Cardiac AAV9-S100A1 Gene Therapy Rescues Post-Ischemic Heart Failure in a Preclinical Large Animal Model

• DOI: 10.1126/scitranslmed.3002097
• Publication Date: 2011-07-20T18:30:32Z
• Authors: Sven T. Pleger; Changguang Shan; Jan Ksienzyk; Raffi Bekeredjian; Peter Boekstegers; Rabea Hinkel; Stefanie Schinkel; Barbara Leuchs; Jochen Ludwig; Gang Qiu; Christophe Weber; Philip Raake; Walter J. Koch; Hugo A. Katus; Oliver J. Müller; Patrick Most
• Keywords: Contractility; Intercalated disc

As a prerequisite for clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated virus (AAV)-S100A1 gene therapy in preclinical large animal model heart failure. S100A1, positive inotropic regulator myocardial contractility, becomes depleted failing cardiomyocytes humans animals, myocardial-targeted S100A1 transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium (Ca(2+)) handling acutely chronically hearts small models. We induced failure domestic pigs balloon occlusion left circumflex coronary artery, resulting infarction. After 2 weeks, when displayed significant ventricular dysfunction, administered, retrograde venous delivery, AAV serotype 9 (AAV9)-S100A1 to ventricular, non-infarcted myocardium. AAV9-luciferase saline treatment served as control. At 14 both control groups showed significantly decreased protein expression along with progressive deterioration performance remodeling. AAV9-S100A1 prevented reversed these functional structural changes levels. normalized cardiomyocyte Ca(2+) cycling, handling, energy homeostasis. Transgene was restricted tissue, extracardiac organ uncompromised. This translational study shows feasibility favorable profile Our results present strong rationale trial human that could potentially complement current strategies treat end-stage