Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease
- Emma Hockly*,
- Victoria M. Richon†,
- Benjamin Woodman*,
- Donna L. Smith*,
- Xianbo Zhou†,
- Eddie Rosa†,
- Kirupa Sathasivam*,
- Shabnam Ghazi-Noori*,
- Amarbirpal Mahal*,
- Philip A. S. Lowden‡,
- Joan S. