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


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.

SUBMITTER: Li Y 

PROVIDER: S-EPMC4817761 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Li Yanjie Y   Polak Urszula U   Bhalla Angela D AD   Rozwadowska Natalia N   Butler Jill Sergesketter JS   Lynch David R DR   Dent Sharon Y R SYR   Napierala Marek M  

Molecular therapy : the journal of the American Society of Gene Therapy 20150311 6


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.  ...[more]

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