Gene-based approaches toward Friedreich ataxia therapeutics

Abstract.

Friedreich ataxia is an autosomal recessive trinucleotide-repeat disease caused by expanded GAA repeats in the first intron of the FRDA gene. These GAA repeats are suspected to form unusual non-B DNA conformations that decrease transcription and subsequently reduce levels of the encoded protein, frataxin. GAA repeats also 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. There is no effective therapy for Friedreich ataxia, but antioxidant therapy has shown promise and is currently in clinical trials. In this review we focus on the mechanisms by which expanded GAA repeats reduce transcription and discuss how these findings have lead to gene-based approaches that may be effective in treating Friedreich ataxia.