酸配制剂。所述试剂盒还可包含第二容器手段,用于装纳无菌的药学可接受缓冲剂和/或其它稀释剂。
本发明的试剂盒通常还会包括为了销售而牢固地安置管形瓶的手段,诸如例如用于安放所需管形瓶的注射和/或吹塑成形的塑料容器。
此类试剂盒还可包括保存或维持miRNA或miRNA抑制性寡核苷酸或者保护它们免于降解的成分。此类成分可以不含RNA酶或针对RNA酶提供保护。此类试剂盒一般会以合适的手段为每种试剂或溶液包含独特的容器。
试剂盒还会包括关于采用试剂盒成分以及使用试剂盒中没有包括的任何其它试剂的说明书。说明书可包括能执行的变化形式。试剂盒还可包括通过各种施用路径(诸如胃肠外或导管施用)施用miRNA激动剂或拮抗剂的器具或装置。
此类试剂是本发明试剂盒的实施方案。然而,此类试剂盒不限于上文鉴定的具体项,而且可包括任何用于miRNA操作或表征的试剂。
用于鉴定调控物的方法
本发明进一步包含用于鉴定miR-29a-c的激动剂的方法,miR-29a-c的激动剂在心脏纤维化、心脏肥大或心力衰竭的预防或治疗或逆转中是有用的。这些测定法可包含随机筛选候选化合物的大型文库;或者,所述测定法可用于聚焦于特定类别的化合物,它们是以针对认为使得化合物更有可能提升miR-29a-c表达和/或功能的结构属性的视角选择的。
为了鉴定miR-29a-c的调控物,一般会在存在和不存在候选化合物的情况中测定miR-29a-c的功能。例如,所述方法一般包含:
(a)提供候选化合物;
(b)将所述候选化合物与miR-29混合;
(c)测量miR-29a-c活性;并
(d)比较步骤(c)中的活性与不存在所述候选化合物时的miR-29a-c活性,其中测量得到的miR-29a-c活性间的差异指示所述候选化合物确实是miR-29a-c的调控物。
也可以在分离的细胞、器官、或活的生物体中进行测定法。
当然要理解,本发明的所有筛选方法自身就是有用的,尽管事实上可能没有找到有效的候选物。本发明提供了用于筛选此类候选物的方法,不仅仅是找到它们的方法。
如本文中所使用的,“候选化合物”指任何可潜在调控miR-29a-c的纤维化或胶原调节方面的分子。通常会从各种商业来源获得认为达到有用药物基本标准的分子文库,从而试图“推动”有用化合物的鉴定。对此类文库(包括通过组合产生的文库,例如小RNA拮抗剂文库)的筛选是对大量相关(和无关)化合物筛选活性的一种快速且有效的方式。通过在有活性但其它方面不合适的化合物的原型上创建第二代、第三代、和第四代化合物,组合法还将它们自身用于潜在药物的快速进化。
体外测定法是一种快速、便宜且容易的测定法。此类测定法一般使用分离的分子,能快速且大量运行,由此提高一小段时间里可获得的信息量。可使用多种容器来运行此类测定法,包括试管、板、盘和其它表面,诸如量杆(dipstick)或珠。
WO 84/03564(通过述及完整收入本文)中记载了一种用于高通量筛选化合物的技术。可以在固体基底(诸如塑料针或一些其它表面)上合成大量小的小RNA拮抗剂(antogomir)化合物。可以对此类分子快速筛选它们抑制miR-29a-c的能力。
本发明还涵盖,对化合物筛选它们调控细胞中miR-29a-c活性和表达的能力。此类筛选测定法可利用各种细胞系,包括自骨骼肌细胞衍生的那些,包括专门为此目的而改造的细胞。也可以使用原代心脏细胞,正如H9C2细胞系。
体内测定法涉及心脏病或肌肉骨骼疾病、纤维化、或胶原丢失的各种动物模型的使用,包括转基因动物,它们已经进行改造以具有特定缺陷或携带可用于测量候选物质到达和影响生物体内不同细胞的能力的标志物。由于它们的体型、易于操作、及关于它们生理学和遗传构成的信息,小鼠是一种优选的实施方案,尤其对于转基因的。然而,其它动物也是合适的,包括大鼠、家兔、仓鼠、豚鼠、沙鼠、旱獭、猫、犬、绵羊、山羊、猪、牛、马和猴(包括黑猩猩、长臂猿和狒狒)。可以使用自任何这些物种衍生的动物模型来进行对抑制剂的测定法。
用测试化合物治疗动物会涉及对动物施用适宜形式的化合物。施用会是任何可用于临床目的的路径。在体内测定化合物的有效性可涉及多种不同标准,包括但不限于肥大信号传导途径和肥大身体症状的改变。而且,可以以比体内或细胞内测定法更有意义的方式在动物中实施对毒性和剂量响应的测量。
转基因动物
本发明的一个具体实施方案提供了缺少两个功能性miR-29a、miR-29b、和/或miR-29c等位基因中的一个或两个的转基因动物。而且,在诱导型的、组织选择性的或组成型的启动子控制下表达miR-29a-c的转基因动物,自此类动物衍生的重组细胞系,及转基因胚在确定miR-29a-c在对纤维化的控制中和在病理性心脏肥大和心力衰竭的发生中发挥的确切作用中可能是有用的。另外,这些转基因动物可洞察心脏发育。可诱导的或可遏制的miR-29a-c编码核酸的使用为过度调节的或不受调节的表达提供了模型。而且,涵盖“敲除”了miR-29a-c的两个等位基因中一个或两个的转基因动物。而且,涵盖“敲除”了一个或两个簇的一个或两个等位基因中的miR-29a-c的转基因动物。
在一个一般的实施方案中,通过以容许转基因表达的方式使给定的转基因整合入基因组中生成了转基因动物。用于生成转基因动物的方法一般性记载于Wagner和Hoppe(美国专利4,873,191;通过述及收入本文);及Brinster等(1985;通过述及收入本文)。
典型的是,通过显微注射将侧翼为基因组序到的基因转移入受精卵。将显微注射后的卵植入宿主雌兽,并对后代筛选转基因表达。可以自来自许多动物(包括但不限于爬行类、两栖类、鸟类、哺乳类、和鱼类)的受精卵生成转基因动物。
