Tunable Frataxin Replacement Therapy

DESCRIPTION (provided by applicant): Friedrich's ataxia (FA) is a devastating inherited degenerative disease that afflicts children and young adults resulting in early death. It is caused by homozygous recessive mutations in the frataxin (FXN) gene, whichm encodes a protein important in the assembly of iron-sulfur clusters in mitochondria. We propose to develop a therapy for FA that uses recombinant adeno-associated viral (AAV) vectors to deliver the FXN gene for tunable, long-term expression in the peripheral nervous system (PNS) and heart. To this end, we have developed an inducible AAV gene transfer system for regulated expression of FXN in target tissues. Oral administration of a small molecule drug can modulate the levels and duration of FXN expression from our third generation vectors. We hypothesize that increased levels of human frataxin containing the native mitochondrial targeting sequence will repair dysfunctional mitochondria and reduce target cell apoptosis. Since ectopic frataxin will be