Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia

Sunil Sahdeo, Brian D. Scott, Marissa Z. McMackin, Mittal Jasoliya, Brandon Brown, Heike Wulff, Susan L. Perlman, Mark A. Pook, Gino A Cortopassi

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6848-6862
Number of pages15
JournalHuman Molecular Genetics
Volume23
Issue number25
DOIs
StatePublished - Dec 20 2014

Fingerprint

Friedreich Ataxia
Cheek
Animal Models
Aconitate Hydratase
Succinate Dehydrogenase
Mitochondrial Proteins
Response Elements
Enzymes
Therapeutics
Rare Diseases
Local Anesthetics
frataxin
dyclonine
Sulfur
Histones
Libraries
Chromatin
Oxidation-Reduction
Transcription Factors
Iron

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia. / Sahdeo, Sunil; Scott, Brian D.; McMackin, Marissa Z.; Jasoliya, Mittal; Brown, Brandon; Wulff, Heike; Perlman, Susan L.; Pook, Mark A.; Cortopassi, Gino A.

In: Human Molecular Genetics, Vol. 23, No. 25, 20.12.2014, p. 6848-6862.

Research output: Contribution to journalArticle

Sahdeo, Sunil ; Scott, Brian D. ; McMackin, Marissa Z. ; Jasoliya, Mittal ; Brown, Brandon ; Wulff, Heike ; Perlman, Susan L. ; Pook, Mark A. ; Cortopassi, Gino A. / Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 25. pp. 6848-6862.
@article{25a80308e6214cd7b877fa345dc5353f,
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.",
author = "Sunil Sahdeo and Scott, {Brian D.} and McMackin, {Marissa Z.} and Mittal Jasoliya and Brandon Brown and Heike Wulff and Perlman, {Susan L.} and Pook, {Mark A.} and Cortopassi, {Gino A}",
year = "2014",
month = "12",
day = "20",
doi = "10.1093/hmg/ddu408",
language = "English (US)",
volume = "23",
pages = "6848--6862",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "25",

}

TY - JOUR

T1 - Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia

AU - Sahdeo, Sunil

AU - Scott, Brian D.

AU - McMackin, Marissa Z.

AU - Jasoliya, Mittal

AU - Brown, Brandon

AU - Wulff, Heike

AU - Perlman, Susan L.

AU - Pook, Mark A.

AU - Cortopassi, Gino A

PY - 2014/12/20

Y1 - 2014/12/20

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85005893624&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85005893624&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddu408

DO - 10.1093/hmg/ddu408

M3 - Article

C2 - 25113747

AN - SCOPUS:85005893624

VL - 23

SP - 6848

EP - 6862

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 25

ER -