CN117715660A - 右心室致心律失常性心肌病的基因治疗组合物和治疗 - Google Patents
右心室致心律失常性心肌病的基因治疗组合物和治疗 Download PDFInfo
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- CN117715660A CN117715660A CN202280034403.0A CN202280034403A CN117715660A CN 117715660 A CN117715660 A CN 117715660A CN 202280034403 A CN202280034403 A CN 202280034403A CN 117715660 A CN117715660 A CN 117715660A
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Abstract
公开了一种治疗或预防人类受试者的心肌病的组合物和方法。在一些实施方案中,所述方法包括将治疗剂量的基因治疗载体递送到所述人类受试者的心肌细胞,其中所述基因治疗载体包含对PKP2进行编码的核酸序列。
Description
相关申请的交叉引用
本发明要求2021年3月19日提交的美国临时专利申请No.63/163,393的优先权利益,该案的公开内容特此以全文引用方式并入本文中。
技术领域
本发明涉及心脏疾病(例如,心肌病)的治疗,并且更具体地说,涉及用于治疗心肌病的基因治疗方法和医药组合物。
背景技术
尽管药理学在治疗诸如心脏衰竭之类的各种心脏疾患中取得进展,但死亡率和发病率仍然高得令人无法接受。此外,某些治疗方法不适于许多患者(例如患有与其他共病症相关的晚期心脏衰竭疾患的患者)。替代方法,诸如基因疗法和细胞疗法,由于可唯一地定制并且有效解决多种心脏疾病的根本致病机制而引起较大关注。
发明内容
本发明的一个目标是提供将治疗多核苷酸序列递送到受试者(诸如人类受试者)的心肌细胞的方法。
本发明的某些实施方案的另一个目标是将对桥粒斑菲素蛋白2(PKP2)蛋白进行编码的多核苷酸序列搭载在病毒载体(诸如腺相关病毒)中。
本发明的某些实施方案的另一个目标是利用基因治疗方法来矫正PKP2突变的心肌细胞中的单倍不足性。
本发明的某些实施方案的另一个目标是在对于PKP2为单倍不足的细胞中增加对功能PKP2蛋白的表达。
以上目标和其他目标是通过本发明来满足,其中至少一个方面涉及一种治疗或预防受试者(例如,人类受试者)的心肌病的方法。所述方法包括例如将治疗剂量的基因治疗载体递送到所述受试者的心肌细胞,其中所述基因治疗载体包含对PKP2进行编码的核酸序列。在一些实施方案中,将所述基因治疗载体递送到对于桥粒斑菲素蛋白2(PKP2)为单倍不足的心肌细胞导致所述心肌细胞对PKP2的桥粒表达增加至少1.1倍、1.2倍、1.3倍、1.4倍、1.5倍、2倍、2.5倍、3倍、4倍或5倍。在一些实施方案中,将所述基因治疗载体递送到所述心肌细胞导致所述PKP2的桥粒表达为非单倍不足心肌细胞进行的桥粒表达的至少50%。
在至少一个实施方案中,所述基因治疗载体包括病毒载体。在至少一个实施方案中,所述病毒载体包括AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、AAV12、其变异体及其组合中的一者或多者。在至少一个实施方案中,所述病毒载体包括AAV6或AAV9。在至少一个实施方案中,所述病毒载体包括AAV6。
在至少一个实施方案中,所述核酸序列还对心肌特异性启动子进行编码。
在至少一个实施方案中,所述治疗剂量足以通过影响所述受试者的所述心肌细胞对所述PKP2或其功能变异体的产生来治疗或预防致心律失常性右心室心肌病(ARVC)。
在至少一个实施方案中,所述治疗剂量的所述递送是通过静脉进行的。
在至少一个实施方案中,所述受试者是人类受试者。
在另一个方面中,一种基因治疗载体适于在受试者的心肌细胞内表达核酸序列。在至少一个实施方案中,所述核酸序列包括:对PKP2或其功能变异体进行编码的第一序列;以及包含心肌特异性启动子的第二序列。在至少一个实施方案中,将所述基因治疗载体递送到对于PKP2为单倍不足的心肌细胞导致所述心肌细胞对PKP2的总桥粒表达增加至少1.5倍、2倍、2.5倍、3倍、4倍或5倍。在至少一个实施方案中,将所述基因治疗载体递送到为单倍不足的心肌细胞导致所述PKP2的总桥粒表达为非单倍不足心肌细胞进行的总桥粒表达的至少50%。
在至少一个实施方案中,所述基因治疗载体包括病毒载体。在至少一个实施方案中,所述病毒载体包括AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、AAV12、其变异体及其组合中的一者或多者。在至少一个实施方案中,所述病毒载体包括AAV6或AAV9。
在至少一个实施方案中,所述心肌特异性启动子包含TNNT2或具有至少99%、95%、90%、85%、80%、75%或70%相似性的功能序列。
在至少一个实施方案中,所述受试者是人类受试者。
在另一个方面中,调配一种用于治疗或预防受试者的心肌病的治疗调配物。在至少一个实施方案中,所述治疗调配物包含:医药学上可接受的赋形剂或载剂;以及包含对PKP2或其功能变异体进行编码的核酸序列的病毒载体。在至少一个实施方案中,将所述治疗调配物递送到对于PKP2为单倍不足的心肌细胞导致所述心肌细胞对PKP2的总桥粒表达增加至少1.5倍、2倍、2.5倍、3倍、4倍或5倍。在至少一个实施方案中,将治疗调配物载体递送到为单倍不足的心肌细胞导致所述PKP2的总桥粒表达为非单倍不足心肌细胞进行的总桥粒表达的至少50%。
在至少一个实施方案中,所述治疗调配物还包含:一个或多个额外病毒载体,所述一个或多个额外病毒载体各自包含对一个或多个非PKP2肌节蛋白或其功能变异体进行编码的核酸序列。在至少一个实施方案中,所述受试者是人类受试者。
在另一个方面中,一种对具有突变的PKP2基因的心肌细胞进行基因修饰以表达功能PKP2或其功能变异体的方法包括:用对所述功能PKP2进行编码的核酸序列来转染或转导所述心肌细胞,其中所述转染或转导导致所述心肌细胞对所述功能PKP2的总桥粒表达增加至少1.5倍、2倍、2.5倍、3倍、4倍或5倍。在至少一个实施方案中,所述转染或转导导致所述功能PKP2的总桥粒表达为具有非突变的PKP2基因的心肌细胞进行的总桥粒表达的至少50%。
在至少一个实施方案中,所述核酸序列是经由病毒载体递送,所述病毒载体包括AAV6或AAV9。在至少一个实施方案中,所述病毒载体包括AAV6。
在至少一个实施方案中,所述核酸序列还对心肌特异性启动子进行编码。在至少一个实施方案中,所述心肌特异性启动子包含TNNT2或具有至少99%、95%、90%、85%、80%、75%或70%相似性的功能序列。
在至少一个实施方案中,前述方法或调配物中的任一项中的PKP2为PKP2异构体2a。
在至少一个实施方案中,前述方法或调配物中的任一项中的PKP2为PKP2异构体2b。
在另一个方面中,一种用于治疗或预防受试者的心肌病的治疗调配物包含:医药学上可接受的赋形剂或载剂;包含对PKP2异构体2a或其功能变异体进行编码的核酸序列的第一病毒载体;以及包含对PKP2异构体2b或其功能变异体进行编码的核酸序列的第二病毒载体。在至少一个实施方案中,将所述治疗调配物递送到对于PKP2异构体2a或异构体2b为单倍不足的心肌细胞导致所述心肌细胞对PKP2异构体2a或异构体2b的总桥粒表达增加至少1.5倍、2倍、2.5倍、3倍、4倍或5倍。在至少一个实施方案中,将治疗调配物载体递送到为单倍不足的心肌细胞导致PKP2异构体2a或异构体2b的总桥粒表达为非单倍不足心肌细胞进行的总桥粒表达的至少50%。
在另一个方面中,使用前述实施方案中的任一者中的基因治疗载体来对隔离细胞进行转导。在至少一个实施方案中,所述细胞是人类细胞。在至少一个实施方案中,所述细胞是心脏细胞。在至少一个实施方案中,所述细胞是人诱导多能干细胞衍生的心肌细胞。
在另一个方面中,一种向上调节具有突变的PKP2基因的心肌细胞中的一个或多个桥粒蛋白的方法包括:用对功能PKP2进行编码的核酸序列来转染或转导所述心肌细胞,所述功能PKP2选自PKP2异构体2a和PKP2异构体2b,其中所述转染或转导导致所述一个或多个桥粒蛋白中的每一者的总桥粒表达增加至少1.1倍、1.2倍、1.3倍、1.4倍、1.5倍、2倍、2.5倍、3倍、4倍或5倍,其中所述一个或多个桥粒蛋白是选自桥粒斑蛋白1、桥粒斑蛋白2、桥粒胶蛋白2、斑珠蛋白、桥粒芯蛋白2和连接蛋白43。
在另一个方面中,一种治疗或预防受试者的心肌病的方法包括:将治疗剂量的基因治疗载体递送到所述受试者的心肌细胞,其中所述心肌细胞对于桥粒斑菲素蛋白2(PKP2)是单倍不足的,其中所述基因治疗载体包含对非显性PKP2异构体或其功能变异体进行编码的核酸序列,其中将所述基因治疗载体递送到所述心肌细胞导致所述心肌细胞对PKP2的总桥粒表达增加至少1.5倍、2倍、2.5倍、3倍、4倍或5倍,并且其中所述PKP2的所述总桥粒表达包括显性PKP2异构体和所述非显性PKP2异构体的表达。在至少一个实施方案中,所述显性PKP2异构体是PKP2异构体2a,并且其中所述非显性PKP2异构体是PKP2异构体2b。
附图说明
在结合附图考虑以下详细描述后,本发明的以上和其他特征、其性质和各种优势将变得更显而易见,其中:
图1示出了位于野生型2D人诱导多能干细胞衍生心肌细胞(“hiPSC-CM”)中的桥粒细胞-细胞连接处的PKP2的荧光显微镜图像;
图2示出了确认在用AAV9对对照心肌细胞进行转导以及位于桥粒细胞-细胞连接处之后PKP2的表达的荧光显微镜图像;
图3示出了PKP2蛋白质表达的蛋白质印迹,其中PKP2突变的细胞系的单倍不足性是通过与对照细胞系相比PKP2表达减少而显而易见;
图4示出了在PKP2突变的hiPSC-CM的AAV9介导转导之后PKP2异构体2b的表达和恰当定位的荧光显微镜图像;
图5示出了与两个野生型hiPSC-CM对照物(Asi和Cau)相比PKP2突变的hiPSC-CM;
图6示出了与无血缘关系的对照心肌细胞、未衰竭人类心脏(NFH)组织和PKP2患者的心肌细胞相比减少的内源性PKP2表达;
图7示出了PKP2异构体2a是人类组织中的主导PKP2异构体;
图8示出了与对照细胞和患者细胞相比在用密码子优化的PKP2异构体2b进行AAV9介导转导之后的RNA水平;
图9A示出了基于内源性肌球蛋白结合蛋白C水平与对照细胞相比在转导之后的PKP2蛋白质水平;
图9B示出了基于内源性心肌肌钙蛋白T水平与对照细胞相比在转导之后的PKP2蛋白质水平;
图10A示出了由于外源性PKP2蛋白的表达导致桥粒斑蛋白1、桥粒斑蛋白2、桥粒胶蛋白2和斑珠蛋白的向上调节的表达;以及
图10B示出了由于外源性PKP2蛋白的表达导致桥粒芯蛋白2和连接蛋白43的向上调节的表达。
定义
除非上下文另外明确指出,否则如本文所使用,单数形式“一个”和“所述”包括多个参考物。因此,例如,提及“药物”包括单一药物以及两种或两种以上不同药物的混合物;并且提及“病毒载体”包括单一病毒载体以及两种或两种以上不同病毒载体的混合物,及其类似情形。
此外,如本文所使用,当结合测得的量使用时,“约”是指如本领域普通技术人员所预期的使测量和操作与测量的目标和测量设备的精确度在所关心的水平上相称的测得的量的正常变化。在某些实施方案中,术语“约”包括所述数值±10%,由此“约10”将包括9到11。
此外,如本文所使用,“多核苷酸”具有它在此项技术中的普通且惯用的含义并且包括任何聚合核酸,诸如DNA或RNA分子,以及本领域技术人员已知的化学衍生物。多核苷酸不仅包括编码治疗蛋白的多核苷酸,并且还包括可用于使用此项技术中已知的技术减少目标核酸序列的表达的序列(例如反义、干扰或小干扰核酸)。多核苷酸还可以用于起始或增加心血管系统的细胞内目标核酸序列的表达或目标蛋白质的产生。目标核酸和蛋白质包括但不限于通常见于目标组织中的核酸和蛋白质、此类天然存在的核酸或蛋白质的衍生物、不常见于目标组织中的天然存在的核酸或蛋白质、或合成核酸或蛋白质。一种或多种多核苷酸可组合使用,同时和/或依次施用,以增加和/或减少一种或多种目标核酸序列或蛋白质。
此外,如本文所使用,“外源”核酸或基因是自然界中不存在于用于核酸转移的载体中的核酸;例如非天然存在于病毒载体中的核酸,但该术语不意欲排除编码天然存在于患者或宿主中的蛋白质或多肽的核酸。
此外,如本文所使用,“心脏细胞”包括参与维持结构或提供心脏功能的任何心脏细胞,诸如心肌细胞、心脏血管结构的细胞或存在于心脏瓣膜中的细胞。心脏细胞包括心肌细胞(具有正常和异常电特性两者)、上皮细胞、内皮细胞、纤维母细胞、传导组织的细胞、心脏起搏细胞和神经元。
此外,如本文所使用,“腺相关病毒”或“AAV”涵盖所有亚型、血清型和假型,以及天然存在的形式和重组形式。多种AAV血清型和病毒株是此项技术中已知的并且可公开得自多种来源,诸如ATCC,和学术或商业来源。另选地,可使用已知技术合成公开和/或得自多种数据库的来自AAV血清型和病毒株的序列。
此外,如本文所使用,“血清型”是指基于与确定的抗血清的衣壳蛋白反应性来鉴别并与其他AAV相区别的AAV。存在至少十二种已知血清型的人类AAV,包括AAV1到AAV12,但仍不断发现另外的血清型,并且考虑使用新发现的血清型。
此外,如本文所使用,“假型”AAV是指含有来自一种血清型的衣壳蛋白和病毒基因体的AAV,所述病毒基因体包括不同或异源血清型的5'和3'反向末端重复序列(ITR)。假型重组AAV(rAAV)预计将具有衣壳血清型的细胞表面结合特性和与ITR血清型一致的遗传特性。假型rAAV可包括AAV衣壳蛋白,包括VP1、VP2和VP3衣壳蛋白;以及来自任何血清型AAV的ITR,包括来自AAV1到AAV12的任何灵长类动物AAV血清型,只要衣壳蛋白为与ITR的血清型异源的血清型即可。在假型rAAV中,5'和3'ITR可为相同或异源的。假型rAAV是使用此项技术中所描述的标准技术产生。
此外,如本文所使用,“嵌合”rAAV载体涵盖包含异源衣壳蛋白的AAV载体;即,rAAV载体关于其衣壳蛋白VP1、VP2和VP3可为嵌合的,使得VP1、VP2和VP3不是都属于相同血清型AAV。如本文所使用,嵌合AAV涵盖AAV,使得衣壳蛋白VP1、VP2和VP3在血清型方面不同,包括例如但不限于来自AAV1和AAV2的衣壳蛋白;是其他细小病毒衣壳蛋白的混合物或包含其他病毒蛋白或其他蛋白质,诸如将AAV靶向递送到所希望细胞或组织的蛋白质。如本文所使用,嵌合rAAV还涵盖包含嵌合5'和3'ITR的rAAV。
此外,如本文所使用,“医药学上可接受的赋形剂或载剂”是指组合物中与调配物中的活性剂组合的任何惰性成分。医药学上可接受的赋形剂可包括但不限于碳水化合物(诸如葡萄糖、蔗糖或聚葡萄糖)、抗氧化剂(诸如抗坏血酸或麸胱甘肽)、螯合剂、低分子量蛋白质、高分子量聚合物、胶凝剂或其他稳定剂和添加剂。医药学上可接受的载剂的其他示例包括润湿剂、乳化剂、分散剂或特别适用于防止微生物生长或作用的防腐剂。各种防腐剂是熟知的并且包括例如苯酚和抗坏血酸。载剂、稳定剂或佐剂的示例可见于Remington'sPharmaceutical Sciences,Mack Publishing Company,Philadelphia,Pa.,第17版.(1985)。
此外,如本文所使用,“患者”是指表现出一种或多种表明需要治疗的特定症状的临床表现、针对疾患进行了预防性治疗、或已诊断患有待治疗的疾患的受试者,特别是人类(但也可以涵盖非人类)。
此外,如本文所使用,“受试者”涵盖术语“患者”的定义并且不排除在其他方面健康的个体。
此外,如本文所使用,“治疗”包括施用药物以旨在降低例如心脏疾病等疾患严重程度,或预防例如心脏疾病等疾患。
此外,如本文所使用,“预防”包括避免例如心脏疾病等疾患的发生。
此外,如本文所使用,“疾患”是指可通过向个体施用有效量的药物来治疗、缓解或预防的医学疾患,诸如心脏疾病。
