Cardiac failure is the most common cause of mortality in Friedreich's ataxia (FRDA), a mitochondrial disease characterized by neurodegeneration, hypertrophic cardiomyopathy and diabetes1,2,3. FRDA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters4,5,6,7,8. Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in the myocardium of individuals with FRDA9,10,11,12. No treatment exists as yet for FRDA cardiomyopathy13,14. A conditional mouse model with complete frataxin deletion in cardiac and skeletal muscle (Mck-Cre-FxnL3/L– mice) recapitulates most features of FRDA cardiomyopathy, albeit with a more rapid and severe course15,16. 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.
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We thank A. Martelli for help in vector construction and for fruitful discussions, P. Bougnères for fruitful discussions and insightful comments on the manuscript, and V. Blouin and P. Moullier (Institut de Recherche Thérapeutique, INSERM UMR 1089) for vector production. This work was supported by the Association Française contre les Myopathies (to H.P.), the US Friedreich Ataxia Research Alliance (to H.P.), the European Community under the European Research Council (206634/ISCATAXIA; to H.P.), the Seventh Framework Programme (242193/EFACTS; to H.P.), the Association the Fondation Simone et Cino del Duca (to P.A.) and the Institut de France (to P.A.), by a personal donation from the Ledru family (to H.P.) and by a French state fund through the Agence Nationale de la Recherche under the frame programme Investissements d'Avenir labeled ANR-10-IDEX-0002-02 (ANR-10-LABX-0030-INRT). M.P. is a recipient of a PhD fellowship from the Association Française pour l'Ataxie de Friedreich.
R.G.C., P.A. and H.P. are scientific founders of AAVLIFE, a gene therapy company focusing on rare diseases.
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Perdomini, M., Belbellaa, B., Monassier, L. et al. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia. Nat Med 20, 542–547 (2014). https://doi.org/10.1038/nm.3510
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