Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery
Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery
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DOI：
10.1038/nm739
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发表时间：
2002-08-01
期刊：
影响因子：
82.9
通讯作者：
Chien, KR
中科院分区：
文献类型：
--
作者：
Hoshijima, M;Ikeda, Y;Chien, KR
基因治疗心肌病、心力衰竭和其他慢性心肌疾病的可行性迄今尚未得到证实。在这里，我们开发了一种体内重组腺相关病毒（rAAV）经冠状动脉传递系统，该系统允许稳定，高效和相对心脏选择性的基因表达。我们使用rAAV表达人磷蛋白（PLN）的假磷酸化突变体，PLN是BIO14.6心肌病仓鼠心肌肌浆网（SR） Ca2+循环的关键调节因子。rAAV/S16EPLN治疗增强心肌SR Ca2+摄取，抑制左心室收缩功能和收缩力的进行性损害，持续28 - 30周，从而保护心肌细胞免受细胞病变质膜破坏。rAAV/S16EPLN治疗也在很大程度上预防了低左室收缩压和左室舒张恶化。因此，通过rAAV载体经冠状动脉转移S16EPLN基因是进行性扩张型心肌病和相关心力衰竭的潜在治疗方法。
The feasibility of gene therapy for cardiomyopathy, heart failure and other chronic cardiac muscle diseases is so far unproven. Here, we developed an in vivo recombinant adeno-associated virus (rAAV) transcoronary delivery system that allows stable, high efficiency and relatively cardiac-selective gene expression. We used rAAV to express a pseudophosphorylated mutant of human phospholamban (PLN), a key regulator of cardiac sarcoplasmic reticulum (SR) Ca2+ cycling in BIO14.6 cardiomyopathic hamsters. The rAAV/S16EPLN treatment enhanced myocardial SR Ca2+ uptake and suppressed progressive impairment of left ventricular (LV) systolic function and contractility for 28 - 30 weeks, thereby protecting cardiac myocytes from cytopathic plasma-membrane disruption. Low LV systolic pressure and deterioration in LV relaxation were also largely prevented by rAAV/S16EPLN treatment. Thus, transcoronary gene transfer of S16EPLN via rAAV vector is a potential therapy for progressive dilated cardiomyopathy and associated heart failure.