此外,如本文所使用,“有效量”是指足以产生某一水平的有益或所希望效果的药物的量,该水平可通过常用于检测此类效果的方法容易地检测到。在一些实施方案中,此类效果引起相对于未施用药物的基础水平的值至少10%的变化。在其他实施方案中,所述变化是相对于基础水平的至少20%、50%、80%或甚至更高百分比。如下文将描述,药物的有效量可取决于受试者的年龄、一般状况、所治疗疾患的严重程度、所施用的特定药物及其类似因素,随各受试者而变化。在任何个别情况下适当的“有效”量可由本领域普通技术人员参考相关文本和文献和/或通过使用常规实验来确定。
此外,如本文所使用,“活性剂”是指预期会产生治疗、预防或其他预期效果的任何物质,无论是否被政府机构批准用于所述目的。
除非本文另外指示,否则本文中的值的范围的叙述仅意欲充当个别地提及在所述范围内的每一单独值的简写方法,并且每一单独值并入本说明书中,如同在本文中个别地叙述一般。除非本文另外指明或与上下文明显矛盾,否则本文所描述的所有方法可以按任何适合的顺序进行。本文所提供的任何和所有示例或示例性语言(例如“诸如”)的使用仅意欲说明某些物质和方法并且不对范围造成限制。本说明书的语言均不应解释为指示任何非主张的要素对于所公开的物质和方法的实践为必不可少的。
具体实施方式
致心律失常性右心室心肌病(ARVC)是主要的心肌疾病并且是年轻人心脏性猝死(SCD)的主要原因。其特征在于心肌的心肌变性和纤维脂肪替代,这可能存在于右心室和/或左心室中并且最终导致渐进性心脏衰竭。临床心脏表型的特征在于典型心电图异常的存在、室性心律失常的负担增加以及心脏磁共振成像上的广泛性心肌疤痕。
ARVC在约50%的病例中是家族性遗传的并且通常作为常染色体显性性状遗传。约30%的白人后裔患者携带PKP2基因的显性突变。大部分突变会由于插入-缺失、无义或剪接位点突变而导致异常或截短蛋白质,从而导致单倍不足性。
ARVC被认为是一种桥粒病,桥粒是在心肌细胞之间提供机械附接的电子致密结构。PKP2是形成桥粒蛋白质复合体的部分的若个基因中的一个,并且其中导致ARVC的突变已经被识别出。PKP2蛋白质的缺少通过单倍不足性使具有机械和信号结果的桥粒蛋白质复合体不稳定。
机械组分在体外通过在机械应力条件下由PKP2蛋白质的缺少引起的异常基因表达模式突出显示,所述机械应力条件涉及若干细胞外基质基因(诸如不同胶原蛋白)的向下调节以及纤维形成胶原蛋白、纤连蛋白和其他促纤维化标志物(诸如TIMP1)的强向上调节。在临床前和临床背景中,这通过在PKP2鼠模型的操练中发生ARVC恶化和对人类(诸如运动员)的表型的操练的不利影响来反映。在信令级,缺少桥粒斑菲素蛋白导致桥粒斑珠蛋白易位到核,这导致典型Wnt/b-catenin信令减少和成纤维和成脂肪基因的表达增加。
PKP2的两种主要形式包括PKP2异构体2a(SEQ ID NO:3)和PKP2异构体2b(SEQ IDNO:5)。PKP2异构体2a的PKP2基因的蛋白质编码部分包含在2764bp cDNA序列(基因库:BC126199.1;SEQ ID NO:1)中,所述2764bp cDNA序列可以通过本发明而搭载在AAV中。如本文所使用,除非另外说明或从上下文中看出,否则“PKP2”或“PKP2蛋白质”应被解释为涵盖PKP2的异构体,包括PKP2异构体2a和PKP2异构体2b。
某些实施方案可以通过经由AAV9-TNNT2-PKP2介导基因转移替换正常的等位基因来矫正PKP2蛋白质的单倍不足性。在某些实施方案中,本发明的组合物和方法能够例如(1)将PKP2蛋白质正确地定位到桥粒;以及(2)在PKP2突变的人诱导多能干细胞衍生心肌细胞(iPSC-CM)中矫正单倍不足性并且因此矫正桥粒蛋白质复合体。某些实施方案还设想到在携带两个反式致病性突变的iPSC-CM中导致完全或近完全PKP2缺陷。测试PKP2多核苷酸到心肌细胞的递送的非限制性说明性实施方案包括:(1)使用TNNT2启动子将PKP2搭载到AAV9和/或AAV6中;产生携带PKP2突变的iPSC-CM(反式的1突变或2突变);在体外用AAV6-PKP2或AAV9-PKP2对2D PKP2突变的心肌细胞培养物(携带1或2突变)进行转导以及测试到桥粒中的亚细胞定位;测试分子和生理数据,包括细胞大小、收缩性和转录组分析。
虽然本文中的许多实施方案是关于PKP2蛋白质进行描述,但应理解,设想到额外蛋白质(例如,肌节蛋白)的表达。除PKP2以外的示例性蛋白质可包括但不限于以下一者或多者:SERCA2、MYBPC3、MYH7、MYL3、MYL2、ACTC1、TPM1、TNNT2、TNNI3、TTN、FHL1、ALPK3、肌缩蛋白、FKRP、其变异体或其组合。所用的一种或多种蛋白质还可以是本文中所提及的蛋白质的功能变异体并且与原始蛋白质相比可以展现出相当大的氨基酸序列一致性。例如,氨基酸一致性可合计为至少约30%、至少约35%、至少约40%、至少约45%、至少约50%、至少约55%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约96%、至少约97%、至少约98%或至少约99%。在此情形下,术语“功能变异体”表示蛋白质的变异体能够部分或完全实现天然存在的相应蛋白质的功能。蛋白质的功能变异体可以包括例如由于一个或多个氨基酸取代、缺失或添加而与其天然存在的对应物不同的蛋白质。
氨基酸取代可以是保守性或非保守性的。优选地,取代是保守性取代,即,氨基酸残基被充当功能等效物的具有类似极性的氨基酸取代。优选地,用作取代物的氨基酸残基是选自与待取代的氨基酸残基相同的氨基酸群组。例如,疏水性残基可被另一疏水性残基取代,或极性残基可被具有相同电荷的另一极性残基取代。可用于保守性取代的功能同源的氨基酸包括例如非极性氨基酸,诸如甘氨酸、缬氨酸、丙氨酸、异亮氨酸、亮氨酸、甲硫氨酸、脯氨酸、苯丙氨酸和色氨酸。不带电极性氨基酸的示例包括丝氨酸、苏氨酸、谷氨酰胺、天冬酰胺、酪氨酸和半胱氨酸。带电极性(碱性)氨基酸的示例包括组氨酸、精氨酸和离氨酸。带电极性(酸性)氨基酸的示例包括天冬氨酸和谷氨酸。
因一个或多个(例如2、3、4、5、10或15个)额外氨基酸而不同于其天然存在的对应物的蛋白质也被视为变异体。这些额外氨基酸可存在于原始蛋白质的氨基酸序列内(即,作为插入物),或它们可添加到蛋白质的一个或两个末端中。基本上,如果添加氨基酸不会削弱多肽在所治疗的受试者中实现天然存在的蛋白质的功能的能力,则插入可在任何位置进行。此外,蛋白质的变异体还包括与原始多肽相比缺乏一个或多个氨基酸的蛋白质。此类缺失可能会影响任何氨基酸位置,只要它不会削弱实现蛋白质的正常功能的能力。
最后,心脏肌节蛋白(例如,PKP2)的变异体还指因结构修饰诸如经修饰的氨基酸而不同于天然存在的蛋白质的蛋白质。经修饰的氨基酸是通过天然方法,诸如处理或转译后修饰或通过此项技术中已知的化学修饰方法修饰的氨基酸。典型氨基酸修饰包括磷酸化;糖基化;乙酰化;O连接的N-乙酰基葡萄糖胺化;谷胱甘肽化;酰化;分支化;ADP核糖基化;交联;二硫桥形成;甲酰化;羟基化;羧化;甲基化;去甲基化;酰胺化;环化;和/或与磷脂酰肌醇、黄素衍生物、脂壁酸、脂肪酸或脂质共价或非共价键结。
编码目标蛋白质的治疗性多核苷酸序列可以以基因治疗载体(即,核酸构筑体)形式施用待治疗的受试者,所述核酸构筑体包含紧邻提供外源核酸的表达所需的其他序列,诸如启动子、kozak序列、聚腺苷酸信号以及其类似序列的编码序列,包括转译和终止密码子。
例如,基因治疗载体可以是哺乳动物表达系统的一部分。有用的哺乳动物表达系统和表达构筑体是可商购的。另外,若干哺乳动物表达系统是由不同制造商经销并且可用于本发明中,诸如基于质体或病毒载体的系统,例如LENTI-SmartTM(InvivoGen)、GenScriptTM表达载体、pAdVAntageTM(Promega)、ViraPowerTM慢病毒、腺病毒表达系统(Invitrogen)和腺相关病毒表达系统(Cell Biolabs)。
用于表达本发明的外源治疗性多核苷酸序列的基因治疗载体可以是例如病毒或非病毒表达载体,所述表达载体适于将外源治疗性多核苷酸序列引入细胞中以用于随后表达由所述核酸编码的蛋白质。表达载体可以是游离型载体,即,能够自主地在宿主细胞内自我复制的载体;或整合载体,即,稳定并入细胞基因体中的载体。宿主细胞中的表达可以是组成型或调节型(例如诱导型)的。
在某一实施方案中,基因治疗载体是病毒表达载体。用于本发明的病毒载体可以包括病毒基因体,其中一部分天然序列已缺失以便引入异源多核苷酸,而不会破坏病毒的感染性。由于病毒组分与宿主细胞受体之间的特异性相互作用,病毒载体特别适于将基因有效转移到目标细胞中。适于促进基因转移到哺乳动物细胞中的病毒载体可来源于不同类型的病毒,例如AAV、腺病毒、反转录病毒、单纯疱疹病毒、牛乳头状瘤病毒、慢病毒、牛痘病毒、多瘤病毒、仙台病毒、正粘病毒、副粘病毒、乳多泡病毒、微小RNA病毒、痘病毒、α病毒或适于基因疗法的任何其他病毒穿梭体、其变异体及其组合。
“腺病毒表达载体”或“腺病毒”意欲包括含腺病毒序列的构筑体,所述腺病毒序列足以(a)支持治疗性多核苷酸序列构筑体的包装,和/或(b)最终表达其中选殖的组织和/或细胞特异性构筑体。在本发明的一个实施方案中,表达载体包含经基因工程改造的形式的腺病毒。了解腺病毒(36千碱基(kb)的线性双股DNA病毒)的遗传组织允许用至多7kb的外来序列取代大片段腺病毒DNA。
腺病毒生长和操作是本领域的技术人员已知的,并且在活体外和活体内展现出较宽宿主范围。该组病毒可以以高效价例如109至1011个蚀斑形成单位/毫升获得,并且它们具有高度感染性。腺病毒的生命周期不需要整合到宿主细胞基因体中。通过腺病毒载体递送的外来基因是游离型的,因此对宿主细胞具有较低基因毒性。在用野生型腺病毒进行疫苗接种的研究中未报导副作用,表明其作为活体内基因转移载体的安全性和/或治疗潜力。
反转录病毒(又称为“反转录病毒载体”)可能会由于它们能够将其基因整合到宿主基因体中、转移大量外来遗传物质、感染广谱物种和细胞类型和用于包装在特殊细胞系中而被选择作为基因递送载体。
反转录病毒基因体含有三个基因,即gag、pol和env,分别编码衣壳蛋白、聚合酶和包膜组分。在gag基因上游发现的序列含有用于将基因体包装到病毒粒子中的信号。两个长末端重复(LTR)序列存在于病毒基因体的5'和3'端。这些序列含有强启动子和强化子序列并且也是整合在宿主细胞基因体中所需的。
为了构筑反转录病毒载体,将编码所关注基因的核酸代替某些病毒序列插入到病毒基因体中,以产生复制缺陷型病毒。为了产生病毒粒子,构筑含有gag、pol和/或env基因但没有LTR和/或包装组分的包装细胞系。当将含有cDNA以及反转录病毒LTR和包装序列的重组质体引入此细胞系中(例如通过磷酸钙沉淀)时,包装序列允许将重组质体的RNA转录物包装在病毒颗粒中,所述病毒颗粒接着分泌到培养基中。接着,收集含有重组反转录病毒的培养基,任选地浓缩并且用于基因转移。反转录病毒载体能够感染广泛多种细胞类型。然而,整合和稳定表达需要宿主细胞分裂。
反转录病毒可来源于任何亚科。例如,可以使用来自鼠肉瘤病毒、牛白血病、病毒劳斯肉瘤病毒、鼠白血病病毒、貂细胞灶诱导病毒、网状内皮细胞增生病病毒或禽类白血病性病毒的载体。本领域的技术人员将能够组合来源于不同反转录病毒的部分,诸如LTR、tRNA结合位点和包装信号,以提供重组反转录病毒。这些反转录病毒接着通常用于产生转导胜任性反转录病毒载体颗粒。出于此目的,将载体引入适合的包装细胞系中。还可以通过将嵌合整合酶并入反转录病毒颗粒中来构筑反转录病毒以便位点特异性整合到宿主细胞的DNA中。
因为单纯疱疹病毒(HSV)是亲神经性的,所以它已在治疗神经系统病症中获得大量关注。此外,HSV在非分裂神经元细胞中产生潜伏感染而不会整合到宿主细胞染色体中或以其他方式改变宿主细胞的代谢的能力,以及在潜伏期期间具有活性的启动子的存在使得HSV成为有吸引力的载体。此外,尽管许多关注都集中于HSV的亲神经性应用,但考虑到其较宽的宿主范围,该载体也可以用于其他组织。
使HSV成为有吸引力载体的另一个因素是基因体的大小和组织。因为HSV很大,所以与其他较小病毒系统相比,并入多个基因或表达盒更不成问题。另外,与其他系统中相比,具有不同性能(时间、强度等)的不同病毒控制序列的可获得性使得有可能在较大程度上控制表达。还有一个优点是所述病毒具有相对较少的剪接消息,进一步便于进行遗传操作。
HSV还相对易于操作并且可生长达到高效价。因此,就获得足够感染倍率(MOI)所需的体积和减少重复给药的需求两个方面而言,递送不成问题。已研发出HSV的无毒变异体并且所述变异体可容易地用于基因疗法情形中。
慢病毒是复杂的反转录病毒,除含有共有的反转录病毒基因gag、pol和env以外,慢病毒还含有其他具有调节或结构功能的基因。较高的复杂度使得病毒能够调节其生命周期,如在潜伏感染过程中。慢病毒的一些示例包括人类免疫缺陷病毒(HIV-1、HIV-2)和猿猴免疫缺陷病毒(SIV)。慢病毒载体已通过多次减弱HIV致病性基因产生,例如基因env、vif、vpr、vpu和nef缺失使得载体在生物学上为安全的。
慢病毒载体是基于质体或基于病毒的,并且经过构形以携带用于并入外来核酸、用于选择和用于将核酸转移到宿主细胞中的必需序列。所关注载体的gag、pol和env基因也是此项技术中已知的。因此,将相关基因选殖到所选载体中并且接着用于转型所关注的目标细胞。
牛痘病毒载体由于其构筑容易、获得的表达量相对较高、较宽的宿主范围和有较大容量用于携带DNA而被广泛使用。牛痘含有约186kb的线性双股DNA基因体,该基因体展现出明显的“A-T”偏好。约10.5kb的反向末端重复序列侧接所述基因体。大部分必需基因看起来是在中心区域内定位,这在痘病毒中具有极高保守性。估计牛痘病毒的开放阅读框数目为150到200个。尽管编码两个股,但阅读框的大量重叠并不常见。
可以将至少25kb插入牛痘病毒基因体中。原型牛痘载体含有经由同源重组插入到病毒胸苷激酶基因中的转殖基因。载体是基于tk表型进行选择。包括脑心肌炎病毒的非转译前导序列产生比常规载体高的表达量,其中转殖基因在24小时内积累10%或更多的受感染细胞的蛋白质。
乳多泡病毒(诸如小鼠多瘤病毒)的空衣壳已作为用于基因转移的可能载体而引起关注。空多瘤病毒的使用最先是在无细胞系统中培育多瘤病毒DNA和经纯化空衣壳时描述。新颗粒的DNA受到保护而免于胰脏脱氧核糖核酸酶的作用。使用经重构颗粒将转型多瘤病毒DNA片段转移到大鼠FIII细胞。空衣壳和经重构颗粒由全部三种多瘤病毒衣壳抗原VP1、VP2和VP3组成。
AAV是属于依赖病毒属的小病毒。它们是无包膜的小单股DNA病毒,需要辅助病毒才能进行复制。需要与辅助病毒(例如腺病毒、疱疹病毒或牛痘病毒)共感染以形成功能完整的AAV病毒粒子。在活体外,在不存在与辅助病毒共感染的情况下,AAV产生病毒基因体以游离型形式存在但不产生感染性病毒粒子的潜伏状态。随后通过辅助病毒的感染“拯救”基因体,允许其复制并且包装于病毒衣壳中,由此重构感染性病毒粒子。最新数据表明,活体内野生型AAV和重组AAV都主要以较大游离型串联体形式存在。在一个实施方案中,本文中所使用的基因治疗载体是AAV载体。AAV载体可以是经纯化的复制非胜任型假型rAAV颗粒。
AAV不与任何已知人类疾病相关,一般不被视为致病性的,并且看起来在整合后不会改变宿主细胞的生理特性。AAV可感染广泛范围的宿主细胞,包括非分裂细胞,并且可感染来自不同物种的细胞。相比于通过细胞和体液反应两者快速清除或不活化的一些载体,已表明AAV载体在活体内在各种组织中诱导持久转殖基因表达。重组AAV介导的转殖基因在活体内在非分裂细胞中的续存可能是由于缺乏天然AAV病毒基因和载体的与ITR关联的形成游离型串联体的能力。
AAV是用于本发明的细胞转导的有吸引力的载体系统,因为它作为游离型串联体具有高频续存性并且它可以感染非分裂细胞,包括心肌细胞,由此使其可用于将基因递送到哺乳动物细胞中,例如在组织培养物中和在活体内。
通常,rAAV是通过共转染含有侧接两个AAV末端重复序列的所关注基因的质体和/或含有野生型AAV编码序列并且无末端重复序列的表达质体(例如pIM45)来制造。细胞还被腺病毒和/或携带AAV辅助功能所需的腺病毒基因的质体感染和/或转染。以此类方式制造的rAAV的储备液被腺病毒污染,腺病毒必须与rAAV颗粒以物理方式分离(例如通过氯化铯密度离心或管柱层析)。另选地,可使用含有AAV编码区的腺病毒载体和/或含有AAV编码区和/或一些或全部腺病毒辅助基因的细胞系。还可以使用携带rAAV DNA作为整合的原病毒的细胞系。