可以通过本领域已知的任何手段来制备用于显微注射的DNA克隆。例如,可以用适宜于清除细菌质粒序列的酶切割用于显微注射的DNA克隆,并使用标准技术在TBE缓冲液中在1%琼脂糖凝胶上对DNA片段电泳。通过溴化乙锭染色来显现DNA条带,并切出含有表达序列的条带。然后将切出的条带置于装有0.3M乙酸钠,pH 7.0的透析袋中。将DNA电洗脱入透析袋中,用1∶1酚∶氯仿溶液抽提,并用两倍体积的乙醇沉淀。将DNA在1ml低盐缓冲液(0.2M NaCl,20mM Tris,pH 7.4,和1mM EDTA)中重新溶解,并在Elutip-DTM柱上纯化。首先用3ml高盐缓冲液(1M NaCl,20mM Tris,pH 7.4,和1mM EDTA)预先准备柱,接着用5ml低盐缓冲液清洗。使DNA溶液穿过柱三次以使DNA结合至柱基质。用3ml低盐缓冲液清洗一次后,用0.4ml高盐缓冲液洗脱DNA,并用两倍体积的乙醇沉淀。在UV分光光度计中通过260nm吸收来测量DNA浓度。为了显微注射,将DNA浓度在5mM Tris,pH 7.4和0.1mM EDTA中调节至3μg/ml。用于纯化用于显微注射的DNA的其它方法记载于Palmiter等(1982);及Sambrook等(2001)。
在一种例示性的显微注射规程中,通过5IU注射(0.1cc,ip)怀孕母马血清促性腺激素(PMSG;Sigma),接着48小时后5IU注射(0.1cc,ip)人绒毛膜促性腺激素(hCG;Sigma),诱导六周龄雌性小鼠超排卵。hCG注射后立即将雌性与雄性放在一起。hCG注射后21小时,通过CO2窒息或颈脱位法处死交配后的雌性,并自切开的输卵管取出胚,放在含0.5%牛血清清蛋白(BSA;Sigma)的Dulbecco氏磷酸盐缓冲盐水中。用透明质酸酶(1mg/ml)清除周围的丘细胞。然后在含0.5%BSA的Earle氏平衡盐溶液(EBSS)中清洗前核胚并放置在具有5%CO2、95%空气的增湿大气的37.5℃温箱中,直至注射时间。可以在两细胞阶段进行胚的植入。
将随机循环的成年雌性小鼠与切除了输精管的雄性配对。为此目的可使用C57BL/6或Swiss小鼠或其它相当的品系。使受体雌性在与供体雌性相同的时间交配。在转移胚时,通过腹膜内注射0.015ml 2.5%阿佛丁每克体重来麻醉受体雌性。通过一个中线背部切口来暴露输卵管。然后穿过刚好在输卵管上方的体壁做一个切口。然后用制表镊撕裂卵巢囊。将要转移的胚放在DPBS(Dulbecco氏磷酸盐缓冲盐水)中且在转移移液管的尖端中(约10-12个胚)。将移液管尖端插入漏斗中并转移胚。转移后,通过两次缝合来关闭切口。
定义
如本文中所使用的,术语“心力衰竭”广泛用于表示降低心脏泵血能力的任何疾患。结果是,在组织中发生充血和水肿。最常见的是,心力衰竭是由源自冠状动脉血流降低的心肌收缩性降低引起的;然而,许多其它因素可导致心力衰竭,包括对心脏瓣膜的损害、维生素缺乏、和原发性心脏肌肉疾病。虽然尚未完全了解心力衰竭的精确生理机制,但是一般认为心力衰竭涉及数项心脏自主特性(包括交感神经的、副交感神经的、和压力感受器应答)中的病症。短语“心力衰竭的表现”广泛用于涵盖与心力衰竭有关的所有后遗症,诸如呼吸短促、压凹性水肿、肝肿大且触痛、颈部静脉充血、肺部罗音等等,包括与心力衰竭有关的实验室发现。
术语“治疗”或“处理”或语法等同形式涵盖心力衰竭症状的改善和/或逆转(即心脏泵血的能力)。可以使用本文所述任何度量(例如测量射血分数、缩短分数、左心室内径、心率等)以及对动物存活的任何效果来评估心脏“生理功能的改善”。在使用动物模型时,使用本文所述任何测定法比较接受治疗的转基因动物和不接受治疗的转基因动物的响应(另外,可以包括经接受治疗的和不接受治疗的非转基因动物作为对照)。在本发明的筛选方法中使用的、引起与心力衰竭有关的任何参数改善的化合物可由此鉴定为治疗性化合物。
术语“扩张性心肌病”指以存在收缩期收缩功能差的对称性扩张左心室为特征且另外常常涉及右心室的一种心力衰竭类型。
术语“化合物”指可用于治疗或预防身体功能的疾病(disease)、病(illness)、不适(sickness)、或病症(disorder)的任何化学实体、药剂、药物等等。化合物包含已知的和潜在的治疗性化合物。可以通过使用本发明的筛选方法进行的筛选来确定化合物是治疗性的。“已知的治疗性化合物”指已经显示出(例如经由动物试验或对人类施用的在先经验)在此类治疗中有效的治疗性化合物。换言之,已知的治疗性化合物不限于在心力衰竭的治疗中有效的化合物。
如本文中所使用的,术语“心脏肥大”指其中成年心脏肌细胞经由肥大性生长来响应压力的过程。此类生长的特征在于细胞大小增大细胞而在没有细胞分裂,在细胞内装配另外的肌节以使力量生成最大化,及胎心基因程序的激活。心脏肥大常常与升高的发病和死亡风险有关,因此致力于了解心脏肥大的分子机制的研究会对人类健康具有重大影响。
如本文中所使用的,术语“调控”指生物性活性的变化或改变。调控可以是蛋白质活性的升高或降低、激酶活性的变化、结合特征的变化、或与蛋白质或其它感兴趣结构的活性有关的生物学、功能、或免疫学特性的任何其它变化。术语“调控物”指如上所述能够变化或改变生物学活性的任何分子或化合物。
