Targeting the gene in Friedreich ataxia.
Pathological expansions of GAA repeats in the first intron of the frataxin gene cause most cases of Friedreich ataxia, a progressively debilitating neurodegenerative disease. The disease is inherited in an autosomal recessive manner and the GAA repeats are suspected to form unusual non B-DNA conformations that decrease transcription and subsequently reduce levels of the encoded protein, frataxin. Recent work has shown that GAA repeats induce heterochromatin formation and silencing of the frataxin gene locus. Frataxin plays a crucial role in iron metabolism and detoxification and interacts with electron transport chain proteins. Clinical trials are currently underway to examine the efficacy of antioxidants in the treatment of Friedreich ataxia, but therapeutics designed to increase frataxin message levels are still in the developmental stages. This review will focus on the progress of potential treatment strategies for Friedreich ataxia that target the GAA expanded gene and seek to increase the level of frataxin message and protein.
Hebert
Michael D
MD
Department of Biochemistry, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA. mhebert@biochem.umsmed.edu
D000818:Animals; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D018911:Trinucleotide Repeats; D000096923:Frataxin
D006570:Heterochromatin; D033862:Iron-Binding Proteins; D024101:Mitochondrial Proteins; D000096923:Frataxin