自然界中存在多种AAV血清型,具有至少十二种血清型(AAV1-AAV12)。尽管具有高度同源性,但不同血清型对不同组织具有趋向性。在转染后,AAV仅在宿主中引发次要免疫反应(若存在)。因此,AAV特别适合于基因疗法方法。
在一些实施方案中,本公开可针对一种药物,所述药物包含AAV载体,所述AAV载体为以下中的一者或多者:AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、AAV12、ANC AAV、来源于其的嵌合AAV、其变异体及其组合,所述AAV载体将甚至更佳地适于所关注组织中的高效转导。在某些实施方案中,基因治疗载体是AAV血清型1载体。在某些实施方案中,基因治疗载体是AAV血清型2载体。在某些实施方案中,基因治疗载体是AAV血清型3载体。在某些实施方案中,基因治疗载体是AAV血清型4载体。在某些实施方案中,基因治疗载体是AAV血清型5载体。在某些实施方案中,基因治疗载体是AAV血清型6载体。在某些实施方案中,基因治疗载体是AAV血清型7载体。在某些实施方案中,基因治疗载体是AAV血清型8载体。在某些实施方案中,基因治疗载体是AAV血清型9载体。在某些实施方案中,基因治疗载体是AAV血清型10载体。在某些实施方案中,基因治疗载体是AAV血清型11载体。在某些实施方案中,基因治疗载体是AAV血清型12载体。
适用于人类的AAV的剂量可在以下范围内:约1×108vg/kg至约3×1014vg/kg、约1×108vg/kg、约1×109vg/kg、约1×1010vg/kg、约1×1011vg/kg、约1×1012vg/kg、约1×1013vg/kg或约1×1014vg/kg。病毒颗粒或DRP的总量为、为约、为至少、为至少约、不超过或不超过约5×1015vg/kg、4×1015vg/kg、3×1015vg/kg、2×1015vg/kg、1×1015vg/kg、9×1014vg/kg、8×1014vg/kg、7×1014vg/kg、6×1014vg/kg、5×1014vg/kg、4×1014vg/kg、3×1014vg/kg、2×1014vg/kg、1×1014vg/kg、9×1013vg/kg、8×1013vg/kg、7×1013vg/kg、6×1013vg/kg、5×1013vg/kg、4×1013vg/kg、3×1013vg/kg、2×1013vg/kg、1×1013vg/kg、9×1012vg/kg、8×1012vg/kg、7×1012vg/kg、6×1012vg/kg、5×1012vg/kg、4×1012vg/kg、3×1012vg/kg、2×1012vg/kg、1×1012vg/kg、9×1011vg/kg、8×1011vg/kg、7×1011vg/kg、6×1011vg/kg、5×1011vg/kg、4×1011vg/kg、3×1011vg/kg、2×1011vg/kg、1×1011vg/kg、9×1010vg/kg、8×1010vg/kg、7×1010vg/kg、6×1010vg/kg、5×1010vg/kg、4×1010vg/kg、3×1010vg/kg、2×1010vg/kg、1×1010vg/kg、9×109vg/kg、8×109vg/kg、7×109vg/kg、6×109vg/kg、5×109vg/kg、4×109vg/kg、3×109vg/kg、2×109vg/kg、1×109vg/kg、9×108vg/kg、8×108vg/kg、7×108vg/kg、6×108vg/kg、5×108vg/kg、4×108vg/kg、3×108vg/kg、2×108vg/kg或1×108vg/kg,或在由这些值中的任何两个限定的范围内。以上所列剂量以vg/kg心脏组织为单位。
除病毒载体之外,还可以使用非病毒表达构筑体将编码目标蛋白质或其功能变异体或片段的基因引入患者细胞中。允许目标细胞中蛋白质的活体内表达的非病毒表达载体包括例如质体、经修饰的RNA、mRNA、cDNA、反义寡聚物、DNA-脂质复合物、纳米颗粒、胞外体、适用于基因疗法的任何其他非病毒穿梭体、其变异体及其组合。
除病毒载体和非病毒表达载体之外,核酸酶系统还可以与载体和/或电穿孔系统结合使用以进入患者的细胞中并且在其中引入编码目标蛋白质或其功能变异体或片段的基因。示例性核酸酶系统可以包括但不限于成簇规律间隔短回文重复序列(CRISPR)、DNA切割酶(例如Cas9)、大范围核酸酶、TALEN、锌指核酸酶、适于基因疗法的任何其他核酸酶系统、其变异体及其组合。例如,在一个实施方案中,一个病毒载体(例如AAV)可用于核酸酶(例如CRISPR)并且另一病毒载体(例如AAV)可用于DNA切割酶(例如Cas9),以将(核酸酶和DNA切割酶)两者引入目标细胞中。
可用于将编码治疗性基因的治疗性多核苷酸序列递送到细胞中的其他载体递送系统是受体介导的递送媒剂。这些受体介导的递送媒剂利用通过受体介导的内饮作用在几乎所有真核细胞中进行的大分子的选择性吸收。由于各种受体的细胞类型特异性分布,递送可具有高度特异性。受体介导的基因靶向媒剂可包括两种组分:细胞受体特异性配体和DNA结合剂。
适用于将非病毒载体转移到目标细胞中的方法是例如脂质转染法、磷酸钙共沉淀法、DEAE-聚葡萄糖法和使用微玻璃管、超声波、电穿孔及其类似方法的直接DNA引入法。在引入载体之前,可用渗透剂处理心肌细胞,所述渗透剂诸如磷脂酰胆碱、链球菌溶血素、癸酸钠、癸酰肉碱、酒石酸、溶血卵磷脂、Triton X-100及其类似物。还可以使用胞外体转移裸DNA或AAV衣壳化DNA。
本发明的基因治疗载体可包含与编码目标蛋白质的核酸序列功能性连接的启动子。启动子序列必须为紧密的并且确保较强表达。优选地,启动子提供已使用基因治疗载体治疗的患者的心肌中目标蛋白质的表达。在一些实施方案中,基因治疗载体包含可操作地连接到编码目标蛋白质的核酸序列的心脏特异性启动子。如本文所使用,“心脏特异性启动子”是指在心脏细胞中的活性比任何其他非心脏细胞类型中的活性高至少2倍的启动子。优选地,适合用于本发明的载体中的心脏特异性启动子在心脏细胞中的活性比其在非心脏细胞类型中的活性要高至少5倍、至少10倍、至少15倍、至少20倍、至少25倍或至少50倍。
心脏特异性启动子可以是所选人类启动子,或包含与所选人类启动子具有至少约80%、至少约90%、至少约95%、至少约96%、至少约97%、至少约98%或至少约99%序列一致性的功能等效序列的启动子。可使用的示例性非限制性启动子是肌钙蛋白T启动子(TNNT2)。启动子的其他非限制性示例包括α肌凝蛋白重链启动子、肌凝蛋白轻链2v启动子、α肌凝蛋白重链启动子、α-心脏肌动蛋白启动子、α-肌旋蛋白启动子、肌钙蛋白C启动子、肌钙蛋白I启动子、心脏肌凝蛋白-结合蛋白C启动子和肌质网/内质网Ca2+-ATP酶(SERCA)启动子(例如该启动子的同功异型物2(SERCA2))。
可用于本发明的载体可具有不同转导效率。因此,病毒载体或非病毒载体转导超过、等于或至少约10%、约20%、约30%、约40%、约50%、约55%、约60%、约65%、约70%、约75%、约80%、约85%、约90%、约95%、约99%或100%的目标血管部位的细胞。可同时或依序使用超过一种载体(病毒或非病毒载体,或其组合)。此可用于转移超过一个多核苷酸,和/或靶向超过一种细胞类型。当使用多种载体或多种试剂时,可产生超过一种转导/转染效率。
含有基因治疗载体的医药组合物可制备为液体溶液或悬浮液形式。本发明的医药组合物可以包括常用的医药学上可接受的赋形剂,诸如稀释剂和载剂。明确地说,所述组合物包含医药学上可接受的载剂,例如水、盐水、林格氏溶液或右旋糖溶液。除载剂以外,医药组合物还可以含有乳化剂、pH缓冲剂、稳定剂、染料及其类似物。
在某些实施方案中,医药组合物将包含治疗有效的基因剂量,所述剂量是能够预防或治疗受试者的心肌病,而对受试者无毒的剂量。心肌病的预防或治疗可以按与心肌病相关联的表型特征的变化评定,其中此类变化可有效预防或治疗心肌病。因此,治疗有效的基因剂量通常是当以生理上可耐受的组合物形式施用时足以改善或预防所治疗受试者的致病性心脏表型的基因剂量。
在某些实施方案中,可经由若干种不同的方法将基因治疗载体转导到受试者体内,包括静脉内递送、动脉内递送或腹腔内递送。在一些实施方案中,基因治疗载体可直接施用于心脏组织,例如,通过冠状动脉内施用。在一些实施方案中,心肌的组织转导可通过导管介导心肌内递送来完成,导管介导心肌内递送可用于将与转导增强载剂偶联或解偶联的无载体cDNA转移到心肌中。
在某些实施方案中,药物将包含治疗有效基因剂量。治疗有效基因剂量是能够预防或治疗患者的特定心脏疾患但不会对患者有毒性的基因剂量。
可通过本文所公开的方法治疗的心脏疾患可包括但不限于以下中的一者或多者:遗传学上确定的心脏疾病(例如遗传学上确定的心肌病)、心律不整性心脏病、心脏衰竭、局部缺血、心律不整、心肌梗塞、充血性心脏衰竭、移植排斥反应、异常心脏收缩、非缺血性心肌病、二尖瓣回流、主动脉瓣狭窄或逆流、异常Ca2+代谢、先天性心脏病、原发性或继发性心脏肿瘤及其组合。
说明性示例
阐述以下示例以帮助理解本公开,并且所述示例当然不应视为特定地限制本文所描述和主张的实施方案。实施方案的此类变化,包括将在本领域技术人员的能力范围内的目前已知或之后研发的所有等效物的替代,以及调配物的变化或实验设计的微小变化,将被认为在并入本文中的实施方案的范围内。
示例1:(预测)
在体外系统的说明性示例中,PKP2异构体2a cDNA序列(2764bp cDNA,基因库:BC126199.1;SEQ ID NO:1)在心脏特异性TNNT2启动子(SEQ ID NO:6)下并且使用AAV2内部末端重复(ITR):ITR-TNNT2-PKP2cDNA-ITR来克隆。对PKP2进行编码的核酸序列可以是对PKP2异构体2a蛋白质进行编码的PKP2基因的密码子优化版本(SEQ ID NO:2)。作为另一个说明性示例,对PKP2进行编码的核酸序列可以是对PKP2异构体2b蛋白质进行编码的PKP2基因的密码子优化版本(SEQ ID NO:4)。
构筑体可搭载到AAV中,诸如AAV6和AAV9。可准备好添加了Flag的构筑体(Flag-PKP2)以便能够在转染之后通过anti-Flag识别蛋白质并且将它与内源性蛋白质区分开。SEQ ID NO:7是用于表达例如PKP2异构体2b的示例性构筑体序列。PKP2在体外的表达可使用PKP2初级抗体通过免疫荧光显微镜观察到,从而显露了PKP2在细胞膜处或致密斑中的定位。
为了进一步提高基因表达水平,设想到,可将一个或多个neo-内含子并入到本文描述的基因治疗载体中。例如,可以利用“嵌合内含子”,嵌合内含子是指包含从两个不同基因衍生的至少两个不同内含子的部分的内含子,诸如从人β-珠蛋白基因和人免疫球蛋白G衍生的内含子序列。在一些实施方案中,neo-内含子可以紧跟着插入于启动子的下游。在一些实施方案中,neo-内含子可放在PKP2 cDNA序列的不同位置,诸如在外显子1之后和在外显子2之前。
使用AAV6-TNNT2-PKP2在2D细胞培养物中转染iPSC-CM,所述2D细胞培养物包括:正常心肌细胞;携带1杂合PKP2突变的心肌细胞(来自ARVC患者);和携带两个反式PKP2突变的心肌细胞。
在PKP2 RNA和蛋白质水平的成功转染和表征之后,对多个读出执行正常与PKP2缺陷和PKP2矫正CM的比较,包括:细胞大小和关于PKP2缺陷具有已知的更改表达的基因(MYL2、SCN5A(其蛋白质产物是NaV1.5)、GJA1和TTN)的矫正。
设想到,类似方法可适于人类3D培养模型中的体外治疗以及PKP2突变鼠模型中的体内治疗。
据信,在(Flag-)PKP2蛋白质被表达时,它将到达它正确的亚细胞定位(桥粒),并且转染在RNA级别和蛋白质级别矫正了PKP2单倍不足或完全缺乏的细胞。在完全PKP2缺乏的细胞中,据信,PKP2转染也能够在桥粒中恢复桥粒蛋白质复合体,尤其是恢复桥粒斑珠蛋白,它在PKP2减少时会减少。
进一步设想到,用于表达PKP2异构体2a、PKP2异构体2b或该两者的基因治疗载体可被递送到人类受试者的心脏组织。例如,基因治疗载体可被调配为治疗调配物,所述治疗调配物包含一个或多个基因治疗载体和医药学上可接受的赋形剂或载剂。可通过若干种不同的方法将调配物转导到人类受试者体内,包括静脉内递送、动脉内递送或腹腔内递送。基因治疗载体可直接施用于心脏组织,例如,通过冠状动脉内施用。基因治疗载体还可以经由导管介导心肌内递送来递送。
进一步设想到,基因治疗载体可以局部施用到受试者的心脏组织,例如,通过使受试者的冠脉循环与受试者的全身循环隔离,因此形成闭合回路,并且将流体(例如,包含基因治疗载体的调配物)灌注到受试者的隔离的冠脉循环中。灌注可以在受试者的不停止搏动的心脏中进行。所述闭合回路可例如由以下各者形成:定位在患者的右冠状动脉中的第一药物递送导管;定位在患者的左主冠状动脉中的第二药物递送导管;定位在冠状窦中的药物收集导管;冠状动脉;冠状静脉系统;以及插入于静脉分支和动脉分支之间的外部膜式氧合器。此类局部递送可以如关于2020年8月26日提交的国际申请No.PCT/IB2020/000692所描述般来执行,该申请的公开内容特此以全文引用方式并入本文中。
示例2:hiPSC衍生心肌细胞中的桥粒PKP2表达
桥粒复合体的蛋白质在二维(2D)细胞培养物中的人诱导多能干细胞衍生(hiPSC-衍生)的正常心肌细胞中表达并且位于形成桥粒的亚细胞结构处。图1示出了位于野生型2DhiPSC-衍生心肌细胞中的桥粒细胞-细胞连接处的PKP2的荧光显微镜图像。
用与示例1中描述的载体类似的还包含FLAG-标签的AAV9-TNNT2-PKP2b进行对照hiPSC心肌细胞的转导。图2示出了确认FLAG-标签信号被表达并且正确地定位到野生型心肌细胞中的桥粒细胞-细胞连接处的萤光显微镜图像。
随后表征PKP2突变的hiPSC衍生心肌细胞并且将其与作为对照组的亚洲人(Asi)和白种人(Cau)的各种野生型细胞系进行比较以在细胞级显示单倍不足性。图3示出了PKP2蛋白质表达的蛋白质印迹,其中PKP2突变的细胞系的单倍不足性是通过与对照细胞系相比PKP2表达减少而显而易见(量化与心肌肌钙蛋白T有关)。
用具有TNNT2启动子的PKP2异构体2b FLAG标签的转基因对PKP2突变的hiPSC衍生心肌细胞的AAV9介导转导被证明为导致PKP2异构体2b的表达和正确定位,如图4的荧光显微镜图像中所示。
在本文描述的实验中,已发现hiPSC衍生心肌细胞仅用于表达PKP2异构体2a,表明这是不够成熟、发育调节的异构体。相反,在成熟的人类心脏组织中,全长度PKP2b异构体2b占主导。在总蛋白质级别,使用蛋白质印迹来确认用AAV9-TNNT2-PKP2b-FLAG进行的转导将单倍不足状态矫正到PKP2突变的hiPSC心肌细胞中的完全PKP2蛋白质表达。图5示出了与两个野生型hiPSC-CM对照组(Asi和Cau)相比PKP2突变的hiPSC-CM(“PKP2”)。MYBPC3和cTnT用作参考蛋白质,用于计算被表达的PKP2的相对量。PKP2突变的hi-IPSC-CM表明与两个对照细胞系相比PKP2蛋白质表达的量显著减少。PKP2表达在用AAV9-PKP2转导之后在数量上得到矫正。请注意,转导的细胞表现出PKP2双细胞(doublet),表示从AAV介导转基因产生的PKP2异构体2b和在hiPSC-CM中自然表达的PKP2异构体2a。PKP2异构体2b的从头表达完全耐受并且不会在PKP2突变心肌细胞或野生型对照心肌细胞中导致明显功能更改。
示例3:减少的内源性PKP2表达
图6示出了与无血缘关系的对照心肌细胞、未衰竭人类心脏(NFH)组织和PKP2患者的心肌细胞(其对于PKP2为单倍不足的)相比减少的内源性PKP2表达。如所示,PKP2患者的心肌细胞与正常的对照细胞相比以及与未衰竭人类心脏(NFH)相比表达较少PKP2。在无转导(“PKP2患者NT NA”)的情况下,在用神经氨酸酶(在细胞培养物中用AAV9进行转导期间用到)治疗时,内源性PKP2的含量不会改变。用密码子优化的PKP2异构体2b载体(“PKP2患者TD2b opt”)来进行转导,其中启动子被选择为不结合到野生型PKP2序列,因此导致在转导之后无变化。
