2. Academic Validation
  3. Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy

Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy

  • PLoS One. 2019 Mar 28;14(3):e0214250. doi: 10.1371/journal.pone.0214250.
Amanda H Kahn-Kirby 1,  Akiko Amagata 1,  Celine I Maeder 1,  Janet J Mei 1,  Steve Sideris 1,  Yuko Kosaka 1,  Andrew Hinman 1,  Stephanie A Malone 1,  Joel J Bruegger 1,  Leslie Wang 1,  Virna Kim 1,  William D Shrader 1,  Kevin G Hoff 1,  Joey C Latham 1,  Euan A Ashley 2,  Matthew T Wheeler 2,  Enrico Bertini 3,  Rosalba Carrozzo 3,  Diego Martinelli 3,  Carlo Dionisi-Vici 4,  Kimberly A Chapman 5,  Gregory M Enns 6,  William Gahl 7,  Lynne Wolfe 7,  Russell P Saneto 8,  Simon C Johnson 9 10,  Jeffrey K Trimmer 1,  Matthew B Klein 1,  Charles R Holst 1
Affiliations

Affiliations

  • 1 BioElectron Technology Corporation, Mountain View, California, United States of America.
  • 2 Stanford Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, California, United States of America.
  • 3 Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Research Hospital, Rome, Italy.
  • 4 Clinical Division and Research Unit of Metabolic Diseases, Bambino Gesù Children's Hospital, Rome, Italy.
  • 5 Children's National Rare Disease Institute, Children's National Health System, Washington, D.C., United States of America.
  • 6 Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
  • 7 NIH Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, Maryland, United States of America.
  • 8 Division of Pediatric Neurology, Department of Neurology, Neuroscience Institute, Seattle Children's Hospital, Seattle, Washington, United States of America.
  • 9 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.
  • 10 Department of Neurology, University of Washington, Seattle, Washington, United States of America.
PMID: 30921410 DOI: 10.1371/journal.pone.0214250
Abstract

Background: Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by Lipoxygenase enzymes. Activation of the Ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that Ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies.

Methods: Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured.

Results: EPI-743 potently prevented Ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE).

Conclusions: These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.

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