Selective elimination of mitochondrial mutations in the germline by genome editing

Cell. 2015 Apr 23;161(3):459-469. doi: 10.1016/j.cell.2015.03.051.

Abstract

Mitochondrial diseases include a group of maternally inherited genetic disorders caused by mutations in mtDNA. In most of these patients, mutated mtDNA coexists with wild-type mtDNA, a situation known as mtDNA heteroplasmy. Here, we report on a strategy toward preventing germline transmission of mitochondrial diseases by inducing mtDNA heteroplasmy shift through the selective elimination of mutated mtDNA. As a proof of concept, we took advantage of NZB/BALB heteroplasmic mice, which contain two mtDNA haplotypes, BALB and NZB, and selectively prevented their germline transmission using either mitochondria-targeted restriction endonucleases or TALENs. In addition, we successfully reduced human mutated mtDNA levels responsible for Leber's hereditary optic neuropathy (LHOND), and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), in mammalian oocytes using mitochondria-targeted TALEN (mito-TALENs). Our approaches represent a potential therapeutic avenue for preventing the transgenerational transmission of human mitochondrial diseases caused by mutations in mtDNA. PAPERCLIP.

Publication types

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

MeSH terms

  • Animals
  • Cell Fusion
  • DNA, Mitochondrial
  • Embryo, Mammalian / metabolism
  • Endonucleases / metabolism
  • Female
  • Gene Targeting*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NZB
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / prevention & control
  • Mutation
  • Oocytes / metabolism

Substances

  • DNA, Mitochondrial
  • Endonucleases