图7示出了PKP2异构体2a是人类组织(无血缘关系的对照组、未衰减人类心脏)中的主导PKP2异构体。在神经氨酸酶作用下并且在用密码子优化的PKP2b(具有上述的非结合的启动子)进行转导之后,这仍保持不变。在NFH细胞、对照细胞或PKP2患者心肌细胞中未检测到PKP2异构体2b全长度异构体。PKP2异构体2a呈现为总PKP2的大约一半。
示例4:总PKP2水平的恢复
图8A和图8B示出了与NFH细胞和两个无血缘关系的对照组的细胞(“wt”)、患者细胞和经治疗的细胞(“NT NA”)的均值相比在用密码子优化的PKP2异构体2b(“TD”)进行AAV9介导转导之后的RNA水平。图9A和图9B示出了在转导之后的总蛋白质水平,将健康的对照CM水平和PKP2患者的CM水平(无转导)与在转导后患者细胞中的PKP2水平进行比较。在图9A中,总PKP2蛋白质水平是关于内源性肌球蛋白结合蛋白C(MYBPC3)水平来确定,并且在图9B中,PKP2蛋白质水平是关于内源性心肌肌钙蛋白T(cTnT)水平来确定。如图8至图9中所示,转导恢复了PKP2患者CM中的总PKP2水平。这是使用PKP2异构体2b的外源性表达来实现的,尽管PKP2异构体2a是主导异构体,如图7所示。
示例5:桥粒蛋白质复合体中的其他蛋白质的恢复
图10A和图10B示出了与在用密码子优化的PKP2异构体2b进行AAV9介导转导之后的患者CM相比未经治疗的患者CM中的桥粒蛋白质复合体的各种蛋白质的表达,所述蛋白质包括桥粒斑蛋白1、桥粒斑蛋白2、桥粒胶蛋白2、斑珠蛋白、桥粒芯蛋白2和连接蛋白43。不愿受理论束缚,据信,外源性PKP2的表达导致与对于PKP2为单倍不足的细胞相比各种桥粒蛋白质的向上调节。
在前述描述中,阐述诸如特定材料、尺寸、工艺参数等众多具体细节,以提供对本发明的透彻理解。在一个或多个实施方案中,特定特征、结构、材料或特性可以用任何适合方式组合。“示例”或“示例性”一词在本文用以表示充当示例、例子或例示。不必将本文中描述为“示例”或“示例性”的任何方面或设计理解为比其他方面或设计更佳或有利。实际上,使用词语“示例”或“示例性”仅意欲以具体方式呈现概念。如本申请中所使用,术语“或”意欲表示包括性的“或”,而非排他性的“或”。即,除非另外说明,或根据上下文显而易见,否则“X包括A或B”意欲表示天然包括性排列中的任一者。即,如果X包括A;X包括B;或X包括A和B二者,则在前述情形中的任一者下满足“X包括A或B”。本说明书通篇提及“一实施方案”、“某些实施方案”或“一个实施方案”表示结合实施方案所描述的特定特征、结构或特性包括在至少一个实施方案中。因此,在本说明书通篇各处出现的词组“一实施方案”、“某些实施方案”或“一个实施方案”未必均指代同一实施方案。
已参考本发明的特定示例性实施方案描述了本发明。因此,应在说明性意义上而非限制性意义上看待说明书和图式。除本文所显示和描述的修改外的本发明的各种修改对于本领域技术人员将变得显而易见,并且其意欲落在所附权利要求书的范围内。
下面的SEQ ID NO:1是包括用于PKP2异构体2a的蛋白质编码序列的mRNA序列的cDNA拷贝(基因库:BC126199.1):
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下面的SEQ ID NO:2是对PKP2异构体2a进行编码的密码子优化的cDNA序列(5'到3'):
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下面的SEQ ID NO:3是用于PKP2异构体2a的氨基酸序列:
下面的SEQ ID NO:4是对PKP2异构体2b进行编码的密码子优化的cDNA序列(5'到3'):
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下面的SEQ ID NO:5是用于PKP2异构体2b的氨基酸序列:
下面的SEQ ID NO:6是对TNNT2启动子编码的核酸序列(5'到3'):
下面的SEQ ID NO:7是用于在心肌细胞中表达PKP2异构体2b的示例性载体构筑体:
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序列表
<110> UCL商业有限公司(UCL BUSINESS LTD)
<120> 右心室致心律失常性心肌病的基因治疗组合物和治疗
<130> U07981WO
<150> US 63/163,393
<151> 2021-03-19
<160> 7
<170> PatentIn版本3.5
<210> 1
<211> 2764
<212> DNA
<213> 人类(Homo sapiens)
<400> 1
gagtccagag gcaggcgagc agctcggtcg cccccaccgg ccccatggca gcccccggcg 60
ccccagctga gtacggctac atccggaccg tcctgggcca gcagatcctg ggacaactgg 120
acagctccag cctggcgctg ccctccgagg ccaagctgaa gctggcgggg agcagcggcc 180
gcggcggcca gacagtcaag agcctgcgga tccaggagca ggtgcagcag accctcgccc 240
ggaagggccg cagctccgtg ggcaacggaa atcttcaccg aaccagcagt gttcctgagt 300
atgtctacaa cctacacttg gttgaaaatg attttgttgg aggccgttcc cctgttccta 360
aaacctatga catgctaaag gctggcacaa ctgccactta tgaaggtcgc tggggaagag 420
gaacagcaca gtacagctcc cagaagtccg tggaagaaag gtccttgagg catcctctga 480
ggagactgga gatttctcct gacagcagcc cggagagggc tcactacacg cacagcgatt 540
accagtacag ccagagaagc caggctgggc acaccctgca ccaccaagaa agcaggcggg 600
ccgccctcct agtgccaccg agatatgctc gttccgagat cgtgggggtc agccgtgctg 660
gcaccacaag caggcagcgc cactttgaca cataccacag acagtaccag catggctctg 720
ttagcgacac cgtttttgac agcatccctg ccaacccggc cctgctcacg taccccaggc 780
cagggaccag ccgcagcatg ggcaacctct tggagaagga gaactacctg acggcagggc 840
tcactgtcgg gcaggtcagg ccgctggtgc ccctgcagcc cgtcactcag aacagggctt 900
ccaggtcctc ctggcatcag agctccttcc acagcacccg cacgctgagg gaagctgggc 960
ccagtgtcgc cgtggattcc agcgggagga gagcgcactt gactgtcggc caggcggccg 1020
cagggggaag tgggaatctg ctcactgaga gaagcacttt cactgactcc cagctgggga 1080
atgcagacat ggagatgact ctggagcgag cagtgagtat gctcgaggca gaccacatgc 1140
tgccatccag gatttctgct gcagctactt tcatacagca cgagtgcttc cagaaatctg 1200
aagctcggaa gagggttaac cagcttcgtg gcatcctcaa gcttctgcag ctcctaaaag 1260
ttcagaatga agacgttcag cgagctgtgt gtggggcctt gagaaactta gtatttgaag 1320
acaatgacaa caaattggag gtggctgaac taaatggggt acctcggctg ctccaggtgc 1380
tgaagcaaac cagagacttg gagactaaaa aacaaataac aggtttgctg tggaatttgt 1440
catctaatga caaactcaag aatctcatga taacagaagc attgcttacg ctgacggaga 1500
atatcatcat ccccttttct gggtggcctg aaggagacta cccaaaagca aatggtttgc 1560
tcgattttga catattctac aacgtcactg gatgcctaag aaacatgagt tctgctggcg 1620
ctgatgggag aaaagcgatg agaagatgtg acggactcat tgactcactg gtccattatg 1680
tcagaggaac cattgcagat taccagccag atgacaaggc cacggagaat tgtgtgtgca 1740
ttcttcataa cctctcctac cagctggagg cagagctccc agagaaatat tcccagaata 1800
tctatattca aaaccggaat atccagactg acaacaacaa aagtattgga tgttttggca 1860
gtcgaagcag gaaagtaaaa gagcaatacc aggacgtgcc gatgccggag gaaaagagca 1920
accccaaggg cgtggagtgg ctgtggcatt ccattgttat aaggatgtat ctgtccttga 1980
tcgccaaaag tgtccgcaac tacacacaag aagcatcctt aggagctctg cagaacctca 2040
cggccggaag tggaccaatg ccgacatcag tggctcagac agttgtccag aaggaaagtg 2100
gcctgcagca cacccgaaag atgctgcatg ttggtgaccc aagtgtgaaa aagacagcca 2160
tctcgctgct gaggaatctg tcccggaatc tttctctgca gaatgaaatt gccaaagaaa 2220
ctctccctga tttggtttcc atcattcctg acacagtccc gagtactgac cttctcattg 2280
aaactacagc ctctgcctgt tacacattga acaacataat ccaaaacagt taccagaatg 2340
cacgcgacct tctaaacacc gggggcatcc agaaaattat ggccattagt gcaggcgatg 2400
cctatgcctc caacaaagca agtaaagctg cttccgtcct tctgtattct ctgtgggcac 2460
acacggaact gcatcatgcc tacaagaagg ctcagtttaa gaagacagat tttgtcaaca 2520
gccggactgc caaagcctac cactccctta aagactgagg aaaatgacaa agtattctcg 2580
gctgcaaaaa tccccaaagg aaaacaccta tttttctact acccagccca agaaacctca 2640
aaagcatgcc ttgtttctat ccttctctat ttccgtggtc ccctgaatcc agaaaacaaa 2700
tagaacataa ttttatgagt cttccagaag acctttgcaa gtttgccacc agtagatacc 2760
ggcc 2764
<210> 2
<211> 2514
<212> DNA
<213> 人工(artificial)
<220>
<223> 对PKP2a进行编码的密码子优化的cDNA
<400> 2
atggctgctc ctggtgctcc tgccgagtac ggctacatca gaacagtgct gggccagcag 60
atcctgggac agctggattc tagctctctg gccctgcctt ctgaggccaa gctgaaactg 120
gccggcagtt ctggaagagg cggccagaca gtgaagtccc tgcggatcca agaacaggtg 180
cagcagaccc tggccagaaa gggcagatct tctgtcggca acggcaacct gcacagaacc 240
agctctgtgc ccgagtacgt gtacaatctg cacctggtgg aaaacgactt cgtcggcggc 300
agatcccctg tgcctaagac ctacgatatg ctgaaggccg gcaccaccgc cacctatgaa 360
ggcagatggg gaagaggcac agcccagtac agcagccaga aaagcgtgga agagagaagc 420
ctgcggcacc ctctgcggag actggaaatc agccctgata gcagcccaga gagagcccac 480
tacacccaca gcgactacca gtactcccag agatctcagg ccggccacac actgcaccac 540
caagagtcta gaagggccgc tctgctggtg cctcctagat acgccagatc tgagatcgtg 600
ggcgtgtcca gagccggcac aacaagcaga cagagacact tcgacaccta ccaccggcag 660
tatcagcacg gcagcgtgtc cgataccgtg ttcgatagca tccccgccaa tcctgctctg 720
ctgacatacc ctagacctgg cacctccaga tccatgggca atctgctgga aaaagagaac 780
tacctgaccg ccggactgac cgtgggacaa gttcgacctc tggttcctct gcagcccgtg 840
acacagaaca gagccagcag aagcagctgg caccagtcca gcttccacag caccagaaca 900
ctgagagaag ctggccctag cgtggccgtg gattcttctg gtagaagggc tcacctgaca 960
gttggccaag cagctgcagg cggaagcgga aatctgctga ccgagagaag caccttcacc 1020
gacagccagc tgggcaacgc cgacatggaa atgacactgg aacgggccgt gtccatgctg 1080
gaagccgatc acatgctgcc cagcagaatt agcgccgctg ccacctttat ccagcacgag 1140
tgcttccaga agtctgaggc ccggaagaga gtgaaccagc tgagaggcat cctgaagctg 1200
