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

Nature Medicine volume 20, pages 542–547 (2014)Cite this article

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Abstract

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.

References

  1. Harding, A.E. Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain 104, 589–620 (1981).

    Article  CAS  Google Scholar 

  2. Tsou, A.Y. et al. Mortality in Friedreich ataxia. J. Neurol. Sci. 307, 46–49 (2011).

    Article  Google Scholar 

  3. Weidemann, F. et al. The heart in Friedreich ataxia: definition of cardiomyopathy, disease severity, and correlation with neurological symptoms. Circulation 125, 1626–1634 (2012).

    Article  Google Scholar 

  4. Campuzano, V. et al. Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum. Mol. Genet. 6, 1771–1780 (1997).

    Article  CAS  Google Scholar 

  5. Campuzano, V. et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423–1427 (1996).

    Article  CAS  Google Scholar 

  6. Tsai, C.L. & Barondeau, D.P. Human frataxin is an allosteric switch that activates the Fe-S cluster biosynthetic complex. Biochemistry 49, 9132–9139 (2010).

    Article  CAS  Google Scholar 

  7. Schmucker, S. et al. Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex. PLoS ONE 6, e16199 (2011).

    Article  CAS  Google Scholar 

  8. Colin, F. et al. Mammalian frataxin controls sulfur production and iron entry during de novo Fe4S4 cluster assembly. J. Am. Chem. Soc. 135, 733–740 (2013).

    Article  CAS  Google Scholar 

  9. Lodi, R. et al. Cardiac energetics are abnormal in Friedreich ataxia patients in the absence of cardiac dysfunction and hypertrophy: an in vivo31P magnetic resonance spectroscopy study. Cardiovasc. Res. 52, 111–119 (2001).

    Article  CAS  Google Scholar 

  10. Lamarche, J., Shapcott, D., Côté, M. & Lemieux, B. Cardiac iron deposits in Friedreich's ataxia. in Handbook of Cerebellar Diseases (ed. Lechtenberg, R.) 453–457 (CRC Press, 1993).

  11. Rötig, A. et al. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat. Genet. 17, 215–217 (1997).

    Article  Google Scholar 

  12. Michael, S. et al. Iron and iron-responsive proteins in the cardiomyopathy of Friedreich's ataxia. Cerebellum 5, 257–267 (2006).

    Article  CAS  Google Scholar 

  13. Perlman, S.L. A review of Friedreich ataxia clinical trial results. J. Child Neurol. 27, 1217–1222 (2012).

    Article  Google Scholar 

  14. Wilson, R.B. Therapeutic developments in Friedreich ataxia. J. Child Neurol. 27, 1212–1216 (2012).

    Article  Google Scholar 

  15. Puccio, H. et al. Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat. Genet. 27, 181–186 (2001).

    Article  CAS  Google Scholar 

  16. Seznec, H. et al. Idebenone delays the onset of cardiac functional alteration without correction of Fe-S enzymes deficit in a mouse model for Friedreich ataxia. Hum. Mol. Genet. 13, 1017–1024 (2004).

    Article  CAS  Google Scholar 

  17. Hu, C., Busuttil, R.W. & Lipshutz, G.S. RH10 provides superior transgene expression in mice when compared with natural AAV serotypes for neonatal gene therapy. J. Gene Med. 12, 766–778 (2010).

    Article  CAS  Google Scholar 

  18. Wang, G. et al. Persistent expression of biologically active anti-HER2 antibody by AAVrh.10-mediated gene transfer. Cancer Gene Ther. 17, 559–570 (2010).

    Article  CAS  Google Scholar 

  19. Bernardo, B.C., Weeks, K.L., Pretorius, L. & McMullen, J.R. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol. Ther. 128, 191–227 (2010).

    Article  CAS  Google Scholar 

  20. Wilkins, B.J. & Molkentin, J.D. Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. Biochem. Biophys. Res. Commun. 322, 1178–1191 (2004).

    Article  CAS  Google Scholar 

  21. Elia, L. et al. Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. Circulation 120, 2377–2385 (2009).

    Article  CAS  Google Scholar 

  22. Barry, W.H. & Bridge, J.H. Intracellular calcium homeostasis in cardiac myocytes. Circulation 87, 1806–1815 (1993).

    Article  CAS  Google Scholar 

  23. Schmucker, S., Argentini, M., Carelle-Calmels, N., Martelli, A. & Puccio, H. The in vivo mitochondrial two-step maturation of human frataxin. Hum. Mol. Genet. 17, 3521–3531 (2008).

    Article  CAS  Google Scholar 

  24. Guillon, B. et al. Frataxin deficiency causes upregulation of mitochondrial Lon and ClpP proteases and severe loss of mitochondrial Fe-S proteins. FEBS J. 276, 1036–1047 (2009).

