A tractable vertebrate model that recapitulates key aspects of Friedreich Ataxia

This proposal seeks to validate a new animal model of FA, a freshwater fish called zebrafish, that has been genetically modified to express low levels of frataxin. This model addresses some of the shortcomings of FA mouse models and can be used for drug testing. Dr. Wilson and his collaborators used gene editing technology to develop an FA zebrafish model by mutating zebrafish frataxin (zFXN). The zFXN-mutant zebrafish constitute a vertebrate, whole-organism model that recapitulates key aspects of FA in humans that mouse models do not. GAA-repeat-expansion mouse models have no significant cardiac phenotype, and the neurological phenotypes take many months to develop and are very mild. zFXN-mutant zebrafish show a decrease in survival, especially when stressed by starvation. Compared to control fish, adults are significantly smaller and have an increased heart size compared to their body size, blood-vessel abnormalities, and stress-response-pathway activation. zFXN-mutant phenotypes develop rapidly and are pronounced, which simplifies drug testing. Finally, zebrafish are much cheaper to work with than mice and allow rapid testing of multiple drugs, as well as screening of compound libraries. Importantly, this organism has human-length telomeres (the ends of chromosomes). Telomeres protect the ends of chromosomes, and there is evidence that telomere damage and shortening contribute to FA pathophysiology. This aspect of FA cannot be recapitulated in mouse models – mouse telomeres are 5-10x longer than human telomeres – but can be modeled in zebrafish. This proposal focuses on two important validations that would enhance the utility of the FA zebrafish model: Aim 1. To validate additional adult phenotypes, such as ataxia. Aim 2. To determine drug effects predictive of efficacy in humans by testing responses to drugs already evaluated in clinical trials for FA, in particular omaveloxolone, which is now FDA-approved. This model will provide a valuable tool for therapeutic development, especially for testing small molecules.