ctgcagctcc tgaaggtgca gaacgaggat gtgcagaggg ctgtgtgtgg ggccctgaga 1260
aatctggtgt tcgaggacaa cgacaacaag ctggaagtgg ccgagctgaa cggcgtgcca 1320
agactgctgc aggttctgaa acagacccgc gacctggaaa caaagaagca gatcaccggc 1380
ctgctctgga acctgagcag caacgacaag ctgaagaacc tgatgatcac agaggccctg 1440
ctgaccctga cagagaacat catcatccct ttcagcggct ggcccgaggg cgattaccct 1500
aaagctaatg gcctgctgga cttcgacatc ttctacaacg tgaccggctg cctgagaaac 1560
atgtctagcg ctggcgccga tggcagaaag gccatgagaa gatgtgacgg cctgatcgac 1620
agcctggtgc actatgtgcg gggcacaatc gccgattacc agcctgatga taaggccacc 1680
gagaactgcg tgtgcatcct gcacaacctg agctaccagc tggaagcaga gctgcccgag 1740
aagtacagcc agaacatcta catccagaac cggaacatcc agaccgacaa caacaagagc 1800
atcggctgct tcggcagccg cagccggaaa gtgaaagaac agtaccagga cgtgcccatg 1860
cctgaggaaa agtctaaccc caaaggcgtg gaatggctgt ggcacagcat cgtgatccgg 1920
atgtacctga gcctgatcgc caagagcgtg cggaattaca cccaagaggc atctctgggc 1980
gccctgcaga atctgacagc aggatctggc cctatgccta cctctgtggc tcagaccgtg 2040
gtgcagaaag agtctggcct gcagcacacc cggaagatgc tgcatgtggg agatcccagc 2100
gtgaagaaaa ccgccatcag cctgctgaga aacctgagcc ggaatctgtc tctgcagaat 2160
gagatcgcca aagagacact gcccgacctg gtgtctatca tccctgacac cgtgcctagc 2220
accgacctgc tgattgagac aacagccagc gcctgctaca ccctgaacaa catcattcag 2280
aactcctacc agaacgcccg cgatctgctg aacacaggcg gcatccagaa aatcatggcc 2340
atctctgccg gcgacgccta cgcctctaac aaggcctcta aagccgccag cgtgctgctg 2400
tattctctgt gggcccatac cgagctgcac catgcctata agaaggccca gttcaaaaag 2460
accgacttcg tgaacagcag aacagccaag gcctaccaca gcctgaagga ctga 2514
<210> 3
<211> 837
<212> PRT
<213> 人类(Homo sapiens)
<400> 3
Met Ala Ala Pro Gly Ala Pro Ala Glu Tyr Gly Tyr Ile Arg Thr Val
1 5 10 15
Leu Gly Gln Gln Ile Leu Gly Gln Leu Asp Ser Ser Ser Leu Ala Leu
20 25 30
Pro Ser Glu Ala Lys Leu Lys Leu Ala Gly Ser Ser Gly Arg Gly Gly
35 40 45
Gln Thr Val Lys Ser Leu Arg Ile Gln Glu Gln Val Gln Gln Thr Leu
50 55 60
Ala Arg Lys Gly Arg Ser Ser Val Gly Asn Gly Asn Leu His Arg Thr
65 70 75 80
Ser Ser Val Pro Glu Tyr Val Tyr Asn Leu His Leu Val Glu Asn Asp
85 90 95
Phe Val Gly Gly Arg Ser Pro Val Pro Lys Thr Tyr Asp Met Leu Lys
100 105 110
Ala Gly Thr Thr Ala Thr Tyr Glu Gly Arg Trp Gly Arg Gly Thr Ala
115 120 125
Gln Tyr Ser Ser Gln Lys Ser Val Glu Glu Arg Ser Leu Arg His Pro
130 135 140
Leu Arg Arg Leu Glu Ile Ser Pro Asp Ser Ser Pro Glu Arg Ala His
145 150 155 160
Tyr Thr His Ser Asp Tyr Gln Tyr Ser Gln Arg Ser Gln Ala Gly His
165 170 175
Thr Leu His His Gln Glu Ser Arg Arg Ala Ala Leu Leu Val Pro Pro
180 185 190
Arg Tyr Ala Arg Ser Glu Ile Val Gly Val Ser Arg Ala Gly Thr Thr
195 200 205
Ser Arg Gln Arg His Phe Asp Thr Tyr His Arg Gln Tyr Gln His Gly
210 215 220
Ser Val Ser Asp Thr Val Phe Asp Ser Ile Pro Ala Asn Pro Ala Leu
225 230 235 240
Leu Thr Tyr Pro Arg Pro Gly Thr Ser Arg Ser Met Gly Asn Leu Leu
245 250 255
Glu Lys Glu Asn Tyr Leu Thr Ala Gly Leu Thr Val Gly Gln Val Arg
260 265 270
Pro Leu Val Pro Leu Gln Pro Val Thr Gln Asn Arg Ala Ser Arg Ser
275 280 285
Ser Trp His Gln Ser Ser Phe His Ser Thr Arg Thr Leu Arg Glu Ala
290 295 300
Gly Pro Ser Val Ala Val Asp Ser Ser Gly Arg Arg Ala His Leu Thr
305 310 315 320
Val Gly Gln Ala Ala Ala Gly Gly Ser Gly Asn Leu Leu Thr Glu Arg
325 330 335
Ser Thr Phe Thr Asp Ser Gln Leu Gly Asn Ala Asp Met Glu Met Thr
340 345 350
Leu Glu Arg Ala Val Ser Met Leu Glu Ala Asp His Met Leu Pro Ser
355 360 365
Arg Ile Ser Ala Ala Ala Thr Phe Ile Gln His Glu Cys Phe Gln Lys
370 375 380
Ser Glu Ala Arg Lys Arg Val Asn Gln Leu Arg Gly Ile Leu Lys Leu
385 390 395 400
Leu Gln Leu Leu Lys Val Gln Asn Glu Asp Val Gln Arg Ala Val Cys
405 410 415
Gly Ala Leu Arg Asn Leu Val Phe Glu Asp Asn Asp Asn Lys Leu Glu
420 425 430
Val Ala Glu Leu Asn Gly Val Pro Arg Leu Leu Gln Val Leu Lys Gln
435 440 445
Thr Arg Asp Leu Glu Thr Lys Lys Gln Ile Thr Gly Leu Leu Trp Asn
450 455 460
Leu Ser Ser Asn Asp Lys Leu Lys Asn Leu Met Ile Thr Glu Ala Leu
465 470 475 480
Leu Thr Leu Thr Glu Asn Ile Ile Ile Pro Phe Ser Gly Trp Pro Glu
485 490 495
Gly Asp Tyr Pro Lys Ala Asn Gly Leu Leu Asp Phe Asp Ile Phe Tyr
500 505 510
Asn Val Thr Gly Cys Leu Arg Asn Met Ser Ser Ala Gly Ala Asp Gly
515 520 525
Arg Lys Ala Met Arg Arg Cys Asp Gly Leu Ile Asp Ser Leu Val His
530 535 540
Tyr Val Arg Gly Thr Ile Ala Asp Tyr Gln Pro Asp Asp Lys Ala Thr
545 550 555 560
Glu Asn Cys Val Cys Ile Leu His Asn Leu Ser Tyr Gln Leu Glu Ala
565 570 575
Glu Leu Pro Glu Lys Tyr Ser Gln Asn Ile Tyr Ile Gln Asn Arg Asn
580 585 590
Ile Gln Thr Asp Asn Asn Lys Ser Ile Gly Cys Phe Gly Ser Arg Ser
595 600 605
Arg Lys Val Lys Glu Gln Tyr Gln Asp Val Pro Met Pro Glu Glu Lys
610 615 620
Ser Asn Pro Lys Gly Val Glu Trp Leu Trp His Ser Ile Val Ile Arg
625 630 635 640
Met Tyr Leu Ser Leu Ile Ala Lys Ser Val Arg Asn Tyr Thr Gln Glu
645 650 655
Ala Ser Leu Gly Ala Leu Gln Asn Leu Thr Ala Gly Ser Gly Pro Met
660 665 670
Pro Thr Ser Val Ala Gln Thr Val Val Gln Lys Glu Ser Gly Leu Gln
675 680 685
His Thr Arg Lys Met Leu His Val Gly Asp Pro Ser Val Lys Lys Thr
690 695 700
Ala Ile Ser Leu Leu Arg Asn Leu Ser Arg Asn Leu Ser Leu Gln Asn
705 710 715 720
Glu Ile Ala Lys Glu Thr Leu Pro Asp Leu Val Ser Ile Ile Pro Asp
725 730 735
Thr Val Pro Ser Thr Asp Leu Leu Ile Glu Thr Thr Ala Ser Ala Cys
740 745 750
Tyr Thr Leu Asn Asn Ile Ile Gln Asn Ser Tyr Gln Asn Ala Arg Asp
755 760 765
Leu Leu Asn Thr Gly Gly Ile Gln Lys Ile Met Ala Ile Ser Ala Gly
770 775 780
Asp Ala Tyr Ala Ser Asn Lys Ala Ser Lys Ala Ala Ser Val Leu Leu
785 790 795 800
Tyr Ser Leu Trp Ala His Thr Glu Leu His His Ala Tyr Lys Lys Ala
805 810 815
Gln Phe Lys Lys Thr Asp Phe Val Asn Ser Arg Thr Ala Lys Ala Tyr
820 825 830
His Ser Leu Lys Asp
835
<210> 4
<211> 2643
<212> DNA
<213> 人工(artificial)
<220>
<223> 密码子优化的PKP2b
<400> 4
atggccgccc ccggagcacc tgccgagtat ggctacattc gcaccgtcct gggacagcag 60
attctgggac agctggattc atcaagcctg gccctgcctt ctgaggccaa gctgaagctg 120
gcaggaagct ccggaagggg aggacagacc gtgaagagcc tgagaatcca ggagcaggtg 180
cagcagacac tggcccggaa gggcagatct agcgtgggca acggcaatct gcacaggacc 240
tcctctgtgc cagagtacgt gtataacctg cacctggtgg agaatgactt cgtgggaggc 300
cgcagcccag tgccaaagac atacgatatg ctgaaggccg gcaccacagc aacctatgag 360
ggcaggtggg gaagaggaac agcacagtac agctcccaga agtctgtgga ggagcggagc 420
ctgagacacc ctctgcggag actggagatc agcccagact ctagccctga gagggcacac 480
tatacccact ccgattacca gtattctcag agaagccagg caggacacac actgcaccac 540
caggagagca ggagggccgc cctgctggtg ccacctagat acgcccgctc tgagatcgtg 600
ggcgtgagca gggcaggaac cacatcccgg cagagacact tcgacaccta ccacagacag 660
tatcagcacg gctctgtgag cgacacagtg tttgattcca tccctgccaa cccagccctg 720
ctgacctatc ctcggccagg cacatccaga tctatgggca acctgctgga gaaggagaat 780
tacctgaccg caggcctgac agtgggacag gtgaggcccc tggtgcctct gcagccagtg 840
acccagaatc gggccagcag atcctcttgg caccagagct ccttccactc taccaggaca 900
ctgagggagg caggaccaag cgtggcagtg gactctagcg gccggagagc ccacctgacc 960
gtgggacagg cagcagcagg aggatccggc aacctgctga cagagaggtc cacctttaca 1020
