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

Morgane Perdomini, Brahim Belbellaa, Laurent Monassier, Laurence Reutenauer, Nadia Messaddeq, Nathalie Cartier, Ronald Crystal, Patrick Aubourg, Hélène Puccio

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

Cardiac failure is the most common cause of mortality in Friedreich's ataxia (FRDA), a mitochondrial disease characterized by neurodegeneration, hypertrophic cardiomyopathy and diabetes1-3. FRDA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters4-8. Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in the myocardium of individuals with FRDA9-12. 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.

Original languageEnglish
Pages (from-to)542-547
Number of pages6
JournalNature Medicine
Volume20
Issue number5
DOIs
Publication statusPublished - 28 Apr 2014
Externally publishedYes

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Friedreich Ataxia
Gene therapy
Mitochondrial Genes
Cardiomyopathies
Genetic Therapy
Iron
Myocardium
Heart Failure
Mitochondrial Proteins
Biosynthesis
Mitochondrial Diseases
Dependovirus
Viruses
Sulfur
Iron Overload
Hypertrophic Cardiomyopathy
Oxidative Phosphorylation
Muscle
Cardiac Myocytes
Energy Metabolism

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Perdomini, M., Belbellaa, B., Monassier, L., Reutenauer, L., Messaddeq, N., Cartier, N., ... Puccio, H. (2014). Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia. Nature Medicine, 20(5), 542-547. https://doi.org/10.1038/nm.3510

Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia. / Perdomini, Morgane; Belbellaa, Brahim; Monassier, Laurent; Reutenauer, Laurence; Messaddeq, Nadia; Cartier, Nathalie; Crystal, Ronald; Aubourg, Patrick; Puccio, Hélène.

In: Nature Medicine, Vol. 20, No. 5, 28.04.2014, p. 542-547.

Research output: Contribution to journalArticle

Perdomini, M, Belbellaa, B, Monassier, L, Reutenauer, L, Messaddeq, N, Cartier, N, Crystal, R, Aubourg, P & Puccio, H 2014, 'Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia', Nature Medicine, vol. 20, no. 5, pp. 542-547. https://doi.org/10.1038/nm.3510
Perdomini M, Belbellaa B, Monassier L, Reutenauer L, Messaddeq N, Cartier N et al. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia. Nature Medicine. 2014 Apr 28;20(5):542-547. https://doi.org/10.1038/nm.3510
Perdomini, Morgane ; Belbellaa, Brahim ; Monassier, Laurent ; Reutenauer, Laurence ; Messaddeq, Nadia ; Cartier, Nathalie ; Crystal, Ronald ; Aubourg, Patrick ; Puccio, Hélène. / Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia. In: Nature Medicine. 2014 ; Vol. 20, No. 5. pp. 542-547.
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