术语“β-肾上腺素能受体拮抗剂”指能够阻断(部分地或完全地)贝塔(β)型肾上腺素受体(即响应儿茶酚胺(尤其是去甲肾上腺素)的肾上腺素能系统受体)的化学化合物或实体。有些β-肾上腺素能受体拮抗剂展现出一定程度的对一种受体亚型(一般是β1)的特异性;此类拮抗剂叫作“β1特异性肾上腺素能受体拮抗剂”和“β2特异性肾上腺素能受体拮抗剂”。术语“β-肾上腺素能受体拮抗剂”指作为选择性和非选择性拮抗剂的化学化合物。β-肾上腺素能受体拮抗剂的例子包括但不限于醋丁洛尔(acebutolol)、阿替洛尔(atenolol)、丁氧胺(butoxamine)、卡替洛尔(carteolol)、艾司洛尔(esmolol)、拉贝洛尔(labetolol)、美托洛尔(metoprolol)、纳多洛尔(nadolol)、喷布洛尔(penbutolol)、普萘洛尔(propanolol)、和噻吗洛尔(timolol)。本发明的方法涵盖已知的β-肾上腺素能受体拮抗剂的衍生物的使用。事实上,本发明的方法涵盖在功能上表现像β-肾上腺素能受体拮抗剂的任何化合物。
术语“血管紧张素转化酶抑制剂”或“ACE抑制剂”指能够抑制(部分地或完全地)肾素-血管紧张素系统中相对无活性的血管紧张素I转化成有活性的血管紧张素II所涉及的酶的化学化合物或实体。另外,ACE抑制剂伴随地抑制缓激肽的降解,这有可能显著增强ACE抑制剂的抗高血压效果。ACE抑制剂的例子包括但不限于贝那普利(benazepril)、卡托普利(captopril)、依那普利(enalopril)、福辛普利(fosinopril)、赖诺普利(lisinopril)、喹那普利(quiapril)和雷米普利(ramipril)。本发明的方法涵盖已知的ACE抑制剂的衍生物的使用。事实上,本发明的方法涵盖在功能上表现像ACE抑制剂的任何化合物。
如本文中所使用的,术语“基因型”指生物体的实际遗传组成,而“表型”指个体所展示的身体性状。另外,“表型”是基国组选择性表达的结果(即它是细胞历史的表达及其对细胞外环境的响应)。事实上,人类基因组含有估计30,000-35,000个基因。在每种细胞类型中,这些基因只有一小部分(即10-15%)表达。
在权利要求书和/或说明书中与术语“包含”联合使用时,词语“一个/种”的使用可以表示“一个/种”,但是也与“一个/种或多个/种”、“至少一个/种”、和“一个/种或超过一个/种”的含义一致。
本文中讨论的任何实施方案可以用本发明的任何方法或组合物来执行,反之亦然。另外,本发明的组合物和试剂盒可用于实现本发明的方法。
贯穿本申请,术语“约”用于表示某数值包括用于测定该数值的装置或方法的误差的标准偏差。
权利要求书中术语“或”的使用用于表示“和/或”,除非明确指明指只选一项或各备选项相互排斥,即使公开文本支持只选一项的定义和“和/或”。
如本说明书和权利要求书中所使用的,词语“包含”(及其任何变形)、“具有”(及其任何变形)、“包括”(及其任何变形)或“含有”(及其任何变形)是包含性/包括性的或开放式的,不排除别的未述及的成分或方法步骤。
虽然已经在本申请中插入了章节标题以便于阅读,但是此类标题不应解释为对实施方案的分割。
包括下列实施例来进一步例示本发明的各个方面。本领域技术人员会领会,下文实施例中公开的技术代表了发明人发现在实施本发明时运转良好且因此能视为构成实施本发明的优选模式的技术和/或组合物。然而,根据本公开内容,本领域技术人员应领会可以在所公开的具体实施方案中进行许多改变且仍然获得类似或相似的结果而不背离本发明的精神和范围。
实施例
miR-208在α-MHC基因的内含子内编码(图1A)。像α-MHC一样,miR-208在心脏中特异性表达,在肺中有痕量表达(图1B)。miR-208是自α-MHCpre-mRNA加工出来的,而不是作为分开的转录物转录得到的。然而,有趣的是,miR-208展现出长得引人注目的、至少14天的半衰期,而且由此甚至能在α-MHC mRNA表达已经下调时发挥功能。虽然小鼠中的miR-208遗传缺失未能诱发明显表型,但是对来自2月龄野生型和miR-208-/-动物的心脏进行的微阵列分析揭示了miR-208的消除导致众多快速骨骼肌收缩蛋白质基因的显著表达,它们在正常情况中在心脏中不表达。如此,这些结果提示在正常条件下,miR-208与唯一的心脏特异性MHC基因共表达,通过遏制骨骼肌基因在心脏中的表达来维持心肌细胞身份。
miR-208无效(null)小鼠对心脏压力的异常响应揭示了miR-208的最显著功能(van Rooij等,2007)。在对通过胸主动脉收缩超载的压力或对钙依赖磷酸酶(一种驱动心脏病理性重塑的钙/钙调蛋白依赖性磷酸酶)的信号传导的响应中,miR-208无效小鼠实际上不显示心肌细胞肥大或纤维化,而且没有能力上调β-MHC表达(图6-8)。相反,其它压力响应性基因(诸如那些编码ANF和BNP的)在miR-208突变动物中被强烈诱导,证明了miR-208专门从事对β-MHC表达的控制,它能与心脏压力应答的其它方面脱钩。
β-MHC表达受甲状腺激素信号传导遏制,且在甲状腺功能减退状态中上调(Leung等,2006)。miR-208-/-动物还对T3抑制剂丙基硫尿嘧啶(PTU)(它诱发甲状腺功能减退)处理后的β-MHC表达上调有抗性。然而,有趣的是,miR-208突变小鼠中出生前的β-MHC表达是正常的,指示miR-208专门从事对β-MHC表达的出生后调节,这与β-MHC基因的甲状腺激素响应性的获得一致(图5)。
miR-208作用机制的一条线索来自miR-208-/-心脏与甲状腺机能亢进心脏的类似,二者都展示出对β-MHC表达的阻断、压力响应基因的上调和针对病理性肥大和纤维化的保护(图6-10)。miR-208-/-心脏中快速骨骼肌基因的上调也模仿甲状腺机能亢进状态中快速骨骼肌纤维的诱导(Wei等,2005)。
