Increasing frataxin gene expression with histone deacetylase inhibitors as a therapeutic approach for Friedreich's ataxia

Journal of Neurochemistry
Joel M GottesfeldMassimo Pandolfo


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...Continue Reading


Jan 11, 2000·Nucleic Acids Research·E Grabczyk, K Usdin
Feb 20, 2002·FEBS Letters·Carlos J MirandaMassimo Pandolfo
Sep 17, 2003·The Journal of Pharmacology and Experimental Therapeutics·Erding HuMichael Jaye
Oct 6, 2005·Nature Reviews. Genetics·Nicholas A Di Prospero, Kenneth H Fischbeck
Aug 22, 2006·Nature Chemical Biology·David HermanJoel M Gottesfeld
Sep 20, 2006·Nature Chemical Biology·Richard Festenstein
Mar 3, 2007·Seminars in Pediatric Neurology·Richard E Lutz
Apr 10, 2007·Annual Review of Neuroscience·Harry T Orr, Huda Y Zoghbi
Apr 25, 2007·International Journal of Cancer. Journal International Du Cancer·Thomas BeckersKarl Sanders
Jun 9, 2007·Bioorganic & Medicinal Chemistry Letters·Phieng SiliphaivanhThomas A Miller
Sep 11, 2007·Cellular and Molecular Life Sciences : CMLS·M D Hebert, A A Whittom
Jan 10, 2008·Bioorganic & Medicinal Chemistry Letters·Joey L MethotThomas A Miller
Jan 24, 2008·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Robert D Wells
Jul 4, 2008·American Journal of Human Genetics·Marco BaralleFranco Pagani
Jul 9, 2008·Trends in Genetics : TIG·Tracey A Rouault, Wing Hang Tong
Sep 19, 2008·Nature Chemical Biology·Philip A Cole
Oct 2, 2008·Nature Reviews. Drug Discovery·Aleksey G Kazantsev, Leslie M Thompson
Oct 28, 2008·The Journal of Biological Chemistry·C James ChouJoel M Gottesfeld
Feb 9, 2010·Nature Chemical Biology·James E BradnerRalph Mazitschek
Apr 8, 2010·EMBO Molecular Medicine·Tanel Punga, Marc Bühler
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Dec 4, 2010·The Journal of Biological Chemistry·Daman KumariKaren Usdin

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Ataxia is a neurological condition characterized by lack of voluntary coordination of muscle movements including loss of coordination, balance, and speech. Discover the latest research on different types of ataxias here.