title: Increasing frataxin gene expression with histone deacetylase inhibitors as a therapeutic approach for Friedreich's ataxia.
abstract: The genetic defect in Friedreich's ataxia (FRDA) is the expansion of a GAA·TCC triplet in the first intron of the FXN gene, which encodes the mitochondrial protein frataxin. Previous studies have established that the repeats reduce transcription of this essential gene, with a concomitant decrease in frataxin protein in affected individuals. As the repeats do not alter the FXN protein coding sequence, one therapeutic approach would be to increase transcription of pathogenic FXN genes. Histone posttranslational modifications near the expanded repeats are consistent with heterochromatin formation and FXN gene silencing. In an effort to find small molecules that would reactivate this silent gene, histone deacetylase inhibitors were screened for their ability to up-regulate FXN gene expression in patient cells and members of the pimelic 2-aminobenzamide family of class I histone deacetylase inhibitors were identified as potent inducers of FXN gene expression and frataxin protein. Importantly, these molecules up-regulate FXN expression in human neuronal cells derived from patient-induced pluripotent stem cells and in two mouse models for the disease. Preclinical studies of safety and toxicity have been completed for one such compound and a phase I clinical trial in FRDA patients has been initiated. Furthermore, medicinal chemistry efforts have identified improved compounds with superior pharmacological properties.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gottesfeld
authors.forename: James R
authors.initials: JR
authors.lastname: Rusche
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D015870:Gene Expression / Q000502:physiology*; D020868:Gene Silencing; D006570:Heterochromatin / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D033862:Iron-Binding Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D013329:Structure-Activity Relationship; D000096923:Frataxin
chemical_list: D006570:Heterochromatin; D056572:Histone Deacetylase Inhibitors; D033862:Iron-Binding Proteins; D000096923:Frataxin
keywords: Friedreich's ataxia; heterochromatin; histone deacetylase inhibitor; neurodegenerative disorder