这些发现提示miR-208(至少部分)通过遏制心脏中压力应答与甲状腺激素信号传导途径的一个共同成分的表达来起作用。miR-208的最强的预测靶物是甲状腺激素受体(TR)辅调节物THRAP1,它能对转录发挥积极和消极效果(Pantos等,2006;Yao和Eghbali,1992;图12)。TR经消极甲状腺激素响应元件(TRE)起作用来遏制成年心脏中的β-MHC表达(Zhao等,2005)。如此,在miR-208缺失的情况中THRAP1表达的升高预测会增强TR对β-MHC表达的遏制活性,与miR-208-/-心脏中对β-MHC表达的阻断一致。然而,虽然THRAP1表现为miR-208的真(bone fide)靶物,但是这些数据不排除别的靶物可能参与对β-MHC表达的调节。
由于对β-MHC的甚至细微变化降低成年心脏的机械性能和功效,因此探索miR-208调节对于在心脏病期间阻止β-MHC表达升高会有治疗价值。miR-208对心脏压力应答(而非正常心脏发育)的心脏特异性和专注性使得miR-208(及其下游效应物(effector))成为操作β-MHC水平的诱人治疗靶(图13)。
材料和方法
Northern印迹分析。自Gilead Colorado(Westminster,CO)获得诊断为具有非衰竭或衰竭心脏的匿名人士的左心室的心脏组织样品。获得诊断为罹患心肌梗死的匿名人士的缘带区域的心脏组织样品。使用Trizol试剂(Gibco/BRL),自细胞、小鼠、大鼠和人类心脏组织样品或分离的肌细胞分离总RNA。通过用溴化乙啶染色Northern凝胶来证实相等的加载。如先前所述(van rooij等,2006)实施Northern印迹来检测微小RNA。U6探针充当加载对照。为了检测α-MHC表达,用覆盖第一外显子和5′UTR区一部分的α-MHCcDNA片段探查含有10μg来自成年野生型和miR-208突变型动物二者心脏组织的RNA的Northern印迹。
PTU处理。通过用补充有0.15%PTU(购自Harlan Teklad Co.,TD 97061,Madison,WI)的无碘食物喂养动物指定持续时间来诱发甲状腺激素缺乏。
微阵列和实时PCR分析。使用Trizol(Invitrogen)自心脏组织分离总RNA。使用小鼠基因组4302.0阵列(Affymetrix)实施微阵列分析。为了检测miRNA水平,使用Taqman微小RNA逆转录酶试剂盒(Applied Biosystems,ABI)依照制造商的推荐实施RT-PCR。用miRNA特异性引物使用5ng RNA来生成cDNA,之后用miRNA特异性Taqman探针来检测感兴趣miRNA的表达水平。用随机六聚物引物(Invitrogen)对RNA样品进行RT-PCR后,使用购自ABI的Taqman探针通过PCR或定量实时PCR分析一个基因子集的表达。
miR-208突变小鼠的生成。为了生成miR-208靶向载体,将向miR-208编码区上游延伸的0.4kb片段(5′臂)用SacII和NotI消化并连接入pGKneoF2L2dta靶向质粒,在loxP位点和侧翼为Frt的新霉素盒的上游。将3.3kb片段(3′臂)用SalI和HindIII消化并连接入载体,在新霉素抗性与和Dta负选择盒之间。用5′和3′探针通过Southern印迹分析来鉴定携带被破坏的等位基因的靶定ES细胞。鉴定出三个miR-208靶定ES克隆并用于胚泡注射。将所得嵌合小鼠与C57BL/6交配以获得突变等位基因的种系传递。
转基因小鼠的生成。将感兴趣miRNA侧翼的小鼠基因组片段亚克隆入含有α-MHC和人GH poly(A)+信号的心脏特异性表达质粒(Kiriazis和Kranias,2000)。自小鼠尾部活检分离基因组DNA,并使用对人GH poly(A)+信号特异性的引物通过PCR来分析。
Western印迹。如文献所述(Morkin,2000)自心脏组织提取肌球蛋白。通过SDS PAGE将MHC同等型分开,并用小鼠单克隆α-MHC(BA-G5)(ATCC,Rockville,MD)和小鼠单克隆抗肌球蛋白(慢速,骨骼M8421)(Sigma,MO)(它是对β-MHC高度特异性的)实施Western印迹。为了检测所有成纹的肌球蛋白,使用泛特异性抗体(pan specific antibody)(小鼠单克隆3-48;Accurate Chemical& Scientific Corporation,NY)。通过来自400μg心脏蛋白质溶胞物的免疫沉淀来检测THRAP1。将样品于4℃预澄清1小时后,将上清液与1μl家兔多克隆抗THRAP1(由Rockefeller University的R.Roeder馈赠)和15μl蛋白质A珠一起于4℃温育过夜。将珠用裂解缓冲液清洗三次并在SDS样品缓冲液中煮沸。通过SDS-PAGE解析免疫沉淀的THRAP1蛋白质,并使用1∶3000稀释的家兔多克隆抗THRAP1和1∶5000稀释的偶联有辣根过氧化物酶的抗家兔IgG分析,其中通过鲁米诺试剂(Santa Cruz)来检测。
组织学分析和RNA原位杂交。将用于组织学的组织在Krebs-Henselheit溶液中温育,在4%低聚甲醛中固定,切片,并为苏木精和曙红(H&E)加工,及Masson氏三色染色或通过标准技术进行的原位杂交(Krenz和Robbins,2004)。使用Maxiscript试剂盒(Amersham)生成35S标记的RNA探针。使用AdobePhotoshop将信号假着色成红色。
经胸超声心动图显象。使用Vingmed System(GE Vingmed Ultrasound,Horten,Norway)和11.5MHz线性阵列转换器,通过有意识的小鼠中的二维超声心动图显象来评估心脏功能和心脏尺度。使用M模式描记来测量心舒末期和心缩末期的前后壁厚。作为心舒期(LVIDd)或心缩期(LVIDs)的最大前后径,测量左心室(LV)内径(LVID)。由一名对小鼠基因型不知情的观察员分析了数据。依照下式计算了LV缩短分数(FS):FS(%)=[(LVIDd-LVIDs)/LVIDd]×100。
