Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue

Article

关键词: CA2+-BINDING PROTEIN S100A1;    VENTRICULAR CARDIOMYOCYTES;    CONTRACTILE PERFORMANCE;    CARDIAC-FUNCTION;    ADULT HEART;    INFARCTION;    RATS;    OVEREXPRESSION;    CARDIOMYOPATHY;    EXPRESSION;   

DOI  :  10.1161/CIRCULATIONAHA.106.671701

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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