Researchers developed a novel monomethyl fumarate prodrug with an improved pharmacokinetic profile that enhanced cardiac function and expanded the lifespan of a Friedreich ataxia (FA) mouse model, according to an abstract presented at the 67th Biophysical Society Annual Meeting in San Diego, California.

The novel bioactive fumarate, IMF, but not dimethyl fumarate (Tecfidera®), extended the lifespan of cardiac-specific frataxin (FXN) knockout mice by 13% and recovered aconitase activity (used to assess FXN’s iron-sulfur biogenesis function) by 18%, suggesting that IMF performs better than dimethyl fumarate in treating severe cardiomyopathy in FA.

Both IMF and dimethyl fumarate partially recovered the cardiac deficits and restored the expression of genes associated with the nuclear factor erythroid 2–related factor 2 (NRF2) and the hydroxycarboxylic acid receptor 2 (HCA2) signaling pathways in cardiac-specific FXN knockout mice.

The analysis of cardiac function by echocardiography revealed severe heart failure in FXN knockout mice with decreased ejection fraction, stroke volume, and cardiac output, and increased left ventricular mass and diameter as compared to wild-type mice.

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Moreover, FXN knockout mice showed decreased expression of genes in NRF2 and HCA2 signaling pathways, including NAD(P)H quinone dehydrogenase 1, superoxide dismutase 2, glutathione S-transferase, HCA2, and sirtuin 1.

The researchers used cardiac-specific FXN knockout mice as a model of severe cardiomyopathy, a characteristic of late-stage FA. Mice were randomly split in vehicle and fumarate-treated groups and initiated treatment at 3 weeks of age. IMF and dimethyl fumarate were used at equimolar doses of monomethyl fumarate.

Cardiac dysfunction is a significant cause of mortality in FA. Approximately two-thirds of patients with FA die from congestive heart failure or arrhythmias.


Salinas L, Figueroa F, Montgomery CB, Thai PN. Bioactive fumarate improves cardiac function and expands lifespan in Friedrech’s ataxia. Abstract presented at: 67th Biophysical Society Annual Meeting: February 18-22, 2023; San Diego, CA.