# Fumarate drugs rescue cardiac dysfunction in mouse models of Friedreich's ataxia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $75,021

## Abstract

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
gen...

## Key facts

- **NIH application ID:** 10975149
- **Project number:** 3R01HL155907-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Elena N. Dedkova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $75,021
- **Award type:** 3
- **Project period:** 2020-12-20 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10975149

## Citation

> US National Institutes of Health, RePORTER application 10975149, Fumarate drugs rescue cardiac dysfunction in mouse models of Friedreich's ataxia (3R01HL155907-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10975149. Licensed CC0.

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