title: 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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Urszula
authors.initials: U
authors.lastname: Polak
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Angela D
authors.initials: AD
authors.lastname: Bhalla
authors.affiliation: 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.
authors.forename: Natalia
authors.initials: N
authors.lastname: Rozwadowska
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Jill Sergesketter
authors.initials: JS
authors.lastname: Butler
authors.affiliation: Division of Neurology and Pediatrics, Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, Pennsylvania, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Lynch
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Science Park, Smithville, Texas, USA.
authors.forename: Sharon Y R
authors.initials: SYR
authors.lastname: Dent
authors.affiliation: 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.
authors.forename: Marek
authors.initials: M
authors.lastname: Napierala
mesh_terms: D000154:Aconitate Hydratase / Q000235:genetics / Q000378:metabolism; D000225:Adenine / Q000378:metabolism*; D000483:Alleles; D002454:Cell Differentiation; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005621:Friedreich Ataxia / Q000235:genetics* / Q000628:therapy*; D015316:Genetic Therapy; D006147:Guanine / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D007438:Introns; D020014:K562 Cells; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion; D016335:Zinc Fingers
chemical_list: D012333:RNA, Messenger; D006147:Guanine; D004706:Endodeoxyribonucleases; D000154:Aconitate Hydratase; D000225:Adenine