gactctcagc tgggcaatgc cgatatggag atgaccctgg agagggccgt gagcatgctg 1080
gaggcagacc acatgctgcc atccaggatc tctgccgcag ccacattcat ccagcacgag 1140
tgctttcaga agtccgaggc aaggaagagg gtgaaccagc tgaggggcat cctgaagctg 1200
ctgcagctgc tgaaggtgca gaacgaggat gtgcagaggg ccgtgtgcgg cgccctgagg 1260
aatctggtgt tcgaggacaa cgataataag ctggaggtgg cagagctgaa cggagtgcca 1320
aggctgctgc aggtgctgaa gcagacccgc gacctggaga caaagaagca gatcaccgat 1380
cacacagtga acctgcggag cagaaatgga tggcctggag cagtggcaca cgcatgcaat 1440
ccaagcaccc tgggaggaca gggaggaagg atcacaagat ccggcgtgcg ggaccagcct 1500
gatcagcacg gcctgctgtg gaacctgtcc tctaatgaca agctgaagaa cctgatgatc 1560
accgaggccc tgctgaccct gacagagaat atcatcatcc cttttagcgg ctggccagag 1620
ggcgattatc ccaaggccaa cggcctgctg gacttcgata tcttttacaa cgtgaccggc 1680
tgcctgagga atatgagctc cgccggagca gacggaagaa aggccatgag gcgctgtgac 1740
ggcctgatcg attccctggt gcactacgtg cggggcacca tcgccgatta tcagcccgac 1800
gataaggcca cagagaactg cgtgtgcatc ctgcacaatc tgtcttatca gctggaggcc 1860
gagctgcctg agaagtacag ccagaacatc tatatccaga acagaaatat ccagaccgac 1920
aacaataaga gcatcggctg cttcggcagc aggtcccgca aggtgaagga gcagtaccag 1980
gatgtgccca tgcctgagga gaagtccaat cccaagggcg tggagtggct gtggcactct 2040
atcgtgatca ggatgtatct gagcctgatc gccaagtccg tgcgcaacta cacccaggag 2100
gcatctctgg gcgccctgca gaatctgaca gcaggatctg gaccaatgcc caccagcgtg 2160
gcccagacag tggtgcagaa ggagtccggc ctgcagcaca cccggaagat gctgcacgtg 2220
ggcgacccat ccgtgaagaa gacagccatc tctctgctga ggaacctgag ccgcaatctg 2280
tccctgcaga acgagatcgc caaggagaca ctgcccgatc tggtgagcat catcccagac 2340
accgtgccct ccacagatct gctgatcgag acaacagcct ccgcctgtta caccctgaac 2400
aatatcatcc agaactctta tcagaatgcc cgggacctgc tgaacacagg cggcatccag 2460
aagatcatgg caatctccgc cggcgatgca tacgcatcta ataaggccag caaggccgcc 2520
tccgtgctgc tgtattctct gtgggcacac accgagctgc accacgcata caagaaggcc 2580
cagtttaaga agactgattt cgtgaatagc agaacagcca aagcctacca cagcctgaag 2640
gac 2643
<210> 5
<211> 881
<212> PRT
<213> 人类(Homo sapiens)
<400> 5
Met Ala Ala Pro Gly Ala Pro Ala Glu Tyr Gly Tyr Ile Arg Thr Val
1 5 10 15
Leu Gly Gln Gln Ile Leu Gly Gln Leu Asp Ser Ser Ser Leu Ala Leu
20 25 30
Pro Ser Glu Ala Lys Leu Lys Leu Ala Gly Ser Ser Gly Arg Gly Gly
35 40 45
Gln Thr Val Lys Ser Leu Arg Ile Gln Glu Gln Val Gln Gln Thr Leu
50 55 60
Ala Arg Lys Gly Arg Ser Ser Val Gly Asn Gly Asn Leu His Arg Thr
65 70 75 80
Ser Ser Val Pro Glu Tyr Val Tyr Asn Leu His Leu Val Glu Asn Asp
85 90 95
Phe Val Gly Gly Arg Ser Pro Val Pro Lys Thr Tyr Asp Met Leu Lys
100 105 110
Ala Gly Thr Thr Ala Thr Tyr Glu Gly Arg Trp Gly Arg Gly Thr Ala
115 120 125
Gln Tyr Ser Ser Gln Lys Ser Val Glu Glu Arg Ser Leu Arg His Pro
130 135 140
Leu Arg Arg Leu Glu Ile Ser Pro Asp Ser Ser Pro Glu Arg Ala His
145 150 155 160
Tyr Thr His Ser Asp Tyr Gln Tyr Ser Gln Arg Ser Gln Ala Gly His
165 170 175
Thr Leu His His Gln Glu Ser Arg Arg Ala Ala Leu Leu Val Pro Pro
180 185 190
Arg Tyr Ala Arg Ser Glu Ile Val Gly Val Ser Arg Ala Gly Thr Thr
195 200 205
Ser Arg Gln Arg His Phe Asp Thr Tyr His Arg Gln Tyr Gln His Gly
210 215 220
Ser Val Ser Asp Thr Val Phe Asp Ser Ile Pro Ala Asn Pro Ala Leu
225 230 235 240
Leu Thr Tyr Pro Arg Pro Gly Thr Ser Arg Ser Met Gly Asn Leu Leu
245 250 255
Glu Lys Glu Asn Tyr Leu Thr Ala Gly Leu Thr Val Gly Gln Val Arg
260 265 270
Pro Leu Val Pro Leu Gln Pro Val Thr Gln Asn Arg Ala Ser Arg Ser
275 280 285
Ser Trp His Gln Ser Ser Phe His Ser Thr Arg Thr Leu Arg Glu Ala
290 295 300
Gly Pro Ser Val Ala Val Asp Ser Ser Gly Arg Arg Ala His Leu Thr
305 310 315 320
Val Gly Gln Ala Ala Ala Gly Gly Ser Gly Asn Leu Leu Thr Glu Arg
325 330 335
Ser Thr Phe Thr Asp Ser Gln Leu Gly Asn Ala Asp Met Glu Met Thr
340 345 350
Leu Glu Arg Ala Val Ser Met Leu Glu Ala Asp His Met Leu Pro Ser
355 360 365
Arg Ile Ser Ala Ala Ala Thr Phe Ile Gln His Glu Cys Phe Gln Lys
370 375 380
Ser Glu Ala Arg Lys Arg Val Asn Gln Leu Arg Gly Ile Leu Lys Leu
385 390 395 400
Leu Gln Leu Leu Lys Val Gln Asn Glu Asp Val Gln Arg Ala Val Cys
405 410 415
Gly Ala Leu Arg Asn Leu Val Phe Glu Asp Asn Asp Asn Lys Leu Glu
420 425 430
Val Ala Glu Leu Asn Gly Val Pro Arg Leu Leu Gln Val Leu Lys Gln
435 440 445
Thr Arg Asp Leu Glu Thr Lys Lys Gln Ile Thr Asp His Thr Val Asn
450 455 460
Leu Arg Ser Arg Asn Gly Trp Pro Gly Ala Val Ala His Ala Cys Asn
465 470 475 480
Pro Ser Thr Leu Gly Gly Gln Gly Gly Arg Ile Thr Arg Ser Gly Val
485 490 495
Arg Asp Gln Pro Asp Gln His Gly Leu Leu Trp Asn Leu Ser Ser Asn
500 505 510
Asp Lys Leu Lys Asn Leu Met Ile Thr Glu Ala Leu Leu Thr Leu Thr
515 520 525
Glu Asn Ile Ile Ile Pro Phe Ser Gly Trp Pro Glu Gly Asp Tyr Pro
530 535 540
Lys Ala Asn Gly Leu Leu Asp Phe Asp Ile Phe Tyr Asn Val Thr Gly
545 550 555 560
Cys Leu Arg Asn Met Ser Ser Ala Gly Ala Asp Gly Arg Lys Ala Met
565 570 575
Arg Arg Cys Asp Gly Leu Ile Asp Ser Leu Val His Tyr Val Arg Gly
580 585 590
Thr Ile Ala Asp Tyr Gln Pro Asp Asp Lys Ala Thr Glu Asn Cys Val
595 600 605
Cys Ile Leu His Asn Leu Ser Tyr Gln Leu Glu Ala Glu Leu Pro Glu
610 615 620
Lys Tyr Ser Gln Asn Ile Tyr Ile Gln Asn Arg Asn Ile Gln Thr Asp
625 630 635 640
Asn Asn Lys Ser Ile Gly Cys Phe Gly Ser Arg Ser Arg Lys Val Lys
645 650 655
Glu Gln Tyr Gln Asp Val Pro Met Pro Glu Glu Lys Ser Asn Pro Lys
660 665 670
Gly Val Glu Trp Leu Trp His Ser Ile Val Ile Arg Met Tyr Leu Ser
675 680 685
Leu Ile Ala Lys Ser Val Arg Asn Tyr Thr Gln Glu Ala Ser Leu Gly
690 695 700
Ala Leu Gln Asn Leu Thr Ala Gly Ser Gly Pro Met Pro Thr Ser Val
705 710 715 720
Ala Gln Thr Val Val Gln Lys Glu Ser Gly Leu Gln His Thr Arg Lys
725 730 735
Met Leu His Val Gly Asp Pro Ser Val Lys Lys Thr Ala Ile Ser Leu
740 745 750
Leu Arg Asn Leu Ser Arg Asn Leu Ser Leu Gln Asn Glu Ile Ala Lys
755 760 765
Glu Thr Leu Pro Asp Leu Val Ser Ile Ile Pro Asp Thr Val Pro Ser
770 775 780
Thr Asp Leu Leu Ile Glu Thr Thr Ala Ser Ala Cys Tyr Thr Leu Asn
785 790 795 800
Asn Ile Ile Gln Asn Ser Tyr Gln Asn Ala Arg Asp Leu Leu Asn Thr
805 810 815
Gly Gly Ile Gln Lys Ile Met Ala Ile Ser Ala Gly Asp Ala Tyr Ala
820 825 830
Ser Asn Lys Ala Ser Lys Ala Ala Ser Val Leu Leu Tyr Ser Leu Trp
835 840 845
Ala His Thr Glu Leu His His Ala Tyr Lys Lys Ala Gln Phe Lys Lys
850 855 860
Thr Asp Phe Val Asn Ser Arg Thr Ala Lys Ala Tyr His Ser Leu Lys
865 870 875 880
Asp
<210> 6
<211> 600
<212> DNA
<213> 人类(Homo sapiens)
<400> 6
gtcatggaga agacccacct tgcagatgtc ctcactgggg ctggcagagc cggcaacctg 60
cctaaggctg ctcagtccat taggagccag tagcctggaa gatgtcttta cccccagcat 120
cagttcaagt ggagcagcac ataactcttg ccctctgcct tccaagattc tggtgctgag 180
acttatggag tgtcttggag gttgccttct gccccccaac cctgctccca gctggccctc 240
ccaggcctgg gttgctggcc tctgctttat caggattctc aagagggaca gctggtttat 300
gttgcatgac tgttccctgc atatctgctc tggttttaaa tagcttatct gagcagctgg 360
aggaccacat gggcttatat ggcgtggggt acatgttcct gtagccttgt ccctggcacc 420
tgccaaaata gcagccaaca ccccccaccc ccaccgccat ccccctgccc cacccgtccc 480
ctgtcgcaca ttcctccctc cgcagggctg gctcaccagg ccccagccca catgcctgct 540
