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

PLoS One. 2019 Jun 3;14(6):e0217776. doi: 10.1371/journal.pone.0217776. eCollection 2019.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dimethyl Fumarate / pharmacology
  • Dimethyl Fumarate / therapeutic use*
  • Disease Models, Animal
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Friedreich Ataxia / blood
  • Friedreich Ataxia / drug therapy*
  • Humans
  • Iron-Binding Proteins / blood
  • Iron-Binding Proteins / genetics
  • Iron-Binding Proteins / metabolism*
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Mice
  • Models, Biological
  • Mutation / genetics
  • Organelle Biogenesis
  • Transcription Initiation, Genetic

Substances

  • Iron-Binding Proteins
  • frataxin
  • Dimethyl Fumarate