Cardiac benefit of drugs that stimulate Nrf2 and HCA2 pathways in Friedreich's ataxia

The most common cause of death in Friedriech’s ataxia (FA) is cardiomyopathy. Thus, a therapeutic drug that increases frataxin, iron-sulfur, and mitochondrial functions has the potential to ameliorate the most lethal consequence of FA. Ixchel Pharma, a UC Davis spinout company, has developed a novel chemical entity, IMF, that increases frataxin, iron-sulfur, and mitochondrial functions in the FXNKD mouse model of FA, which closely resembles the human FA condition. IMF dosing in these FXNKD mice rescues their cardiac pathology. Furthermore, IMF dosing increases survival in the frataxin MCK-Cre mouse, which only lacks frataxin in the heart and dies because of this loss. Thus, IMF is potentially a novel therapeutic with greater efficacy than the related DMF, operating through other mechanisms. This group proposes that IMF works by increasing frataxin expression and mitochondrial gene expression, which appears to be upstream from the target of RTA408, Omaveloxolone, which does not increase frataxin and works to benefit oxidative status downstream of frataxin deficiency. Thus, this group proposes to compare the efficacy of IMF and RTA408 in mice, and if IMF has higher efficacy, then to carry out pharmacokinetics, metabolism, and toxicity studies of IMF. If successful, this would take IMF to the next level of preclinical development.