Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue
Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue
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DOI：
10.1161/circulationaha.106.671701
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发表时间：
2007-05-15
期刊：
影响因子：
37.8
通讯作者：
Koch, Walter J.
中科院分区：
文献类型：
--
作者：
Pleger, Sven T.;Most, Patrick;Koch, Walter J.
背景-心力衰竭的发病率不断增长，迫切需要开发改进的治疗方法。一个有吸引力的方法是基因治疗;然而，由于几个问题，包括缺乏支持安全和长期心肌转基因表达的理想载体，临床屏障尚未被打破。我们表明使用含有新的心脏选择性增强子/启动子元件的重组腺相关病毒（rAAV 6）载体可以指导治疗性转基因的稳定心脏表达，钙敏感S100 A1在大鼠心力衰竭模型中的作用。心肌S100 A1表达的慢性心力衰竭拯救特性，改善肌浆网Ca 2+处理的结果，包括改善收缩功能和左心室重塑。添加到临床相关性，长期的S100 A1治疗有独特的和附加的有益效果，β-肾上腺素能受体阻滞剂，目前的药理学heart failure treatment.Conclusions -这些研究结果表明，稳定增加表达的S100 A1在衰竭的心脏可用于长期逆转左心室功能障碍和重塑。因此，长期的心脏靶向rAAV 6-S100 A1基因治疗可能在人类心力衰竭中具有潜在的临床实用性。
Background - The incidence of heart failure is ever-growing, and it is urgent to develop improved treatments. An attractive approach is gene therapy; however, the clinical barrier has yet to be broken because of several issues, including the lack of an ideal vector supporting safe and long-term myocardial transgene expression.Methods and Results - Here, we show that the use of a recombinant adeno-associated viral (rAAV6) vector containing a novel cardiac-selective enhancer/promoter element can direct stable cardiac expression of a therapeutic transgene, the calcium (Ca2+)-sensing S100A1, in a rat model of heart failure. The chronic heart failure-rescuing properties of myocardial S100A1 expression, the result of improved sarcoplasmic reticulum Ca2+ handling, included improved contractile function and left ventricular remodeling. Adding to the clinical relevance, long-term S100A1 therapy had unique and additive beneficial effects over beta-adrenergic receptor blockade, a current pharmacological heart failure treatment.Conclusions - These findings demonstrate that stable increased expression of S100A1 in the failing heart can be used for long-term reversal of LV dysfunction and remodeling. Thus, long-term, cardiac-targeted rAAV6-S100A1 gene therapy may be of potential clinical utility in human heart failure.