质粒和转染测定法。通过PCR扩增涵盖miR-208编码区的305bp基因组片段并连接入pCMV6。PCR扩增涵盖整个鼠THRAP1-UTR的1kb片段并连接入带HA标签的pCMV6表达构建体和萤火虫萤光素酶(f-luc)报告构建体(pMIR-REPORTTM,Ambion)。经由基于PCR的诱变构建了UCGUCUUAmiR-208种子结合序列的一种突变形式。
细胞培养、转染和萤光素酶测定法。通过PCR扩增涵盖miR-29b-1和miR-29a编码区的1793bp基因组片段并连接入pCMV6。PCR扩增涵盖miR-29a-c结合位点的鼠3′UTR的基因组片段并连接入萤火虫萤光素酶(f-luc)报告构建体(pMIR-REPORTTM,Ambion)。用Fugene 6(Stratagene)依照制造商的指令转染COS细胞。通过添加相应量的不含cDNA插入物的表达载体,保持每个孔的DNA总量恒定。转染后48小时,使用萤光素酶测定法试剂盒(Promega)测定细胞提取物的萤光素酶表达。相对启动子活性表述成相对于细胞提取物中β-半乳糖苷酶表达标准化的发光相对单位。
如先前所述(Simpson和Savion,1982)分离心脏成纤维细胞(CF)。简言之,自麻醉的新生1-2日龄Sprague-Dawley大鼠(Harlan Sprague Dawley,Indianapolis,IN)切出心脏,切碎,并用0.1%胰酶制剂消化。将细胞铺涂在primaria板上2小时,并清除含有经消化组织的心肌细胞级分的培养基。心脏成纤维细胞比心脏肌细胞快得多地附着和增殖;这实际上在第一次传代后生成纯的成纤维细胞培养物,这通过反复的分化铺板(differential plating)和显微镜评估得到证实。为了传代用0.05%胰蛋白酶使细胞脱离,并在第2-4代实施培养物研究。在含有10%热灭活FBS和抗生素(青霉素和链霉素)的高葡萄糖(4.5gm/lt)的Dulbecco氏改良Eagle氏培养基(DMEM)中培养细胞。通过将培养物变成低血清(2%FBS)及L-抗坏血酸(10μg/μl)并施用10ng/ml TGFβl 48小时来诱导肌成纤维细胞分化。
通过反miR处理进行的体内miR-29b沉默。使用经过化学修饰的、包含与miR-29b互补的序列的反义寡核苷酸(反miR-29b)来抑制miR-29b表达。所有碱基都是2′-OMe修饰的,头两个和最后四个碱基含有硫代磷酸酯核苷间键,且该寡核苷酸的3′端偶联有胆固醇。八周龄C57BL/6雄性小鼠经尾部静脉注射以80mg/kg体重的剂量接受反miR-29b(AsAsCACUGAUUUCAAAUGGUsGsCsUsAs-胆固醇)或错配miR-29b(AsAsAACUGAUGUCACAUGGUsGsAsUsAs-胆固醇)或体积相当的盐水。处理后3天或3周收集组织。
实施例1:压力响应性miRNA对心脏肥大和心力衰竭的调节
根据它们在调控细胞表型中的参与,发明人假设miRNA在调节心脏对心脏压力的响应中发挥作用,已知这导致基因表达的转录和翻译变化。为了调查miRNA在心脏肥大中可能的参与,他们使用代表186种不同miRNA的微阵列(Babak等,2004)在2种已建立的小鼠心脏肥大模型中实施了并行(side-by-side)miRNA微阵列分析。将进行胸主动脉绷扎(这通过提高心脏的后负荷而诱发肥大)的小鼠(TAB)(Hill等,2000)与进行假手术的动物进行比较。在第二种模型中,将在心脏中表达激活的钙依赖磷酸酶(CnA)(这导致严重的、已表征形式的肥大)的转基因小鼠(Molkentin等,1998)与野生型同窝幼仔进行比较(图14A)。自进行TAB的小鼠的心脏分离的RNA显示出与进行假手术的对照相比升高的27种miRNA表达,而CnA Tg小鼠显示出与非转基因同窝幼仔对照相比升高的33种miRNA表达,其中21种在这两种模型中都上调。类似地,TAB和CnA诱发的肥大分别伴有降低的15种和14种miRNA表达,其中7种miRNA共同下调(图14B)。对这些miRNA的Northern分析(未公开的数据)和先前的微阵列分析(Barad等,2004;Sempere等,2004;Shingara等,2005;Liu等,2004)指出了它们在广泛的组织中表达。基于它们的相对表达水平,人类、大鼠和小鼠序列的保守性,及肥大期间的表达水平,发明人聚焦于11种上调的miRNA和5种下调的miRNA(图14C)。
对来自WT和CnA Tg动物的心脏RNA的Northern印迹分析证实了升高的miR-21、-23、-24、-125b、-195、-199a、和-214表达及降低的miR-29、-93、-150和-181b表达(图14C和图15)。总之,这些数据指示独特的miRNA在心脏肥大期间上调,提示它们发挥此过程调控物的功能的可能性。
实施例2:miR-29家族作为miR-208调节的下游靶物的发现
在鉴定可能介导miR-208的作用的下游miRNA的努力中,本发明人对来自野生型和miR-208无效小鼠的心脏实施了miRNA微阵列(图16)。他们发现miR-29家族的多个成员在miR-208无效小鼠中上调(图17)。靶物预测指示miR-29家族成员靶向编码多种胶原和细胞外基质其它成分的mRNA(图18)。如此,miR-208无效小鼠中miR-29家族成员的上调有可能说明在这些动物中看到的对纤维化的阻断(图19)。
