Drug reprofile for Friedreich’s ataxia: Screening of an FDA-approved drugs library searching for small molecules that increase frataxin

Freidreich’s Ataxia (FRDA) is a neurodegenerative, autosomal hereditary disease characterized by progressive neurodegeneration, cardiomyopathy and increased incidence of diabetes. The disease is caused by a trinucleotide GAA repeat expansion within the first intron of the gene coding for frataxin protein (FXN). Pathological GAA expansion (from ~70 to >1,000 triplets) results in “sticky” DNA structures and epigenetic changes that severely reduce transcription of the gene. FRDA patients live with 10-30% residual frataxin. The severity of the disease is proportionally related to the number of GAA triplets, which in turn correlates to the reduction in frataxin levels. Sensory neurons in dorsal root ganglia (DRG) are particularly involved and damaged by inflammatory condition derived from frataxin deficiency. Currently there is no approved and specific therapy for FRDA able to increase the protein deficient in this disease. Here we propose a drug repositioning approach looking for a new application of known drugs in this pathology. A significant advantage of drug repositioning over traditional drug development is that since the repositioned drug has already passed a significant number of trials, its safety is known and the risk of failure for reasons of adverse toxicology are reduced. Therefore, drug repositioning represents an attractive approach to identify a new therapy for Friedreich ataxia.