Abstract 15376: Nrf2 Agonist Omaveloxolone Improves Cardiac Function in Mice With Friedreich's Ataxia

Abstract

Introduction: Friedreich’s ataxia (FA) is an inherited, life-shortening, degenerative neuromuscular disorder affecting ~1 in every 50,000 people in the USA and Europe. Initial symptoms, typically seen in children and teenagers, include loss of balance and coordination, muscle weakness placing these patients in wheelchairs. Early death is common and most of FA patients die in their 30s or earlier from cardiac failure, caused by deficient frataxin (FXN) expression in the heart. Omaveloxolone (OMAV), a known Nrf-2 activator, has been recently proposed as the first treatment of the neurological symptoms of FA; however less is known about OMAV effects on cardiac function in FA. Aim: To test the hypothesis that OMAV improves cardiac function in a mouse model of FA via Nfr2 signaling pathway 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 OMAV-treated groups. Treatment with 24 mg/kg OMAV started at 3 weeks of age and continued for 5 weeks. Cardiac function was examined in-vivo by echocardiography. We found that FXN cKO 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. OMAV (n=14) significantly decreased LV mass (-24%), LV diameter (-28%), and partially recovered a decrease in ejection fraction (+40%), stroke volume (+22%) and cardiac output (+35%). Gene expression of NADP(H) quinoline oxidoreductase-1 (NQO1), superoxide dismutase 2 (SOD2), and glutathione S-transferase were decreased by 60-90% in FA and recovered by 60-90% by OMAV. Aconitase activity, used as a surrogate measure of frataxin's iron-sulfur biogenesis function, was decreased in FA by 49% and recovered 33% by OMAV. Conclusions: This is the first study to demonstrate sexual dimorphism in FA hearts and show that OMAV can improve cardiac function in FA mice with severe cardiomyopathy.