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Pharmacotherapy for Friedreich Ataxia

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Abstract

Friedreich ataxia (FA) is a progressive genetic neurological disorder associated with degeneration of the dorsal columns, spinocerebellar tracts and other regions of the nervous system. The disorder results from mutations in the gene referred to as FXN. Almost all mutations are expansions of an intronic GAA repeat in this gene, which gives rise to decreased transcription of the gene product (called frataxin). Following these discoveries, drug discovery has moved at a rapid pace. Therapeutic trials in the next 5 years are expected to address amelioration of the effects of frataxin deficiency and methods for increasing frataxin expression. These therapies are directed at all levels of biochemical dysfunction in FA. Agents such as idebenone potentially improve mitochondrial function and decrease production of reactive oxygen species. Idebenone is presently in a phase III trial in the US and in Europe, with the primary outcome measure being neurological function. Deferiprone, an atypical iron chelator, may decrease build-up of toxic iron in the mitochondria in patients. It has entered a phase II trial in Europe, Australia and Canada directed toward improvement of neurological abilities. Finally, targeted histone deacetylase (HDAC) inhibitors and erythropoietin increase levels of frataxin when used in vitro, suggesting that they may provide methods for increasing frataxin levels in patients. Erythropoietin has been tested in a small phase II trial in Austria, while HDAC inhibitors are still at a preclinical stage. Symptomatic therapies are also in use for specific symptoms such as spasticity (baclofen). Thus, there is substantial optimism for development of new therapies for FA in the near future, and we suggest that one or several may be available over the next few years. However, continued development of new therapies will require creation of new, more sensitive measures for neurological dysfunction in FA, and clinically relevant measures of cardiac dysfunction.

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Acknowledgements

Dr Lynch and Dr Wilson are both supported by grants from the Friedreich Ataxia Research Alliance and the Muscular Dystrophy Association. Drs Lynch and Wilson have also received consulting compensation from Apopharma. Dr Wilson is also on the Data and Safety Monitoring Board for the phase II clinical trials of deferiprone in the US and Europe. Dr Lynch is a site principal investigator in the phase III idebenone trial and was offered a role as principal investigator in the phase II trial of deferiprone in the US. Dr Tsou and Dr Friedman have no conflicts of interest that are directly relevant to the content of this review.

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Tsou, A.Y., Friedman, L.S., Wilson, R.B. et al. Pharmacotherapy for Friedreich Ataxia. CNS Drugs 23, 213–223 (2009). https://doi.org/10.2165/00023210-200923030-00003

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