Translating HDAC inhibitors in Friedreich's ataxia

Expert Opinion on Orphan Drugs
Elisabetta Soragni, Joel M Gottesfeld


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


Jan 11, 2000·Nucleic Acids Research·E Grabczyk, K Usdin
Oct 6, 2005·Nature Reviews. Genetics·Nicholas A Di Prospero, Kenneth H Fischbeck
Dec 13, 2005·Journal of Medicinal Chemistry·Andrew D NapperRory Curtis
Jul 22, 2006·Proceedings of the National Academy of Sciences of the United States of America·Ryan BurnettJoel M Gottesfeld
Aug 10, 2006·Chemical Reviews·Michael J Evans, Benjamin F Cravatt
Aug 22, 2006·Nature Chemical Biology·David HermanJoel M Gottesfeld
Sep 20, 2006·Nature Chemical Biology·Richard Festenstein
Jan 18, 2007·Proceedings of the National Academy of Sciences of the United States of America·Cleo M Salisbury, Benjamin F Cravatt
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
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
Aug 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Daniel A HarkiPeter B Dervan
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
Oct 31, 2009·PLoS Genetics·Scott DitchEd Grabczyk
Feb 9, 2010·Nature Chemical Biology·James E BradnerRalph Mazitschek
Apr 8, 2010·EMBO Molecular Medicine·Tanel Punga, Marc Bühler
Dec 4, 2010·The Journal of Biological Chemistry·Daman KumariKaren Usdin
Jan 25, 2011·Nature Biotechnology·Marcus BantscheffGerard Drewes
Jun 10, 2011·Journal of the Neurological Sciences·Amy Y TsouDavid R Lynch
Dec 14, 2011·Annals of Neurology·Giovanni CoppolaDaniel H Geschwind
Mar 1, 2012·PLoS Biology·Kim DebackerRobert S Lahue
Mar 27, 2012·Human Molecular Genetics·Barbara TomassiniRoberto Testi

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