Abstract 15690: Bioactive Fumarate Improves Cardiac Function and Expands Lifespan in Friedreich's Ataxia

Introduction: Friedreich ataxia (FA) is a monogenic recessive ataxia caused by reduction of a single mitochondrial protein, frataxin (FXN). Although the name of FA refers to the neurodegenerative ataxia, the lethal event is cardiomyopathy, caused by deficient FXN expression in the heart. Previously, we identified that bioactive fumarates are protective in FA cell models. We have developed a novel monomethyl fumarate prodrug, IMF, which has much improved pharmacokinetic profile and compared its effect to the known fumarate prodrug dimethyl fumarate (DMF, Tecfidera). Aim: To test the hypothesis that novel bioactive fumarate improves cardiac function and survival via Nrf2 and HCA 2 signaling pathways activation. Methods and Results: Cardiospecific FXN knockout (FXN Mck-Cre KO) mice were used as a model of severe cardiomyopathy which is characteristic for the late stage of FA. Animals of either sex were randomly split in vehicle and fumarate-treated groups. Animals were treated by IMF or DMF at concentrations which release equimolar amount of monomethyl fumarate. Treatment started at 3 weeks of age and continued for 5 weeks in the cross-sectional study or until animal death in the survival study. Cardiac function was examined in-vivo by echocardiography. We found that FXN Mck-Cre KO mice developed severe heart failure with 45% reduction in ejection fraction, increased left ventricular (LV) mass (+80%) and diameter (+308%), decreased stroke volume (-26%) and cardiac output (-38%, n=10) as compared to WT mice (n=12). Cardiac deficits were more pronounced in FA males compared to females. Both DMF and IMF partially recovered cardiac deficits in FXN Mck-Cre KO mice but only IMF extended the lifespan in these mice by 13%. Expression of genes in Nrf2 (NQO1, SOD2, glutathione S-transferase) and HCA 2 (HCA 2 and Sirt1) signaling pathways were decreased in FXN Mck-Cre KO and restored to a different degree by DMF and IMF. Aconitase activity, used as a surrogate measure of frataxin's iron-sulfur biogenesis function, was decreased in FA by 49% and recovered 18% by IMF only. Conclusions: Novel fumarate prodrug IMF improved cardiac function and expanded the lifespan in FXN Mck-Cre KO mouse model of FA more effectively than DMF.