MitoTALEN reduces mutant mtDNA load and restores tRNA Ala levels in a mouse model of heteroplasmic mtDNA mutation

Nat Med. 2018 Nov;24(11):1696-1700. doi: 10.1038/s41591-018-0166-8. Epub 2018 Sep 24.

Abstract

Mutations in the mitochondrial DNA (mtDNA) are responsible for several metabolic disorders, commonly involving muscle and the central nervous system1. Because of the critical role of mtDNA in oxidative phosphorylation, the majority of pathogenic mtDNA mutations are heteroplasmic, co-existing with wild-type molecules1. Using a mouse model with a heteroplasmic mtDNA mutation2, we tested whether mitochondrial-targeted TALENs (mitoTALENs)3,4 could reduce the mutant mtDNA load in muscle and heart. AAV9-mitoTALEN was administered via intramuscular, intravenous, and intraperitoneal injections. Muscle and heart were efficiently transduced and showed a robust reduction in mutant mtDNA, which was stable over time. The molecular defect, namely a decrease in transfer RNAAla levels, was restored by the treatment. These results showed that mitoTALENs, when expressed in affected tissues, could revert disease-related phenotypes in mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA, Mitochondrial / genetics
  • Disease Models, Animal
  • Heart / physiopathology*
  • Humans
  • Mice
  • Mitochondria, Heart / genetics
  • Mitochondria, Heart / pathology
  • Mitochondria, Muscle / genetics
  • Mitochondria, Muscle / pathology
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / physiopathology
  • Mitochondrial Diseases / therapy
  • Muscle, Skeletal / physiopathology*
  • Oxidative Phosphorylation
  • Point Mutation / genetics
  • Transcription Activator-Like Effector Nucleases / genetics*
  • Transcription Activator-Like Effector Nucleases / therapeutic use

Substances

  • DNA, Mitochondrial
  • Transcription Activator-Like Effector Nucleases