Friedreich's Ataxia (FA) is the most common inherited recessive ataxia, for which there is no FDA-approved therapy. FA's pathophysiological mechanism is caused by the reduction of just one mitochondrial protein, frataxin (FXN), that functions in iron-sulfur (Fe-S) cluster biogenesis. Symptoms typically begin between the ages of 5 and 15 years and worsen over time. Although sensory and balance deficits put FA patients in wheelchairs, nearly all FA patients die of cardiomyopathy. Currently, there are no drug therapies that ameliorate FA cardiomyopathy and most with FA die of the cardiomyopathy in their 30s. We identified redox deficiency in FA human fibroblasts, and used this to screen a library of 1600 drugs already safely used in humans, to test for their ability to prevent cell death in FA. We identified dimethyl fumarate (DMF), a prodrug precursor of monomethyl fumarate (MMF), as the most protective among all tested drugs. DMF (also known as Tecfidera and Skilarence) is the FDA approved drug for treatment of multiple sclerosis (MS) and psoriasis. In the most physiological mouse model of FA (the FXNKD), we found that 1) DMF dose-dependently rescued FXN levels and the mitochondrial Fe-S cluster enzymes aconitase and succinate dehydrogenase activity in the heart; 2) DMF significantly rescued three critical cardiac deficits in mice that resemble human FA cardiac defects: a) left ventricular hypertrophy; b) decreased stroke volume; and c) decreased cardiac output. Preliminary data support the claim that DMF is providing mitochondrial->frataxin-> Fe-S cluster support via Nrf2-dependent mechanism. Additionally, we recently synthesized an alternative MMF prodrug called IMF, with improved pharmacokinetics that may be even more potent than DMF. Therefore, we hypothesize that fumarates DMF/IMF represent a novel therapeutic strategy that can potentially be repurposed for the lethal cardiomyopathy in FA.
The aim of the current work is to determine the effects of DMF/IMF on the function of most affected tissues in FA (heart and skeletal muscles), and to determine the mechanism of protective action. DMF has already passed through FDA's safety, toxicology and DMPK hurdles, and thus could enter clinical trials much more quickly than a new compound that must pass through extensive safety and toxicology testing before it could be used in clinical trials. However, before attempting to use the drug in humans with FA, completion of the 'pre-clinical package' for DMF/IMF and their role for cardiac/skeletal muscle protection in FA are important, and can be addressed in the three Specific Aims.
Aim 1 is designed to determine optimal dosing of DMF & IMF that rescue cardiac and skeletal muscles deficits.
Aim 2 is designed to determine the mechanism responsible for functional recovery in the FXNKD mouse.
Aim 3 is designed to determine whether optimal dosing of DMF/IMF extends the life span of mouse with cardiac-specific FXN KO (MCK-Cre). Cumulatively these aims will generate pre-clinical data for the potential use of DMF and IMF for lethal cardiomyopathy in FA. Because DMF is already approved for use in humans with safety/DMPK/toxicology and Phase I studies already completed, it has a greater opportunity to be 'fast-tracked' for treatment of cardiac myopathy in FA.

Public Health Relevance

The present proposal will test the efficacy of two fumarate-based drugs, dimethyl fumarate (DMF) and its derivative IMF, to prevent or delay the development of lethal cardiomyopathy in Friedreich's ataxia (FA). Currently, there are no drug therapies that ameliorate FA cardiomyopathy and most with FA die of the cardiomyopathy in their 30s. We will identify the optimal dosing and determine underlying cardioprotective mechanisms of these drugs in validated mouse models of FA which can generate important pre-clinical data because it would address the primary cause of mortality in Friedreich's patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Veterinary Sciences
Schools of Veterinary Medicine
United States
Zip Code