title: Translating HDAC inhibitors in Friedreich's ataxia.
abstract: Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by expansion of a GAA·TTC triplet in the first intron of theFXNgene, 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 theFXNprotein 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 forFXNgene 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.
  
  
  
  2-aminobenzamide class I HDAC inhibitors are attractive therapeutic small molecules for FRDA. These molecules increaseFXNgene expression in human neuronal cells derived from patient induced pluripotent stem cells, and in two mouse models for the disease, as well as in circulating lymphocytes in patients treated in a phase Ib clinical trial. Medicinal chemistry efforts have identified compounds with improved brain penetration, metabolic stability and efficacy in the human neuronal cell model. A clinical candidate will soon be identified for further human testing.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037 USA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Soragni
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037 USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gottesfeld
keywords: Friedreich ataxia; epigenetics; heterochromatin; histone deacetylase inhibitor; neurodegenerative disease