miR-29a-c在患病心脏中下调并靶向编码胶原和细胞外基质蛋白质的mRNA的发现提示增强miR-29a-c表达或其与靶物mRNA的结合的策略会对病理性心脏重塑和纤维化背景中的心脏具有有益效果。此外,miR-29a-c表达或功能的升高可阻止组织(诸如骨骼肌、肝、肺、肾和其它)中与许多疾病有关的纤维化。另外,miR-208遏制miR-29a-c表达及miR-208的丢失上调miR-29a-c表达的发现指示miR-29a-c是miR-208对心脏的作用的下游介导物。
实施例3:miR-29a-c调节纤维变性基因的表达
为了开始限定MI后心脏中miR-29a-c可能的功能,发明人利用计算预测来鉴定可能的miR-29a-c靶物。Targetscan预测万维网站指出了数目出乎意料高的编码胶原、金属肽酶、和整联蛋白的纤维化相关mRNA作为可能的miR-29a-c靶物(万维网网站位于targetscan.org)。为了确定miR-29a-c下调可能调节心脏纤维化,发明人聚焦于涉及心脏中ECM生成的预测靶物。弹性蛋白(ELN)、微纤维蛋白1(FBN1)、I型胶原α1和α2(COL1A1、COL1A2)及III型胶原α1(COL3A1)都含有miR-29a-c的一种或多种保守的潜在种子序列(图20A)。
因为miRNA下调其靶mRNA的稳态水平以及翻译,发明人分析了预测miR-29a-c mRNA靶的表达。对MI后3天心脏样品中心脏纤维化的这些关键调节性基因的实时RT-PCR分析指示梗死区域中miR-29a-c的特异性下调与COL1A1、COL1A2、COL3A1、和FBN1表达升高有关。相反,ELN表现出在缘带中无变化,而且甚至显示出在远端心肌中升高(图20B)。
使用CMV驱动的表达质粒,发明人用含有预测miR-29a-c靶物3′-UTR的萤光素酶表达质粒在COS细胞中过表达miR-29b-1和miR-29a(图20C)。提高CMV驱动的miR-29b-1/miR-29a的量导致萤光素酶活性的剂量依赖性降低,但是相当量的miR-206(作为对照)没有效果(图20C-D),证明了这些mRNA是受miR-29a-c遏制的靶物。
实施例4:心脏成纤维细胞中对miR-29a-c的调节
心脏纤维化是在衰竭心脏中通常看到的重塑过程的一个重要方面。成纤维细胞的增殖和ECM成分的沉积增加导致心肌僵硬和舒张功能障碍。转化生长因子β(TGFβ)已经显示出在心脏中胶原的生成和沉积方面发挥支配性作用,并诱导成纤维细胞转变成肌成纤维细胞(Border和Noble,1994)。对暴露于TGFβ的心脏成纤维细胞进行的实时PCR分析揭示了miR-29a-c表达的降低,提示MI后的miR-29a-c降低可能受TGFβ调节(图21A)。有趣的是,利钠肽(像B型利钠肽(BNP))已经显示出抑制与纤维化和肌成纤维细胞转变有关的、受TGEβ调节的基因表达(Kapoun等,2004)。在这点上,发明人先前报告了缺乏心脏特异性miRNA miR-208的小鼠对心脏纤维化和重塑有抗性,而且在基线时展现出升高的BNP表达(van Rooij等,2007)。由于已知BNP拮抗TGFβ的效果,因此本发明人推测这些小鼠中升高的BNP水平可能增强miR-29a-c的表达。事实上,Northern分析显示了清除miR-208后miR-29a-c表达的剂量依赖性升高,这与越来越高的BNP表达水平相符(图21B)。这些数据指示TGFβ在成纤维细胞中诱导胶原相关基因表达,至少部分经由降低miR-29a-c水平来实现,它们可以被由心肌细胞分泌的BNP抑制。
实施例5:miR-29a-c体内敲低诱导纤维化和胶原基因表达
为了进一步探索miR-29a-c作为胶原表达的负调节物的潜在作用,发明人使用与miR-29b的成熟miRNA序列互补的胆固醇修饰寡核苷酸(反miR-29b)在体内敲低miR-29b,以盐水或包含四碱基错配的寡核苷酸(mm miR-29b)作为阴性对照(图22A)。单次尾部静脉注射反miR-29b(80mg/kg)后三天,发明人观察到所检查的所有组织中miR-29b表达的显著降低(图22B)。相反,与盐水对照相比,相当剂量的mm miR-29b反义寡核苷酸对miR-29b的表达水平没有影响。通过反miR-29b实现的敲低表现出是对成熟miRNA特异性的,因为pre-miRNA的水平在反miR和mm处理的动物间仍然相当。虽然肝和肾中的敲低表现出是完全的,但是在心和肺中仍然可检测到低水平的miR-29b(图22B)。
由于其它miR-29成员与miR-29b共享高序列同源性,因此还检查了响应反miR-29b的miR-29a和-c表达。虽然在肝和肾中检测到显著的敲低(尤其是miR-29c),但是心脏表达没有表现出变化(图23)。实时PCR分析指示miR-29b敲低足以在肝中特异性诱导胶原基因表达,但是错配对照中没有这种效果(图22C)。
为了增强miR-29b的心脏敲低,发明人连续两天静脉内注射80mg/kg寡核苷酸,并在3周后收集材料。与mm miR-29b注射后看到的表达水平相比,Northern分析指示肾和肝中响应反miR-29b的miR-29b完全敲低。miR-29b的心脏水平也显著降低,但是肺中的miR-29b表达表现出不受反miR-29b影响(图22D)。心中的胶原表达响应miR-29b抑制而升高(图22E)。总之,这些数据指示miR-29b在体内发挥胶原基因表达的负调节物的功能,并由此影响心和肝中的胶原沉积和纤维化。
实施例6:用miR-29a-c模拟物下调胶原表达
