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

ST Pleger, P Most, M Boucher, S Soltys, JK Chuprun… - Circulation, 2007 - Am Heart Assoc
ST Pleger, P Most, M Boucher, S Soltys, JK Chuprun, W Pleger, E Gao, A Dasgupta
Circulation, 2007Am Heart Assoc
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 …
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 β-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.
Am Heart Assoc