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Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia


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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Figure 1: Treatment of asymptomatic Mck mice prevents the onset of cardiac failure and rescues survival.
Figure 2: Expression of human FXN prevents Fe-S protein deficiency and disorganization of mitochondrial and cardiomyocyte ultrastructure in asymptomatic Mck mice.
Figure 3: Treatment of Mck mice with cardiac failure quickly reverses the cardiac contractile dysfunction and arrest interstitial cardiac fibrosis.
Figure 4: Treatment of Mck mice with cardiac failure leads to rapid correction of Fe-S deficit and of cardiac mitochondrial and sarcomere ultrastructure.


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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.

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Authors and Affiliations



M.P. injected the mice, analyzed the echocardiographic results, and performed and analyzed the molecular and biochemical experiments; B.B. performed the survival, echocardiography and histological experiments; N.M. prepared and analyzed the samples for the electron microscopy analysis; L.M. trained B.B. for echocardiography and cardiac function analysis; L.R. was responsible for mouse production; R.G.C. and N.C. provided advice for the design of the study; M.P., B.B., P.A. and H.P. designed the study; H.P. and P.A. conceived of the study and were responsible for research coordination and strategy. M.P., B.B., P.A. and H.P. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Patrick Aubourg or Hélène Puccio.

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Competing interests

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).

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