为了确定miR-29a-c过表达是否能够降低胶原表达,本发明将成纤维细胞暴露于miR-29b模拟物。暴露于miR-29b模拟物3天后,成纤维细胞培养物中的miR-29b表达水平升高了多达400倍(图22F)。miR-29a表达不受影响,而miR-29c表达只被miR-29b模拟物轻微升高(图22F)。实时PCR分析指示胶原基因的表达响应miR-29b模拟物而降低(图22G)。然而,胶原表达的降低程度与miR-29b表达的升高相比是中等的,指示miR-29a-c水平不是胶原水平的唯一决定子。
通过述及将本文中所讨论和引用的所有出版物、专利和专利申请完整收入本文。根据本公开文本,无需过度实验就能做出和执行本文中所公开的和要求保护的所有组合物和方法。虽然已经在优选实施方案方面描述了本发明的组合物和方法,但是对本领域技术人员会显而易见的是,可以对本文所述组合物和方法,及所述方法的各步骤或各步骤的顺序进行改变而不背离本发明的概念、精神和范围。更具体的说,会显而易见的是,在化学和生理学这两方面相关的某些试剂可以替代本文所述药剂,而会实现相同或相似的结果。认为对本领域技术人员显而易见的所有此类相似替代和修改在本发明的精神、范围和概念内,它们由所附权利要求限定。
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序列表
<110>得克萨斯系统大学董事会
<120>调控纤维化的微小RNA家族及其用途
<130>UTFD:2021WO
<150>US 60/952,917
<151>2007-07-31
<150>US 60/980,303
<151>2007-10-16
<150>US 61/047,014
<151>2008-04-22
<160>22
<170>PatentIn version 3.5
<210>1
<211>71
<212>DNA
<213>人(Homo sapiens)
<400>1
tgacgggcga gcttttggcc cgggttatac ctgatgctca cgtataagac gagcaaaaag 60
cttgttggtc a 71
<210>2
<211>71
<212>DNA
<213>小家鼠(Mus sp.)
<400>2
tgacgggtga gcttttggcc cgggttatac ctgactctca cgtataagac gagcaaaaag 60
cttgttggtc a 71
<210>3
<211>71
<212>DNA
<213>家鼠(Rattus sp.)
<400>3
tgacgggtga gcttttggcc cgggttatac ctgactctca cgtataagac gagcaaaaag 60
cttgttggtc a 71
<210>4
<211>71
<212>DNA
<213>犬(Canis sp.)
<400>4
tgacgcatga gcttttggct cgggttatac ctgatgctca cgtataagac gagcaaaaag 60
cttgttggtc a 71
<210>5
<211>22
<212>RNA
<213>未知的
<220>
<223>miR-208序列
<400>5
auaagacgag caaaaagcuu gu 22
<210>6
<211>69
<212>RNA
<213>人
<400>6
uucuugcuuu aaagcaauug gucuaaaaua uauguaaucg ucuuaauuaa aaaguugcag 60
uaggguugc 69
<210>7
<211>69
<212>RNA
<213>黑猩猩(Pan sp.)
<400>7
uucuugcuuu aaagcaauug gucuaaaaua uauguaaucg ucuuaauuaa aacguugcag 60
uaggguugc 69
<210>8
<211>69
<212>RNA
<213>小家鼠
<400>8
uucuugcuuu aaagcaauug gucuaaaaua uauguaaucg ucuuaauuaa aacguugcag 60
uaggguugc 69
<210>9
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<213>家鼠
<400>9
uucuugcuuu aaagcaauug gucuaaaaua uauguaaucg ucuuaauuaa aacguugcag 60
uaggguugc 69
<210>10
<211>69
<212>RNA
<213>犬
<400>10
uucuugcuuu aaagcaauug gucuaaaaua uauguaaucg ucuuaauuaa aacguugcag 60
uaggguugc 69
<210>11
<211>69
<212>RNA
<213>原鸡(Gallus sp.)
<400>11
uucuugcuuu aaagcaauug gucuaaaaua uauguaaucg ucuuaauuaa aacguugcag 60
uaggguugc 69
<210>12
<211>72
<212>RNA
<213>东方鲀(Takifugu)
<400>12
uuccugcuuu aagcaauugg uugaaaauau auguauguaa uggucuuaau uaaaaaaaca 60
aacuaagaca aa 72
<210>13
<211>69
<212>RNA
<213>短担尼鱼(Danio sp.)
