Excision of expanded GAA repeats alleviates the molecular phenotype of Friedreich's ataxia.
Friedreich's ataxia (FRDA) is an autosomal recessive neurological disease caused by expansions of 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 (ZFN)-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 ZFN-edited fibroblasts to induced pluripotent stem cells (iPSCs) 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 ZFN-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.Molecular Therapy (2015); doi:10.1038/mt.2015.41.