taaagccctc tccatcctct gcctcaccca gtccccgctg agactgagca gacgcctcca 600
<210> 7
<211> 8383
<212> DNA
<213> 人工(artificial)
<220>
<223> 表达PKP2b的示例性载体
<400> 7
ggcactgggc aggtaagtat caaggttaca agacaggttt aaggagacca atagaaactg 60
ggcttgtcga gacagagaag actcttgcgt ttctgatagg cacctattgg tcttactgac 120
atccactttg cctttctctc cacaggtgtc cactcccagt tcaattacag ctcttaaggc 180
tagagtactt aatacgactc actataggct agcggtaccg gtcgccacca tggactacaa 240
agaccatgac ggtgattata aagatcatga catcgattac aaggatgacg atgacaagct 300
tggtaccgag ctcggatcca tggccgcccc cggagcacct gccgagtatg gctacattcg 360
caccgtcctg ggacagcaga ttctgggaca gctggattca tcaagcctgg ccctgccttc 420
tgaggccaag ctgaagctgg caggaagctc cggaagggga ggacagaccg tgaagagcct 480
gagaatccag gagcaggtgc agcagacact ggcccggaag ggcagatcta gcgtgggcaa 540
cggcaatctg cacaggacct cctctgtgcc agagtacgtg tataacctgc acctggtgga 600
gaatgacttc gtgggaggcc gcagcccagt gccaaagaca tacgatatgc tgaaggccgg 660
caccacagca acctatgagg gcaggtgggg aagaggaaca gcacagtaca gctcccagaa 720
gtctgtggag gagcggagcc tgagacaccc tctgcggaga ctggagatca gcccagactc 780
tagccctgag agggcacact atacccactc cgattaccag tattctcaga gaagccaggc 840
aggacacaca ctgcaccacc aggagagcag gagggccgcc ctgctggtgc cacctagata 900
cgcccgctct gagatcgtgg gcgtgagcag ggcaggaacc acatcccggc agagacactt 960
cgacacctac cacagacagt atcagcacgg ctctgtgagc gacacagtgt ttgattccat 1020
ccctgccaac ccagccctgc tgacctatcc tcggccaggc acatccagat ctatgggcaa 1080
cctgctggag aaggagaatt acctgaccgc aggcctgaca gtgggacagg tgaggcccct 1140
ggtgcctctg cagccagtga cccagaatcg ggccagcaga tcctcttggc accagagctc 1200
cttccactct accaggacac tgagggaggc aggaccaagc gtggcagtgg actctagcgg 1260
ccggagagcc cacctgaccg tgggacaggc agcagcagga ggatccggca acctgctgac 1320
agagaggtcc acctttacag actctcagct gggcaatgcc gatatggaga tgaccctgga 1380
gagggccgtg agcatgctgg aggcagacca catgctgcca tccaggatct ctgccgcagc 1440
cacattcatc cagcacgagt gctttcagaa gtccgaggca aggaagaggg tgaaccagct 1500
gaggggcatc ctgaagctgc tgcagctgct gaaggtgcag aacgaggatg tgcagagggc 1560
cgtgtgcggc gccctgagga atctggtgtt cgaggacaac gataataagc tggaggtggc 1620
agagctgaac ggagtgccaa ggctgctgca ggtgctgaag cagacccgcg acctggagac 1680
aaagaagcag atcaccgatc acacagtgaa cctgcggagc agaaatggat ggcctggagc 1740
agtggcacac gcatgcaatc caagcaccct gggaggacag ggaggaagga tcacaagatc 1800
cggcgtgcgg gaccagcctg atcagcacgg cctgctgtgg aacctgtcct ctaatgacaa 1860
gctgaagaac ctgatgatca ccgaggccct gctgaccctg acagagaata tcatcatccc 1920
ttttagcggc tggccagagg gcgattatcc caaggccaac ggcctgctgg acttcgatat 1980
cttttacaac gtgaccggct gcctgaggaa tatgagctcc gccggagcag acggaagaaa 2040
ggccatgagg cgctgtgacg gcctgatcga ttccctggtg cactacgtgc ggggcaccat 2100
cgccgattat cagcccgacg ataaggccac agagaactgc gtgtgcatcc tgcacaatct 2160
gtcttatcag ctggaggccg agctgcctga gaagtacagc cagaacatct atatccagaa 2220
cagaaatatc cagaccgaca acaataagag catcggctgc ttcggcagca ggtcccgcaa 2280
ggtgaaggag cagtaccagg atgtgcccat gcctgaggag aagtccaatc ccaagggcgt 2340
ggagtggctg tggcactcta tcgtgatcag gatgtatctg agcctgatcg ccaagtccgt 2400
gcgcaactac acccaggagg catctctggg cgccctgcag aatctgacag caggatctgg 2460
accaatgccc accagcgtgg cccagacagt ggtgcagaag gagtccggcc tgcagcacac 2520
ccggaagatg ctgcacgtgg gcgacccatc cgtgaagaag acagccatct ctctgctgag 2580
gaacctgagc cgcaatctgt ccctgcagaa cgagatcgcc aaggagacac tgcccgatct 2640
ggtgagcatc atcccagaca ccgtgccctc cacagatctg ctgatcgaga caacagcctc 2700
cgcctgttac accctgaaca atatcatcca gaactcttat cagaatgccc gggacctgct 2760
gaacacaggc ggcatccaga agatcatggc aatctccgcc ggcgatgcat acgcatctaa 2820
taaggccagc aaggccgcct ccgtgctgct gtattctctg tgggcacaca ccgagctgca 2880
ccacgcatac aagaaggccc agtttaagaa gactgatttc gtgaatagca gaacagccaa 2940
agcctaccac agcctgaagg acctcgaggg atctggagca acaaacttct cactactcaa 3000
acaagcaggt gacgtggagg agaatcccgg gcctaagctt atgaaaacct tcaacatctc 3060
tcagcaggat ctggagctgg tggaggtcgc cactgagaag atcaccatgc tctatgagga 3120
caacaagcac catgtcgggg cggccatcag gaccaagact ggggagatca tctctgctgt 3180
ccacattgaa gcctacattg gcagggtcac tgtctgtgct gaagccattg ccattgggtc 3240
tgctgtgagc aacgggcaga aggactttga caccattgtg gctgtcaggc acccctactc 3300
tgatgaggtg gacagatcca tcagggtggt cagcccctgt ggcatgtgta gagagctgat 3360
ctctgactat gctcctgact gctttgtgct cattgagatg aatggcaagc tggtcaaaac 3420
caccattgag gaactcatcc ccctcaagta caccaggaac taataagcgg ccgcttccct 3480
ttagtgaggg ttaatgcttc gagcagacat gataagatac attgatgagt ttggacaaac 3540
cacaactaga atgcagtgaa aaaaatgctt tatttgtgaa atttgtgatg ctattgcttt 3600
atttgtaacc attataagct gcaataaaca agttaacaac aacaattgca ttcattttat 3660
gtttcaggtt cagggggaga tgtgggaggt tttttaaagc aagtaaaacc tctacaaatg 3720
tggtaaaatc cgataaggga ctagagcatg gctacgtaga taagtagcat ggcgggttaa 3780
tcattaacta caaggaaccc ctagtgatgg agttggccac tccctctctg cgcgctcgct 3840
cgctcactga ggccgggcga ccaaaggtcg cccgacgccc gggctttgcc cgggcggcct 3900
cagtgagcga gcgagcgcgc cagctggcgt aatagcgaag aggcccgcac cgatcgccct 3960
tcccaacagt tgcgcagcct gaatggcgaa tggaattcca gacgattgag cgtcaaaatg 4020
taggtatttc catgagcgtt tttccgttgc aatggctggc ggtaatattg ttctggatat 4080
taccagcaag gccgatagtt tgagttcttc tactcaggca agtgatgtta ttactaatca 4140
aagaagtatt gcgacaacgg ttaatttgcg tgatggacag actcttttac tcggtggcct 4200
cactgattat aaaaacactt ctcaggattc tggcgtaccg ttcctgtcta aaatcccttt 4260
aatcggcctc ctgtttagct cccgctctga ttctaacgag gaaagcacgt tatacgtgct 4320
cgtcaaagca accatagtac gcgccctgta gcggcgcatt aagcgcggcg ggtgtggtgg 4380
ttacgcgcag cgtgaccgct acacttgcca gcgccctagc gcccgctcct ttcgctttct 4440
tcccttcctt tctcgccacg ttcgccggct ttccccgtca agctctaaat cgggggctcc 4500
ctttagggtt ccgatttagt gctttacggc acctcgaccc caaaaaactt gattagggtg 4560
atggttcacg tagtgggcca tcgccctgat agacggtttt tcgccctttg acgttggagt 4620
ccacgttctt taatagtgga ctcttgttcc aaactggaac aacactcaac cctatctcgg 4680
tctattcttt tgatttataa gggattttgc cgatttcggc ctattggtta aaaaatgagc 4740
tgatttaaca aaaatttaac gcgaatttta acaaaatatt aacgtctaca atttaaatat 4800
ttgcttatac aatcttcctg tttttggggc ttttctgatt atcaaccggg gtacatatga 4860
ttgacatgct agttttacga ttaccgttca tcgattctct tgtttgctcc agactctcag 4920
gcaatgacct gatagccttt gtagagacct ctcaaaaata gctaccctct ccggcatgaa 4980
tttatcagct agaacggttg aatatcatat tgatggtgat ttgactgtct ccggcctttc 5040
tcacccgttt gaatctttac ctacacatta ctcaggcatt gcatttaaaa tatatgaggg 5100
ttctaaaaat ttttatcctt gcgttgaaat aaaggcttct cccgcaaaag tattacaggg 5160
tcataatgtt tttggtacaa ccgatttagc tttatgctct gaggctttat tgcttaattt 5220
tgctaattct ttgccttgcc tgtatgattt attggatgtt ggaatcgcct gatgcggtat 5280
tttctcctta cgcatctgtg cggtatttca caccgcatat ggtgcactct cagtacaatc 5340
tgctctgatg ccgcatagtt aagccagccc cgacacccgc caacacccgc tgacgcgccc 5400
tgacgggctt gtctgctccc ggcatccgct tacagacaag ctgtgaccgt ctccgggagc 5460
tgcatgtgtc agaggttttc accgtcatca ccgaaacgcg cgagacgaaa gggcctcgtg 5520
atacgcctat ttttataggt taatgtcatg ataataatgg tttcttagac gtcaggtggc 5580
acttttcggg gaaatgtgcg cggaacccct atttgtttat ttttctaaat acattcaaat 5640
atgtatccgc tcatgagaca ataaccctga taaatgcttc aataatattg aaaaaggaag 5700
agtatgagta ttcaacattt ccgtgtcgcc cttattccct tttttgcggc attttgcctt 5760
