Translating HDAC inhibitors in Friedreich's ataxia

Expert Opinion on Orphan Drugs
Elisabetta Soragni, Joel M Gottesfeld

Abstract

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by expansion of a GAA·TTC triplet in the first intron of the FXN gene, encoding the essential mitochondrial protein frataxin. Repeat expansion results in transcriptional silencing through an epigenetic mechanism, resulting in significant decreases in frataxin protein in affected individuals. Since the FXN protein coding sequence is unchanged in FRDA, an attractive therapeutic approach for this disease would be to increase transcription of pathogenic alleles with small molecules that target the silencing mechanism. We review the evidence that histone postsynthetic modifications and heterochromatin formation are responsible for FXN gene silencing in FRDA, along with efforts to reverse silencing with drugs that target histone modifying enzymes. Chemical and pharmacological properties of histone deacetylase (HDAC) inhibitors, which reverse silencing, together with enzyme target profiles and kinetics of inhibition, are discussed. Two HDAC inhibitors have been studied in human clinical trials and the properties of these compounds are compared and contrasted. Efforts to improve on bioavailability, metabolic stability, and target activity are reviewed...Continue Reading

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Citations

Aug 26, 2017·Journal of Neurogenetics·Oliver EdenharterJuan A Navarro
Mar 4, 2018·Neurologia i neurochirurgia polska·Geneieve TaiMartin B Delatycki
Jan 10, 2019·Movement Disorders : Official Journal of the Movement Disorder Society·Giulia AlfediAlessandra Rufini
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Mar 5, 2019·Expert Opinion on Orphan Drugs·Anna M SchreiberMarek Napierala
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Dec 3, 2020·Biology·Claudio LuparelloMirella Vazzana
Aug 8, 2021·International Journal of Molecular Sciences·Beata TarnackaMaria Maślińska
Jun 23, 2018·ACS Chemical Neuroscience·Wen-Ning ZhaoStephen J Haggarty

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