title: Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia.
abstract: Inherited deficiency in the mitochondrial protein frataxin (FXN) causes the rare disease Friedreich's ataxia (FA), for which there is no successful treatment. We identified a redox deficiency in FA cells and used this to model the disease. We screened a 1600-compound library to identify existing drugs, which could be of therapeutic benefit. We identified the topical anesthetic dyclonine as protective. Dyclonine increased FXN transcript and FXN protein dose-dependently in FA cells and brains of animal models. Dyclonine also rescued FXN-dependent enzyme deficiencies in the iron-sulfur enzymes, aconitase and succinate dehydrogenase. Dyclonine induces the Nrf2 [nuclear factor (erythroid-derived 2)-like 2] transcription factor, which we show binds an upstream response element in the FXN locus. Additionally, dyclonine also inhibited the activity of histone methyltransferase G9a, known to methylate histone H3K9 to silence FA chromatin. Chronic dosing in a FA mouse model prevented a performance decline in balance beam studies. A human clinical proof-of-concept study was completed in eight FA patients dosed twice daily using a 1% dyclonine rinse for 1 week. Six of the eight patients showed an increase in buccal cell FXN levels, and fold induction was significantly correlated with disease severity. Dyclonine represents a novel therapeutic strategy that can potentially be repurposed for the treatment of FA.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sahdeo
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Scott
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine.
authors.forename: Marissa Z
authors.initials: MZ
authors.lastname: McMackin
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine.
authors.forename: Mittal
authors.initials: M
authors.lastname: Jasoliya
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Brown
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: Department of Neurology, University of California School of Medicine, Los Angeles, CA 90095, USA and.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Perlman
authors.affiliation: School of Health Sciences and Social Care, Brunel University, Uxbridge UB8 3PH, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Pook
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine gcortopassi@ucdavis.edu.
authors.forename: Gino A
authors.initials: GA
authors.lastname: Cortopassi
mesh_terms: D000154:Aconitate Hydratase / Q000235:genetics / Q000378:metabolism; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D057166:High-Throughput Screening Assays; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D033862:Iron-Binding Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009061:Mouth Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D011427:Propiophenones / Q000494:pharmacology*; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000096923:Frataxin
chemical_list: D000154:Aconitate Hydratase; D000779:Anesthetics, Local; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D033862:Iron-Binding Proteins; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D011427:Propiophenones; D054852:Small Molecule Libraries; D013385:Succinate Dehydrogenase; D000096923:Frataxin; C495635:NFE2L2 protein, human; C100063:dyclonine; C533711:G9a protein, mouse
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