Research Article: Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich’s Ataxia

Date Published: June 3, 2019

Publisher: Public Library of Science

Author(s): Mittal Jasoliya, Francesco Sacca, Sunil Sahdeo, Frederic Chedin, Chiara Pane, Vincenzo Brescia Morra, Alessandro Filla, Mark Pook, Gino Cortopassi, Diego F. Gomez-Casati.


Friedreich’s Ataxia (FA) is an inherited neurodegenerative disorder resulting from decreased expression of the mitochondrial protein frataxin, for which there is no approved therapy. High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. Here we demonstrate that DMF significantly increases frataxin gene (FXN) expression in FA cell model, FA mouse model and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell model. We further examined the mechanism of DMF’s frataxin induction in FA patient cells. It has been shown that transcription-inhibitory R-loops form at GAA expansion mutations, thus decreasing FXN expression. In FA patient cells, we demonstrate that DMF significantly increases transcription initiation. As a potential consequence, we observe significant reduction in both R-loop formation and transcriptional pausing thereby significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. Since inherited deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, DMF could be considered for Friedreich’s therapy.

Partial Text

Friedreich’s ataxia (FA) is caused by inheritance of GAA tri-nucleotide expansions and reduced expression the mitochondrial protein frataxin. FA is an ultimately lethal neurodegenerative disease for which there is currently no approved therapy [1]. All pathophysiological consequences, severity and age of onset of FA are directly related to the extent of frataxin deficiency, greater the frataxin deficiency, worse the outcome [2–5]. Common symptoms associated with this disease include loss of muscle coordination, cardiomyopathy, hearing defect and diabetes [6,7].




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