<400>13
uuccugcuuu aaagcaauug gucuaaaaua uauguaaucg ucuucauuac aaaaacgaac 60
caucaaacg 69
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<212>DNA
<213>人
<400>14
acgggcgagc ttttggcccg ggttatacct gatgctcacg tataagacga gcaaaaagct 60
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<210>15
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<212>DNA
<213>小家鼠
<400>15
acgggtgagc ttttggcccg ggttatacct gactctcacg tataagacga gcaaaaagct 60
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<210>16
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<212>DNA
<213>家鼠
<400>16
acgggtgagc ttttggcccg ggttatacct gactctcacg tataagacga gcaaaaagct 60
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<210>17
<211>71
<212>DNA
<213>犬
<400>17
acgcatgagc ttttggctcg ggttatacct gatgctcacg tataagacga gcaaaaagct 60
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<210>18
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<212>RNA
<213>人
<400>18
uagcaccauc ugaaaucggu ua 22
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<211>23
<212>RNA
<213>人
<400>19
uagcaccauu ugaaaucagu guu 23
<210>20
<211>22
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<213>人
<400>20
uagcaccauu ugaaaucggu ua 22
<210>21
<211>71
<212>RNA
<213>未知的
<220>
<223>Pre miR-208序列
<400>21
ugacgggcga gcuuuuggcc cggguuauac cugaugcuca cguauaagac gagcaaaaag 60
cuuguugguc a 71
<210>22
<211>27
<212>RNA
<213>人
<400>22
uagcaccauu ugaaagaaau caguguu 27
Claims (30)
1.一种在组织中诱导胶原沉积的药物组合物,其包含miR-29a-c的拮抗剂,其中所述拮抗剂是具有与成熟miR-29a、miR-29b或miR-29c序列100%互补的序列的小RNA拮抗剂或反义寡核苷酸,并且其中所述组合物是凝胶、洗剂、或软膏剂。
2.权利要求1的药物组合物,其中所述小RNA拮抗剂或反义寡核苷酸具有与SEQ ID NO:18、SEQ ID NO:19或SEQ ID NO:20100%互补的序列。
3.权利要求1的药物组合物,其中所述软膏剂是乳膏。
4.miR-29a-c的拮抗剂在制备用于治疗皮肤老化、拉伸纹、或包含伤口、晒伤、化学损伤、烫伤、或冻伤的组织的药物中的用途,其中所述药物在有需要的受试者的组织中诱导胶原沉积,并且其中所述拮抗剂是具有与成熟miR-29a、miR-29b或miR-29c序列100%互补的序列的小RNA拮抗剂或反义寡核苷酸。
5.权利要求4的用途,其中所述小RNA拮抗剂或反义寡核苷酸具有与SEQ ID NO:18、SEQ ID NO:19、或SEQ ID NO:20100%互补的序列。
6.权利要求4的用途,其中所述组织是面部组织。
7.权利要求6的用途,其中所述面部组织是额组织、唇、颊、颏、眉、眼睑、眼的下面、或口的附近。
8.权利要求4的用途,其中所述组织是手组织、颈组织、臂组织、腿组织、胃组织、或乳房组织。
9.权利要求4的用途,其中所述组织包括伤口、皮肤移植物、瘢痕组织、皱纹、皮肤松垂、晒伤、化学损伤、烫伤、冻伤、和/或拉伸纹。
10.权利要求4的用途,其中所述药物制备成注射入所述组织中、注射入供给所述组织的脉管系统中、或局部应用的药物。
11.权利要求10的用途,其中局部应用包括软膏剂或凝胶的使用。
12.权利要求10的用途,其中局部应用包括乳膏、油膏剂或香膏的使用。
13.权利要求10的用途,所述药物为与压迫绷带或裹覆物使用的药物。
14.权利要求4的用途,所述药物为与第二药剂或第二处理应用的药物。
15.权利要求14的用途,其中所述第二药剂是局部维生素A、局部维生素C、或维生素E。
16.权利要求14的用途,其中所述第二处理包括化学脱皮、激光处理、皮肤整平、或皮肤磨削术。
17.miR-29a-c的拮抗剂在制备用于预防有需要的受试者脉管系统中软斑破裂的药物中的用途,其中将所述药物递送至所述受试者的血管壁中的一个或多个软斑部位,其中在递送所述药物后所述一个或多个软斑转变成纤维变性组织,并且其中所述拮抗剂是具有与成熟miR-29a、miR-29b或miR-29c序列100%互补的序列的小RNA拮抗剂或反义寡核苷酸。
18.权利要求17的用途,其中所述反义寡核苷酸或小RNA拮抗剂具有与SEQ ID NO:18、SEQ ID NO:19或SEQ ID NO:20的序列100%互补的序列。
19.权利要求17的用途,其中所述药物通过导管递送至所述一个或多个软斑部位。
20.权利要求17的用途,其中所述药物通过用所述药物包被的支架或球囊递送至所述一个或多个软斑部位。
21.一种用于将血管壁中的软斑转变成纤维变性组织的药物组合物,其包含用miR-29a-c的至少一种拮抗剂包被的医学装置,其中所述拮抗剂是具有与成熟miR-29a、miR-29b或miR-29c序列100%互补的序列的小RNA拮抗剂或反义寡核苷酸。
22.权利要求21的组合物,其中所述医学装置是支架或球囊。
23.权利要求21的组合物,其中所述反义寡核苷酸或小RNA拮抗剂具有与SEQ ID NO:18、SEQ ID NO:19或SEQ ID NO:20的序列100%互补的序列。
24.权利要求21的组合物,其中所述组合物进一步包含抗再狭窄化合物,该抗再狭窄化合物选自下组:帕利他塞、雷帕霉素、他克莫司、唑他莫司、依维莫司、多西他塞和吡美莫司。
25.权利要求1-3和21-24中任一项的组合物,其中所述反义寡核苷酸具有至少一个糖和/或骨架修饰。
26.权利要求25的组合物,其中所述糖修饰是锁定核酸或2’-O-烃基修饰。
27.权利要求25的组合物,其中所述骨架修饰是硫代磷酸酯连接。
28.权利要求4-20中任一项的用途,其中所述反义寡核苷酸具有至少一个糖和/或骨架修饰。
29.权利要求28的用途,其中所述糖修饰是锁定核酸或2’-O-烃基修饰。
30.权利要求28的用途,其中所述骨架修饰是硫代磷酸酯连接。
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