Abstract 13618: Novel Fumarate Prodrug Rescues Cardiomyopathy and Motor Function in Friedreich’s Ataxia

Background: Friedreich ataxia (FA) is a monogenic recessive ataxia caused by reduction of a single mitochondrial protein, frataxin (FXN), for which there is no approved therapy. Although the name of FA refers to the neurodegenerative ataxia, the lethal event is cardiomyopathy, caused by deficient FXN expression in the heart. Through a drug discovery screening program, we identified that bioactive fumarates are protective in FA cell models. We have subsequently developed a novel monomethyl fumarate precursor which has a higher retention time in the gut and also releases nicotinamide ( NAD + ). Hypothesis: To test the hypothesis that novel NAD + and fumarate precursor IMF provides more efficient protection against development of lethal cardiomyopathy in the inducible mouse model of FA (FXNKD) compared to a known fumarate precursor dimethyl fumarate (DMF, also known as Tecfidera). Methods: To suppress FXN expression, FXNKD mice were fed doxycycline chow and cardiac function was examined by in-vivo echocardiography. Aconitase activity, used as a surrogate measure of frataxin’s iron-sulfur biogenesis function, complex I and II activities, NAD + /NADH levels were measured by biochemical assays. Results: FXNKD and CTL mice were given vehicle, DMF or IMF daily for 8 weeks at concentrations that match the equimolar amount of monomethyl fumarate (MMF) released by the drugs. After 4 weeks of doxycycline treatment, FXNKD mice developed significant balance and locomotor deficits as assessed by the rotarod, 16 mm balance beam and open field tests. All neurobehavior parameters were improved after 8 weeks of treatment with IMF but not with DMF. Echocardiography revealed a significant increase in left ventricular wall thickness, and a decrease in LV internal diameter, stroke volume, and cardiac output, hallmarks of clinical cardiomyopathy in FA patients. IMF but not DMF prevented a decline in cardiac function in FXNKD mice. FXNKD mice treated with IMF showed increase in FXN expression levels, NAD + /NADH, aconitase and complex I and II activities. Conclusions: Because cardiomyopathy is the usual lethal event in FA, we suggest that nicotinamidated monomethyl fumarate is more potent drug compared to DMF and could improve the quality of life in FA affected individuals.