Mitochondrial genetic disease is severe and can be lethal, and there is no FDA-approved drug for mitochondrial disease. Increasing mitochondrial biogenesis has been a long-term strategy for amelioration of mitochondrial genetic disease. We recently demonstrated that dimethyl fumarate (DMF), increases mitochondrial biogenesis in cells dosed in vitro, and mice and humans dosed in vivo. Thus, DMF is the first drug approved for use in humans by FDA and EMA that is demonstrated to induce mitochondrial biogenesis in mice and humans dosed in vivo, and by this fact is a leader in the search for effective therapy in mitochondrial disease. However, at the current time optimal conditions have not been identified for the mitochondrial biogenesis effect, and the drug has not been tested for efficacy in animal models of mitochondrial disease, which FDA will likely require for approval of IND for mitochondrial disease indication. Thus, our aims for the IGNITE proposal, PAR-15-071: Pharmacodynamics and In vivo Efficacy Studies are to have a 2-year R21 phase, that includes the following go/no go endpoints: Year 1, to identify the optimal dosing for DMF's maximal mitobiogenic effect in C57Bl6 mice, in the range of 10-100mg/kg dosing. The dose at which a significant and >30% increase in mitochondrial biogenesis in brain tissue, and a >50% increase in mitochondrial gene expression will be considered a 'go', and anything less will be considered a 'no go'. In Year 2 of R21, pharmacokinetics and functional consequences at maximal mitochondrially-responsive dose and target engagement demonstration will be carried out. In Year 3, R33 Phase, at the optimal dose for mitochondrial effect and with known PK, the effect of DMF to rescue the mitochondrial biogenesis defect, frataxin deficiency, and neurobehavioral deficits in the Friedreich's ataxia mouse model FXNKD will be tested, and additionally the mouse model of mitochondrial myopathy, Cox10. If DMF is successful in rescuing defects in two relevant mouse models of mitochondrial disease, these data could support an investigator-initiated IND for DMF in Friedreich's ataxia or other mitochondrial myopathy, shortening the time from bench to bedside.

Public Health Relevance

There is no FDA-approved therapy for rare, inherited and often lethal mitochondrial disease. We identified a drug that triggers mitochondrial biogenesis; i.e., the increased number and function of mitochondria per cell, dosed in mice and people, and wish to identify its optimal dosing, mechanism and efficacy in validated mouse models of serious mitochondrial disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Roof, Rebecca
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University of California Davis
Veterinary Sciences
Schools of Veterinary Medicine
United States
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