cctgtttttg ctcacccaga aacgctggtg aaagtaaaag atgctgaaga tcagttgggt 5820
gcacgagtgg gttacatcga actggatctc aacagcggta agatccttga gagttttcgc 5880
cccgaagaac gttttccaat gatgagcact tttaaagttc tgctatgtgg cgcggtatta 5940
tcccgtattg acgccgggca agagcaactc ggtcgccgca tacactattc tcagaatgac 6000
ttggttgagt actcaccagt cacagaaaag catcttacgg atggcatgac agtaagagaa 6060
ttatgcagtg ctgccataac catgagtgat aacactgcgg ccaacttact tctgacaacg 6120
atcggaggac cgaaggagct aaccgctttt ttgcacaaca tgggggatca tgtaactcgc 6180
cttgatcgtt gggaaccgga gctgaatgaa gccataccaa acgacgagcg tgacaccacg 6240
atgcctgtag caatggcaac aacgttgcgc aaactattaa ctggcgaact acttactcta 6300
gcttcccggc aacaattaat agactggatg gaggcggata aagttgcagg accacttctg 6360
cgctcggccc ttccggctgg ctggtttatt gctgataaat ctggagccgg tgagcgtggg 6420
tctcgcggta tcattgcagc actggggcca gatggtaagc cctcccgtat cgtagttatc 6480
tacacgacgg ggagtcaggc aactatggat gaacgaaata gacagatcgc tgagataggt 6540
gcctcactga ttaagcattg gtaactgtca gaccaagttt actcatatat actttagatt 6600
gatttaaaac ttcattttta atttaaaagg atctaggtga agatcctttt tgataatctc 6660
atgaccaaaa tcccttaacg tgagttttcg ttccactgag cgtcagaccc cgtagaaaag 6720
atcaaaggat cttcttgaga tccttttttt ctgcgcgtaa tctgctgctt gcaaacaaaa 6780
aaaccaccgc taccagcggt ggtttgtttg ccggatcaag agctaccaac tctttttccg 6840
aaggtaactg gcttcagcag agcgcagata ccaaatactg tccttctagt gtagccgtag 6900
ttaggccacc acttcaagaa ctctgtagca ccgcctacat acctcgctct gctaatcctg 6960
ttaccagtgg ctgctgccag tggcgataag tcgtgtctta ccgggttgga ctcaagacga 7020
tagttaccgg ataaggcgca gcggtcgggc tgaacggggg gttcgtgcac acagcccagc 7080
ttggagcgaa cgacctacac cgaactgaga tacctacagc gtgagctatg agaaagcgcc 7140
acgcttcccg aagggagaaa ggcggacagg tatccggtaa gcggcagggt cggaacagga 7200
gagcgcacga gggagcttcc agggggaaac gcctggtatc tttatagtcc tgtcgggttt 7260
cgccacctct gacttgagcg tcgatttttg tgatgctcgt caggggggcg gagcctatgg 7320
aaaaacgcca gcaacgcggc ctttttacgg ttcctggcct tttgctggcc ttttgctcac 7380
atgttctttc ctgcgttatc ccctgattct gtggataacc gtattaccgc ctttgagtga 7440
gctgataccg ctcgccgcag ccgaacgacc gagcgcagcg agtcagtgag cgaggaagcg 7500
gaagagcgcc caatacgcaa accgcctctc cccgcgcgtt ggccgattca ttaatgcagc 7560
tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc cgggcgtcgg gcgacctttg 7620
gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg agtggccaac tccatcacta 7680
ggggttcctt gtagttaatg attaacccgc catgctactt atctacgtag ccatgctcta 7740
gatgtcatgg agaagaccca ccttgcagat gtcctcactg gggctggcag agccggcaac 7800
ctgcctaagg ctgctcagtc cattaggagc cagtagcctg gaagatgtct ttacccccag 7860
catcagttca agtggagcag cacataactc ttgccctctg ccttccaaga ttctggtgct 7920
gagacttatg gagtgtcttg gaggttgcct tctgcccccc aaccctgctc ccagctggcc 7980
ctcccaggcc tgggttgctg gcctctgctt tatcaggatt ctcaagaggg acagctggtt 8040
tatgttgcat gactgttccc tgcatatctg ctctggtttt aaatagctta tctgagcagc 8100
tggaggacca catgggctta tatggcgtgg ggtacatgtt cctgtagcct tgtccctggc 8160
acctgccaaa atagcagcca acacccccca cccccaccgc catccccctg ccccacccgt 8220
cccctgtcgc acattcctcc ctccgcaggg ctggctcacc aggccccagc ccacatgcct 8280
gcttaaagcc ctctccatcc tctgcctcac ccagtccccg ctgagactga gcagacgcct 8340
ccagagctcg gatcctgaga acttcagggt gagtctatgg gac 8383
Claims (40)
1.一种治疗或预防受试者的心肌病的方法,所述方法包括将治疗剂量的基因治疗载体递送到所述受试者的心肌细胞,其中所述心肌细胞对于桥粒斑菲素蛋白2(PKP2)是单倍不足的,其中所述基因治疗载体包含对PKP2或其功能变异体进行编码的核酸序列,并且其中将所述基因治疗载体递送到所述心肌细胞导致所述心肌细胞对PKP2的总桥粒表达增加了至少1.5倍、2倍、2.5倍、3倍、4倍或5倍。
2.一种治疗或预防受试者的心肌病的方法,所述方法包括将治疗剂量的基因治疗载体递送到所述受试者的心肌细胞,其中所述心肌细胞对于桥粒斑菲素蛋白2(PKP2)是单倍不足的,其中所述基因治疗载体包含对PKP2或其功能变异体进行编码的核酸序列,并且其中将所述基因治疗载体递送到所述心肌细胞导致所述PKP2的总桥粒表达为非单倍不足心肌细胞进行的总桥粒表达的至少50%。
3.如权利要求1或权利要求2所述的方法,其中所述基因治疗载体包括病毒载体。
4.如权利要求3所述的方法,其中所述病毒载体包括AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、AAV12、其变异体及其组合中的一者或多者。
5.如权利要求3所述的方法,其中所述病毒载体包括AAV6或AAV9。
6.如权利要求3所述的方法,其中所述病毒载体包括AAV6。
7.如权利要求1-6中任一项所述的方法,其中所述核酸序列还对心肌特异性启动子进行编码。
8.如权利要求1-7中任一项所述的方法,其中所述治疗剂量足以通过影响所述受试者的所述心肌细胞对所述PKP2或其功能变异体的产生来治疗或预防致心律失常性右心室心肌病(ARVC)。
9.如权利要求1-8中任一项所述的方法,其中所述治疗剂量的所述递送是通过静脉进行。
10.如权利要求1-9中任一项所述的方法,其中所述受试者是人类受试者。
11.一种适于在受试者的心肌细胞内表达核酸序列的基因治疗载体,所述核酸序列包括:
对PKP2或其功能变异体进行编码的第一序列;以及
包含心肌特异性启动子的第二序列,
其中将所述基因治疗载体递送到对于PKP2为单倍不足的心肌细胞导致所述心肌细胞对PKP2的总桥粒表达增加至少1.5倍、2倍、2.5倍、3倍、4倍或5倍。
12.一种适于在受试者的心肌细胞内表达核酸序列的基因治疗载体,所述核酸序列包括:
对PKP2或其功能变异体进行编码的第一序列;以及
包含心肌特异性启动子的第二序列,
其中将所述基因治疗载体递送到为单倍不足的心肌细胞导致所述PKP2的总桥粒表达为非单倍不足心肌细胞进行的总桥粒表达的至少50%。
13.如权利要求11或权利要求12所述的基因治疗载体,其中所述基因治疗载体包括病毒载体。
14.如权利要求13所述的基因治疗载体,其中所述病毒载体包括AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、AAV12、其变异体及其组合中的一者或多者。
15.如权利要求13所述的基因治疗载体,其中所述病毒载体包括AAV6或AAV9。
16.如权利要求11-15中任一项所述的基因治疗载体,其中所述心肌特异性启动子包含TNNT2或具有至少99%、95%、90%、85%、80%、75%或70%相似性的功能序列。
17.如权利要求11-15中任一项所述的基因治疗载体,其中所述受试者是人类受试者。
18.一种用于治疗或预防受试者的心肌病的治疗调配物,所述治疗调配物包含:
医药学上可接受的赋形剂或载剂;以及
包含对PKP2或其功能变异体进行编码的核酸序列的病毒载体,
其中将所述治疗调配物递送到对于PKP2为单倍不足的心肌细胞导致所述心肌细胞对PKP2的总桥粒表达增加至少1.5倍、2倍、2.5倍、3倍、4倍或5倍。
19.一种用于治疗或预防受试者的心肌病的治疗调配物,所述治疗调配物包含:
医药学上可接受的赋形剂或载剂;以及
包含对PKP2或其功能变异体进行编码的核酸序列的病毒载体,
其中将治疗调配物载体递送到为单倍不足的心肌细胞导致所述PKP2的总桥粒表达为非单倍不足心肌细胞进行的总桥粒表达的至少50%。
20.如权利要求18或权利要求19所述的治疗调配物,所述治疗调配物还包含:
一个或多个额外病毒载体,所述一个或多个额外病毒载体各自包含对一个或多个非PKP2肌节蛋白或其功能变异体进行编码的核酸序列。
21.如权利要求18-20中任一项的治疗调配物,其中所述受试者是人类受试者。
22.一种对具有突变的PKP2基因的心肌细胞进行基因修饰以表达功能PKP2或其功能变异体的方法,所述方法包括:
用对所述功能PKP2进行编码的核酸序列来转染或转导所述心肌细胞,其中所述转染或转导导致所述心肌细胞对所述功能PKP2的总桥粒表达增加至少1.5倍、2倍、2.5倍、3倍、4倍或5倍。
23.一种对具有突变的PKP2基因的心肌细胞进行基因修饰以表达功能PKP2或其功能变异体的方法,所述方法包括:
用对所述功能PKP2进行编码的核酸序列来转染或转导所述心肌细胞,其中所述转染或转导导致所述功能PKP2的总桥粒表达为具有非突变的PKP2基因的心肌细胞进行的总桥粒表达的至少50%。
24.如权利要求22或23所述的方法,其中所述核酸序列是经由病毒载体递送,所述病毒载体包括AAV6或AAV9。
25.如权利要求24所述的方法,其中所述病毒载体包括AAV6。
26.如权利要求22-25中任一项的方法,其中所述核酸序列还对心肌特异性启动子进行编码。
27.如权利要求26所述的方法,其中所述心肌特异性启动子包含TNNT2或具有至少99%、95%、90%、85%、80%、75%或70%相似性的功能序列。
28.如权利要求1-10或22-27中任一项所述的方法,其中所述PKP2是PKP2异构体2a。
29.如权利要求1-10或22-27中任一项所述的方法,其中所述PKP2是PKP2异构体2b。
30.如权利要求11-21中任一项所述的基因治疗载体或治疗调配物,其中所述PKP2是PKP2异构体2a。
31.如权利要求11-21中任一项所述的基因治疗载体或治疗调配物,其中所述PKP2是PKP2异构体2b。
32.一种用于治疗或预防受试者的心肌病的治疗调配物,所述治疗调配物包含:
医药学上可接受的赋形剂或载剂;
包含对PKP2异构体2a或其功能变异体进行编码的核酸序列的第一病毒载体;以及
包含对PKP2异构体2b或其功能变异体进行编码的核酸序列的第二病毒载体,
其中将所述治疗调配物递送到对于PKP2异构体2a或异构体2b为单倍不足的心肌细胞导致所述心肌细胞对PKP2异构体2a或异构体2b的总桥粒表达增加至少1.5倍、2倍、2.5倍、3倍、4倍或5倍。
33.一种用于治疗或预防受试者的心肌病的治疗调配物,所述治疗调配物包含:
医药学上可接受的赋形剂或载剂;
包含对PKP2异构体2a或其功能变异体进行编码的核酸序列的第一病毒载体;
包含对PKP2异构体2b或其功能变异体进行编码的核酸序列的第二病毒载体,
其中将治疗调配物载体递送到为单倍不足的心肌细胞导致PKP2异构体2a或异构体2b的总桥粒表达为非单倍不足心肌细胞进行的总桥粒表达的至少50%。
34.一种使用如权利要求11-17中任一项所述的基因治疗载体进行转导的隔离细胞。
35.如权利要求34所述的隔离细胞,其中所述细胞是人类细胞。
36.如权利要求34所述的隔离细胞,其中所述细胞是心脏细胞。
37.如权利要求34所述的隔离细胞,其中所述细胞是人诱导多能干细胞衍生的心肌细胞。
38.一种向上调节具有突变的PKP2基因的心肌细胞中的一个或多个桥粒蛋白的方法,所述方法包括:
用对功能PKP2进行编码的核酸序列来转染或转导所述心肌细胞,所述功能PKP2选自PKP2异构体2a和PKP2异构体2b,其中所述转染或转导导致所述一个或多个桥粒蛋白中的每一者的总桥粒表达增加至少1.1倍、1.2倍、1.3倍、1.4倍、1.5倍、2倍、2.5倍、3倍、4倍或5倍,其中所述一个或多个桥粒蛋白是选自桥粒斑蛋白1、桥粒斑蛋白2、桥粒胶蛋白2、斑珠蛋白、桥粒芯蛋白2和连接蛋白43。
39.一种治疗或预防受试者的心肌病的方法,所述方法包括将治疗剂量的基因治疗载体递送到所述受试者的心肌细胞,其中所述心肌细胞对于桥粒斑菲素蛋白2(PKP2)是单倍不足的,其中所述基因治疗载体包含对非显性PKP2异构体或其功能变异体进行编码的核酸序列,其中将所述基因治疗载体递送到所述心肌细胞导致所述心肌细胞对PKP2的总桥粒表达增加至少1.5倍、2倍、2.5倍、3倍、4倍或5倍,并且其中所述PKP2的所述总桥粒表达包括显性PKP2异构体和所述非显性PKP2异构体的表达。
40.如权利要求39所述的方法,其中所述显性PKP2异构体是PKP2异构体2a,并且其中所述非显性PKP2异构体是PKP2异构体2b。
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