0300: Systemic delivery of AAVrh10 expressing frataxin corrects the severe mitochondrial cardiomyopathy of frataxin deficient mice

Abstract

Cardiac failure is the most common cause of mortality in Friedreich ataxia (FRDA), a mitochondrial disease with neurodegeneration, hypertrophic cardiomyopathy and diabetes. FRDA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in mitochondrial bioenergetics. To date, no treatment exists for FRDA cardiomyopathy. Here, we show that adenoassociated virus (AAV) rh10 vector expressing human FXN injected intravenously not only prevented the onset of the cardiac disease in a faithful FRDA cardiac mouse model, but also, when administered at the time of heart failure, reversed rapidly and completely cardiac disease at the functional, cellular and molecular level in all treated animals. Our results also demonstrate the capacity of defective cardiomyocytes with severe energy failure and ultrastructure disorganization to be rapidly corrected and remodeled by gene therapy. These results establish the primary proof-of-concept for developing gene therapy of FRDA cardiomyopathy.