Please use this identifier to cite or link to this item: http://buratest.brunel.ac.uk/handle/2438/9868
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dc.contributor.authorSahdeo, S-
dc.contributor.authorScott, BD-
dc.contributor.authorMcMackin, MZ-
dc.contributor.authorJasoliya, M-
dc.contributor.authorBrown, B-
dc.contributor.authorWulff, H-
dc.contributor.authorPerlman, SL-
dc.contributor.authorPook, MA-
dc.contributor.authorCortopassi, GA-
dc.date.accessioned2015-01-21T11:25:10Z-
dc.date.available2014-08-11-
dc.date.available2015-01-21T11:25:10Z-
dc.date.issued2014-
dc.identifier.citationHum Mol Genet, 2014en_US
dc.identifier.issn1460-2083-
dc.identifier.urihttp://hmg.oxfordjournals.org/content/23/25/6848-
dc.identifier.urihttp://bura.brunel.ac.uk/handle/2438/9868-
dc.description.abstractInherited 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.en_US
dc.languageENG-
dc.language.isoenen_US
dc.subjectInherited deficiencyen_US
dc.subjectMitochondrial protein frataxin (FXN)en_US
dc.subjectFriedreich's ataxia (FA)en_US
dc.titleDyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia.en_US
dc.typeArticleen_US
dc.identifier.doihttp://dx.doi.org/10.1093/hmg/ddu408-
dc.relation.isPartOfHum Mol Genet-
dc.relation.isPartOfHum Mol Genet-
pubs.organisational-data/Brunel-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Health and Life Sciences-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Health and Life Sciences/Dept of Life Sciences-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Health and Life Sciences/Dept of Life Sciences/Biological Sciences-
pubs.organisational-data/Brunel/Brunel Staff by Institute/Theme-
pubs.organisational-data/Brunel/Brunel Staff by Institute/Theme/Institute of Environmental, Health and Societies-
pubs.organisational-data/Brunel/Brunel Staff by Institute/Theme/Institute of Environmental, Health and Societies/Synthetic Biology-
pubs.organisational-data/Brunel/University Research Centres and Groups-
pubs.organisational-data/Brunel/University Research Centres and Groups/School of Health Sciences and Social Care - URCs and Groups-
pubs.organisational-data/Brunel/University Research Centres and Groups/School of Health Sciences and Social Care - URCs and Groups/Brunel Institute for Ageing Studies-
pubs.organisational-data/Brunel/University Research Centres and Groups/School of Health Sciences and Social Care - URCs and Groups/Centre for Systems and Synthetic Biology-
Appears in Collections:Biological Sciences
Dept of Life Sciences Research Papers

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