SERCA2a基因转导治疗心力衰竭的研究进展-PPT.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,SERCA2a,基因转导治疗心力衰竭的研究进展,心力衰竭是各种器质性心脏病发展的终末阶段，虽然心衰诊疗已经取得很大进展，但其患病率高,致残死亡率高,发病率随年龄增长而增加，仍然是世界范围内的主要公共卫生问题，急需新的治疗方法。,20,世纪发展起来的转基因技术为心力衰竭的治疗寻找到了一个新的突破口,(Roger,2013),。,一、心力衰竭和,SERCA2a,基因治疗简介,Ca,2+,是心肌收缩和舒张活动的中心环节，,Ca,2+,稳态失调是慢性心力衰竭发生、发展的重要病理生理机制。,肌浆网是细胞内重要的钙贮存器，其在维持,Ca,2+,稳态时发挥重要作用，,Ca,2+,经肌浆网上斯里兰卡碱受体,(RYR),大量释放触发心肌收缩,而,Ca,2+,被肌浆网重新摄取引起心肌舒张。肌浆网重新摄取主要,通,过肌浆网钙泵（,SERCA2a,）发挥作用,(,Bers,2002),。一旦,SERCA2a,功能异常，会导致肌浆网贮存钙减少，影响钙释放从而影响心肌收缩活动，也会导致细胞质中钙负荷增加，影响心肌舒张活动。,大量研究发现，心衰细胞中,SERCA2a,表达和活性下降，同时伴有,Ca,2+,稳态失衡和心脏功能障碍,(,Hasenfuss,et al.,1994,；,Meyer et al.,1995,；,Flesch,et al.,1996),。因此通过基因转导技术过表达,SERCA2a,成为基因,转导,治疗心衰的关键点。,一系列,细胞模型、啮齿动物模型和大动物模型均表明，利用病毒载体,导入,SERCA2a,基因至衰竭心脏细胞均能改善心脏收缩和舒张功能,(,Hajjar,et al.,1997,；,Miyamoto et al.,2000,；,Byrne et al.,2008,；,Kawase,and,Hajjar,2008),。,二、,SERCA2a,过表达的动物试验和临床试验,2007,年心力衰竭转,SERCA2a,基因治疗第一项临床试验在美国开始,(CUPID,研究,),，此项研究使用重组腺相关病毒,1,型载体,(AAV1),搭载,SERCA2a,通过直接冠脉内注射方式，治疗晚期心衰患者，旨在判断不同剂量的,AAV1/SERCA2a,的有效性及安全性,(,Hajjar,et al.,2008),。,AAV1/SERCA2a,研究发现，随访,1,年，,AAV1-SERCA2a,高剂量组，心功能改善情况，,6,分钟步行距离明显优于安慰剂组，随访,3,年末，主要不良心血管事件发生率（包括再发心梗、心衰恶化、心衰再入院、心原性死亡等的复合事件）显著低于安慰剂组,(,Jaski,et al.,2009,；,Jessup et al.,2011,；,Zsebo,et al.,2014),。基于,CUPID,的研究结果，于,2012,年进行了样本量更大的,CUPID2,研究，此项研究纳入晚期心衰患者,250,人，初步结果令人惊讶，,AAV1-SERCA2a,组与安慰剂组相比，主要终点事件及次要终点事件方面均未发现明显获益,(Greenberg et al.,2016),。,CUPID,研究者获得了行心脏移植术或左室辅助装置植入术及死亡的患者的组织样本,，,经,RT-PCR,测定后发现,CUPID2,患者心肌细胞中载体,DNA,表达量远远低于,CUPID1,中的数量,(,Zsebo,et al.,2014,；,Greenberg et al.,2016),。虽然组织样本数目很少，但是也提示,CUPID2,的失败可能是由于在该试验中,SERCA2a,转染效率较低,。,三、,CUPID,临床试验,失败,的原因,分析,导致,SERC2a,转染效率低的,可能,因素,：,1,、,AAV,中和抗体的出现,2,、,CUPID2,中应用的空病毒衣壳（,empty virus capsid,）比例（,25%,）远远低于,CUPID1,中应用的空病毒衣壳比例（,75%,）,(,Mingozzi,et al.,2013),。,3.CUPID,试验中应用的经导管冠状动脉内注射基因导入方法也可能影响了影响基因转染效率。,CUPID2,试验虽然失败，但该试验证实了,SERCA2a,基因治疗心衰是安全的。基因治疗仍然是,当前,最有,发展,潜力的疾病治疗手段。,SERCA2a,基因治疗中遇到的问题将来有望得到解决。,目前已有研究,发现,通过建立再循环的闭环系统，,可,提高冠脉内注射导入效率的目的,（,Fargnoli,et 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