Excision of Expanded GAA Repeats Alleviates the Molecular Phenotype of Friedreich's Ataxia.

Academic Article


  • 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
  • Keywords

  • Aconitate Hydratase, Adenine, Alleles, Cell Differentiation, Endodeoxyribonucleases, Fibroblasts, Friedreich Ataxia, Genetic Therapy, Guanine, Heterozygote, Humans, Induced Pluripotent Stem Cells, Introns, K562 Cells, Neurons, Phenotype, RNA, Messenger, Trinucleotide Repeat Expansion, Zinc Fingers
  • 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