title: Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model.
abstract: As a prerequisite for clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated virus (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 animals, and myocardial-targeted S100A1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium (Ca(2+)) 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, resulting in myocardial infarction. After 2 weeks, when the pigs displayed significant left ventricular contractile dysfunction, we administered, by retrograde coronary venous delivery, AAV serotype 9 (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 these functional and structural changes by restoring cardiac S100A1 protein levels. S100A1 treatment normalized cardiomyocyte Ca(2+) cycling, sarcoplasmic reticulum calcium handling, and energy homeostasis. Transgene expression was restricted to cardiac tissue, and extracardiac organ function was uncompromised. This translational study shows the preclinical feasibility of long-term therapeutic effectiveness of and a favorable safety profile for cardiac AAV9-S100A1 gene therapy in a preclinical model of heart failure. Our results present a strong rationale for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure.
authors.affiliation: Center for Molecular and Translational Cardiology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Sven T
authors.initials: ST
authors.lastname: Pleger
authors.forename: Changguang
authors.initials: C
authors.lastname: Shan
authors.forename: Jan
authors.initials: J
authors.lastname: Ksienzyk
authors.forename: Raffi
authors.initials: R
authors.lastname: Bekeredjian
authors.forename: Peter
authors.initials: P
authors.lastname: Boekstegers
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schinkel
authors.forename: Barbara
authors.initials: B
authors.lastname: Leuchs
authors.forename: Jochen
authors.initials: J
authors.lastname: Ludwig
authors.forename: Gang
authors.initials: G
authors.lastname: Qiu
authors.forename: Christophe
authors.initials: C
authors.lastname: Weber
authors.forename: Philip
authors.initials: P
authors.lastname: Raake
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Müller
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002118:Calcium / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects; D006333:Heart Failure / Q000097:blood / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D006334:Heart Function Tests; D006706:Homeostasis; D006801:Humans; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000097:blood / Q000150:complications* / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D009418:S100 Proteins / Q000235:genetics* / Q000627:therapeutic use*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D034421:Sus scrofa
chemical_list: D015415:Biomarkers; D009418:S100 Proteins; C110294:S100A1 protein; D002118:Calcium