1. Stable Myocardial-Specific AAV6-S100A1 Gene Therapy Results in Chronic Functional Heart Failure Rescue
- Author
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Walter J. Koch, Hugo A. Katus, Joseph E. Rabinowitz, Patrick Most, Erhe Gao, Abhijit Dasgupta, Andrew Remppis, J. Kurt Chuprun, Wiebke Pleger, Sven T. Pleger, Andrea D. Eckhart, Giuseppe Rengo, Matthieu Boucher, Stephen Soltys, Pleger, S. T., Most, P., Boucher, M., Soltys, S., Chuprun, J. K., Pleger, W., Gao, E., Dasgupta, A., Rengo, G., Remppis, A., Katus, H. A., Eckhart, A. D., Rabinowitz, J. E., and Koch, W. J.
- Subjects
Heart disease ,Genetic enhancement ,Myocardial Infarction ,Mice ,Genes, Reporter ,Vector (molecular biology) ,Promoter Regions, Genetic ,Heart Function Test ,S100 Proteins ,Dependovirus ,Dependoviru ,Enhancer Elements, Genetic ,Lac Operon ,S100 Protein ,Organ Specificity ,Heart Function Tests ,Cardiology ,Genetic Vector ,Cardiology and Cardiovascular Medicine ,Human ,medicine.medical_specialty ,S100A1 protein ,Recombinant Fusion Proteins ,Transgene ,Genetic Vectors ,Green Fluorescent Proteins ,Cardiomegaly ,Green Fluorescent Protein ,Long-term care ,Gene therapy ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Humans ,Clinical significance ,Calcium Signaling ,Enhancer ,Ventricular remodeling ,Actin ,Heart Failure ,Binding Sites ,Animal ,business.industry ,Binding Site ,Genetic Therapy ,medicine.disease ,Myocardial Contraction ,Actins ,Rats ,Mice, Inbred C57BL ,Endocrinology ,Heart failure ,Rat ,business ,Recombinant Fusion Protein - Abstract
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 (Ca 2+ )-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 Ca 2+ 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.
- Published
- 2007
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