Cardiac AAV 9S 100 A 1 gene therapy rescues postischemic heart failure in a preclinical large animal model

As a prerequisite to clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated viral (AAV) S100A1 gene therapy in a preclinical, large animal model of heart failure. S100A1, a positive inotropic regulator of myocardial contractility, becomes depleted in failing cardiomyocytes in humans and various animal models, and myocardial-targeted S100A1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium Ca2+ handling in acutely and chronically failing hearts in small animal models. We induced heart failure in domestic pigs by balloon-occlusion of the left circumflex coronary artery, Address for correspondence: Patrick Most, MD, Molecular and Translational Cardiology, Department of Medicine III, University of Heidelberg, 69120 Heidelberg, Germany, patrick.most@med.uni-heidelberg.de. Oliver Müller, MD, Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, 69120 Heidelberg, Germany, oliver.mueller@med.uni-heidelberg.de. *These authors contributed equally to this work. Author contributions: S.T. P. and P.M. wrote the manuscript. S.T. P., C.S. , J.K. J.A. K, P.R, W.J.K. , H.A. K. , O.J.M. and P.M. designed the experiments. S.T. P, C.S. , J.K. , R.B. , P.B. , R.H. , S.S. , B.L. , J.L. , C.W. and O.J.M performed the experiments and analyzed the data. Competing interests: P.M. and H.A. K. have filed a U.S. and an EU patent application on the therapeutic use of the S100A1 protein to treat heart failure. NIH Public Access Author Manuscript Sci Transl Med. Author manuscript; available in PMC 2014 July 14. Published in final edited form as: Sci Transl Med. 2011 July 20; 3(92): 92ra64. doi:10.1126/scitranslmed.3002097. N IH -P A A uhor M anscript N IH -P A A uhor M anscript N IH -P A A uhor M anscript resulting in myocardial infarction. After 2 weeks, when the pigs displayed significant left ventricular contractile dysfunction, we administered through retrograde coronary venous delivery, AAV9-S100A1 to the left ventricular non-infarcted myocardium. AAV9-luciferase and saline treatment served as control. At 14 weeks, both control groups showed significantly decreased myocardial S100A1 protein expression along with progressive deterioration of cardiac performance and left ventricular remodeling. AAV9-S100A1 treatment prevented and reversed this phenotype by restoring cardiac S100A1 protein levels. S100A1 treatment normalized cardiomyocyte Ca2+ cycling, sarcoplasmic reticulum calcium handling and energy homeostasis. Transgene expression was restricted to cardiac tissue and extra-cardiac organ function was uncompromised indicating a favorable safety profile. This translational study shows the preclinical feasibility, long-term therapeutic effectiveness and a favorable safety profile of cardiac AAV9-S100A1 gene therapy in a preclinical model of heart failure. Our study presents a strong rational for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure.