Friedreich's Ataxia: from the (GAA)n repeat mediated silencing to new promising molecules for therapy.

Cerebellum 8(3):245-59 (2009) PMID 19165552

Friedreich's ataxia (FRDA) is a neurodegenerative disease due to a pathological expansion of a GAA triplet repeat in the first intron of the FXN gene encoding for the mitochondrial protein frataxin. The expansion is responsible for most cases of FRDA through the formation of a nonusual B-DNA structure and heterochromatin conformation that determine a direct transcriptional silencing and the subsequent reduction in frataxin expression. Among other functions, frataxin is an iron chaperone central for the assembly of iron-sulfur clusters in mitochondria; its reduction is associated with iron accumulation in mitochondria, increased cellular sensitivity to oxidative stress and cell damage. There is, nowadays, no effective therapy for FRDA and current therapeutic strategies mainly act to slow down the consequences of frataxin deficiency. Therefore, drugs that are able to increase the amount of frataxin are excellent candidates for a rational approach to FRDA therapy. Recently, several drugs have been assessed for their ability to increase the amount of cellular frataxin, including human recombinant erythropoietin, histone deacetylase inhibitors, and the PPAR-gamma agonists.