Format

Send to

Choose Destination
Mol Ther. 2015 Jun;23(6):1055-1065. doi: 10.1038/mt.2015.41. Epub 2015 Mar 11.

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

Author information

1
Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA.
2
Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Science Park, Smithville, Texas, USA; Department of Cell Biology, Poznan University of Medical Sciences, Poznan, Poland.
3
Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA; Institute of Human Genetics, Polish Academy of Science, Poznan, Poland.
4
Division of Neurology and Pediatrics, Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, Pennsylvania, USA.
5
Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Science Park, Smithville, Texas, USA.
6
Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland. Electronic address: mnapiera@uab.edu.

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.

PMID:
25758173
PMCID:
PMC4817761
DOI:
10.1038/mt.2015.41
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center