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.
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 humanheart failure.
Authors: Michael G Katz; Anthony S Fargnoli; Catherine E Tomasulo; Louella A Pritchette; Charles R Bridges Journal: J Gene Med Date: 2011-10 Impact factor: 4.565
Authors: Naohiro Yamaguchi; Benjamin L Prosser; Farshid Ghassemi; Le Xu; Daniel A Pasek; Jerry P Eu; Erick O Hernández-Ochoa; Brian R Cannon; Paul T Wilder; Richard M Lovering; David Weber; Werner Melzer; Martin F Schneider; Gerhard Meissner Journal: Am J Physiol Cell Physiol Date: 2011-02-02 Impact factor: 4.249
Authors: Benjamin L Prosser; Nathan T Wright; Erick O Hernãndez-Ochoa; Kristen M Varney; Yewei Liu; Rotimi O Olojo; Danna B Zimmer; David J Weber; Martin F Schneider Journal: J Biol Chem Date: 2007-12-17 Impact factor: 5.157