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, which m 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 expressed locally in neural cells, the blood brain barrier (BBB) will not limit frataxin access to affected neurons, a potential problem with protein-based approaches. AAV-delivered FXN solves the BBB problem of systemic protein therapy and represents a novel and potentially practical approach to the treatment of FA. In Phase I, we will construct the vectors and test their constitutive and inducible expression in vitro and in the hearts and PNS of recipient mice. Meaningful augmentation of mitochondrial bioenergetic profiles is expected. Phase II will focus on expanded proof-of-concept studies in animal models. Given the remarkable recent progress in using AAV therapeutically-there are over 50 clinical trials using AAV as delivery vehicles, including safe delivery of transgenes to the heart-we are optimistic that our regulated AAV expression system for delivery of FXN to the brains and hearts of patients will provide a novel restorative therapy for this devastating neurodegenerative and cardiomyopathic disease. Because expression from AAV vectors is expected to be stable over long periods of time, our approach represents a potential critical step on the road to a cure for FA.

Public Health Relevance

Friedrich's ataxia (FA) is a fatal inherited disorder that results when a patient has two defective copies of the frataxin (FXN) gene. We will use a novel, tunable genetic approach to restore normal levels of frataxin in the cardiac and nervous tissues of FA patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Fertig, Stephanie
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Panorama Research, Inc.
United States
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