© 2014 Nature America, Inc. All rights reserved. LETTERS NATURE MEDICINE ADVANCE ONLINE PUBLICATION  Cardiac failure is the most common cause of mortality in Friedreich’s ataxia (FRDA), a mitochondrial disease characterized by neurodegeneration, hypertrophic cardiomyopathy and diabetes 1–3 . FRDA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters 4–8 . Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in the myocardium of individuals with FRDA 9–12 . No treatment exists as yet for FRDA cardiomyopathy 13,14 . A conditional mouse model with complete frataxin deletion in cardiac and skeletal muscle (Mck-Cre-Fxn L3/L– mice) recapitulates most features of FRDA cardiomyopathy, albeit with a more rapid and severe course 15,16 . Here we show that adeno-associated virus rh10 vector expressing human FXN injected intravenously in these mice fully prevented the onset of cardiac disease. Moreover, later administration of the frataxin- expressing vector, after the onset of heart failure, was able to completely reverse the cardiomyopathy of these mice at the functional, cellular and molecular levels within a few days. Our results demonstrate that cardiomyocytes with severe energy failure and ultrastructure disorganization can be rapidly rescued and remodeled by gene therapy and establish the preclinical proof of concept for the potential of gene therapy in treating FRDA cardiomyopathy. Among adeno-associated virus (AAV) serotypes that efficiently target the heart, AAVrh10 is readily transported within the myocardium after intravenous injection 17,18 . We conducted a biodistribution study in wild-type (WT) mice injected intravenously with either the GFP-encoding AAVrh10-CAG-GFP vector or the frataxin-encoding AAVrh10-CAG-hFXN-HA vector. Transgene expression was robust in the heart and liver, with a substantial overexpression of human FXN (more than tenfold over that of endogenous mouse frataxin) (Supplementary Fig. 1a–j). In contrast, transgene expression was much lower in skeletal muscle and in the nervous system, although neurons of the dorsal root ganglia were highly positive for GFP expression all along the vertebral column as well as in their axonal projections in the posterior column of the spinal cord and in the medulla oblongata (Supplementary Fig. 1a–j). The tropism of AAVrh10 for heart and dorsal root ganglia, the two most affected tissues in FRDA, validates the choice of the AAVrh10 serotype for our studies. To investigate the potential of gene therapy approaches in the treatment of the FRDA cardiomyopathy, we performed a single intravenous injection of AAVrh10-CAG-hFXN at a dose of 5.4 × 10 13 vector genomes per kilogram body weight (vg kg −1 ) into asymptomatic 3-week-old Mck-Cre-Fxn L3/L– mice (carrying a conditional allele (L3) allowing deletion of exon 4 of Fxn and the Fxn exon 4–deleted allele (L–) and a muscle creatine kinase promoter–driven Cre trans- gene), called here Mck mice 15 (n = 9) (Supplementary Fig. 2a). Serial echocardiographic measurements showed normal hemodynamic and morphological development in treated Mck mice (Fig. 1a and Supplementary Tables 1–3). Mck mice injected with AAVrh10-CAG- hFXN remained undistinguishable from WT mice at 35 weeks of age, demonstrating a complete prevention of cardiac disease. In contrast, untreated Mck mice developed, as previously demonstrated 15,16 , a rapidly progressive cardiac insufficiency, with a marked decrease in left ventricle shortening fraction and cardiac output, as well as left ventricle hypertrophy associated with massive geometric remodeling (Fig. 1a and Supplementary Tables 1–3). These mice lost weight progressively and died of cardiac failure at 65 ± 10 d (9.3 ± 1.4 weeks) (Fig. 1b and Supplementary Fig. 2b). Consistent with the development of heart failure, untreated Mck mice at 8 weeks of age displayed a strong increase in mRNA expression of atrial natriuretic peptide (Nppa) and brain natriuretic peptide (Nppb), two biomarkers of hemodynamic overload 19 (Fig. 1c). Biomarkers of hypertrophy 20 were also present, with increased Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich’s ataxia Morgane Perdomini 1–5,11 , Brahim Belbellaa 1–5,11 , Laurent Monassier 6 , Laurence Reutenauer 1–5 , Nadia Messaddeq 1–5 , Nathalie Cartier 7 , Ronald G Crystal 8 , Patrick Aubourg 7,9,10 & Hélène Puccio 1–5 1 Départment de Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France. 2 INSERM, U596, Illkirch, France. 3 CNRS, UMR7104, Illkirch, France. 4 Université de Strasbourg, Strasbourg, France. 5 Collège de France, Chaire de génétique humaine, Illkirch, France. 6 Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Fédération de Médecine Translationnelle, Faculté de Médecine, Université de Strasbourg, Strasbourg, France. 7 INSERM, U986, Le Kremlin-Bicêtre, France. 8 Department of Genetic Medicine, Weill Cornell Medical College, New York, USA. 9 University Paris-Sud, Paris, France. 10 Assistance Publique-Hôpitaux de Paris, Paris, France. 11 These authors contributed equally to this work. Correspondence should be addressed to H.P. (hpuccio@igbmc.fr) or P.A. (patrick.aubourg@inserm.fr). Received 20 November 2013; accepted 20 February 2014; published online 6 April 2014; doi:10.1038/nm.3510