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

Yanjie Li, Urszula Polak, Angela D. Bhalla, Natalia Rozwadowska, Jill Sergesketter Butler, David R. Lynch, Sharon Y.R. Dent, Marek Napierala

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1055-1065
Number of pages11
JournalMolecular Therapy
Volume23
Issue number6
DOIs
StatePublished - Jun 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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