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

Nat Med. 2014 May;20(5):542-7. doi: 10.1038/nm.3510. Epub 2014 Apr 6.


Cardiac failure is the most common cause of mortality in Friedreich's ataxia (FRDA), a mitochondrial disease characterized by neurodegeneration, hypertrophic cardiomyopathy and diabetes. FRDA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in the myocardium of individuals with FRDA. No treatment exists as yet for FRDA cardiomyopathy. 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. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomyopathies / genetics
  • Cardiomyopathies / pathology
  • Cardiomyopathies / therapy*
  • Disease Models, Animal
  • Friedreich Ataxia / genetics*
  • Friedreich Ataxia / pathology
  • Friedreich Ataxia / therapy*
  • Gene Expression
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • Iron-Binding Proteins / administration & dosage
  • Iron-Binding Proteins / genetics*
  • Iron-Sulfur Proteins / biosynthesis
  • Mice
  • Mitochondria, Heart / genetics
  • Mitochondria, Heart / pathology
  • Myocytes, Cardiac / pathology


  • Iron-Binding Proteins
  • Iron-Sulfur Proteins
  • frataxin