Excision of expanded GAA repeats alleviates the molecular phenotype of friedreich's ataxia

Academic Article


  • © 2015 The American Society of Gene & Cell Therapy. Friedreich's ataxia (FRDA) is an autosomal recessive neurological disease caused by expansions of guanine-adenine-adenine (GAA) repeats in intron 1 of the frataxin (FXN) gene. The expansion results in significantly decreased frataxin expression. We report that human FRDA cells can be corrected by zinc finger nuclease-mediated excision of the expanded GAA repeats. Editing of a single expanded GAA allele created heterozygous, FRDA carrier-like cells and significantly increased frataxin expression. This correction persisted during reprogramming of zinc finger nuclease-edited fibroblasts to induced pluripotent stem cells and subsequent differentiation into neurons. The expression of FRDA biomarkers was normalized in corrected patient cells and disease-associated phenotypes, such as decreases in aconitase activity and intracellular ATP levels, were reversed in zinc finger nuclease corrected neuronal cells. Genetically and phenotypically corrected patient cells represent not only a preferred disease-relevant model system to study pathogenic mechanisms, but also a critical step towards development of cell replacement therapy.
  • Published In

  • Molecular Therapy  Journal
  • Digital Object Identifier (doi)

    Author List

  • Li Y; Polak U; Bhalla AD; Rozwadowska N; Butler JS; Lynch DR; Dent SYR; Napierala M
  • Start Page

  • 1055
  • End Page

  • 1065
  • Volume

  • 23
  • Issue

  • 6