    Article  CAS  Google Scholar 

  25. Navarro-Sastre, A. et al. A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins. Am. J. Hum. Genet. 89, 656–667 (2011).

    Article  CAS  Google Scholar 

  26. Huang, M.L. et al. Molecular and functional alterations in a mouse cardiac model of Friedreich ataxia: activation of the integrated stress response, eIF2α phosphorylation, and the induction of downstream targets. Am. J. Pathol. 183, 745–757 (2013).

    Article  CAS  Google Scholar 

  27. Seznec, H. et al. Friedreich ataxia: the oxidative stress paradox. Hum. Mol. Genet. 14, 463–474 (2005).

    Article  CAS  Google Scholar 

  28. Vorgerd, M. et al. Mitochondrial impairment of human muscle in Friedreich ataxia in vivo. Neuromuscul. Disord. 10, 430–435 (2000).

    Article  CAS  Google Scholar 

  29. St John Sutton, M. et al. Longitudinal strain in friedreich ataxia: a potential marker for early left ventricular dysfunction. Echocardiography 31, 50–57 (2014).

    Article  Google Scholar 

  30. Dedobbeleer, C., Rai, M., Donal, E., Pandolfo, M. & Unger, P. Normal left ventricular ejection fraction and mass but subclinical myocardial dysfunction in patients with Friedreich's ataxia. Eur. Heart J. Cardiovasc. Imaging 13, 346–352 (2012).

    Article  Google Scholar 

  31. Raman, S.V. et al. Impaired myocardial perfusion reserve and fibrosis in Friedreich ataxia: a mitochondrial cardiomyopathy with metabolic syndrome. Eur. Heart J. 32, 561–567 (2011).

    Article  Google Scholar 

  32. Wagner, G.R., Pride, P.M., Babbey, C.M. & Payne, R.M. Friedreich's ataxia reveals a mechanism for coordinate regulation of oxidative metabolism via feedback inhibition of the SIRT3 deacetylase. Hum. Mol. Genet. 21, 2688–2697 (2012).

    Article  CAS  Google Scholar 

  33. Chan, D.C. Fusion and fission: interlinked processes critical for mitochondrial health. Annu. Rev. Genet. 46, 265–287 (2012).

    Article  CAS  Google Scholar 

  34. Sedlak, T.L., Chandavimol, M. & Straatman, L. Cardiac transplantation: a temporary solution for Friedreich's ataxia–induced dilated cardiomyopathy. J. Heart Lung Transplant. 23, 1304–1306 (2004).

    Article  Google Scholar 

  35. Sondhi, D. et al. Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus macaque-derived adeno-associated virus vector. Mol. Ther. 15, 481–491 (2007).

    Article  CAS  Google Scholar 

  36. Rabinowitz, J.E. et al. Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J. Virol. 76, 791–801 (2002).

    Article  CAS  Google Scholar 

  37. Martelli, A. et al. Clinical data and characterization of the liver conditional mouse model exclude neoplasia as a non-neurological manifestation associated with Friedreich's ataxia. Dis. Model. Mech. 5, 860–869 (2012).

    Article  CAS  Google Scholar 

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Acknowledgements

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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Author notes

  1. Morgane Perdomini and Brahim Belbellaa: These authors contributed equally to this work.

Authors and Affiliations

  1. Départment de Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France

    Morgane Perdomini, Brahim Belbellaa, Laurence Reutenauer, Nadia Messaddeq & Hélène Puccio

  2. INSERM, U596, Illkirch, France

    Morgane Perdomini, Brahim Belbellaa, Laurence Reutenauer, Nadia Messaddeq & Hélène Puccio

  3. CNRS, UMR7104, Illkirch, France

    Morgane Perdomini, Brahim Belbellaa, Laurence Reutenauer, Nadia Messaddeq & Hélène Puccio

  4. Université de Strasbourg, Strasbourg, France

    Morgane Perdomini, Brahim Belbellaa, Laurence Reutenauer, Nadia Messaddeq & Hélène Puccio

  5. Collège de France, Chaire de génétique humaine, Illkirch, France

    Morgane Perdomini, Brahim Belbellaa, Laurence Reutenauer, Nadia Messaddeq & Hélène Puccio

  6. Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Fédération de Médecine Translationnelle, Faculté de Médecine, Université de Strasbourg, Strasbourg, France

    Laurent Monassier

  7. INSERM, U986, Le Kremlin-Bicêtre, France

    Nathalie Cartier & Patrick Aubourg

  8. Department of Genetic Medicine, Weill Cornell Medical College, New York, USA

    Ronald G Crystal

  9. University Paris-Sud, Paris, France

    Patrick Aubourg

  10. Assistance Publique-Hôpitaux de Paris, Paris, France

    Patrick Aubourg

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  1. Morgane Perdomini
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Contributions

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.

Corresponding authors

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). https://doi.org/10.1038/nm.3510

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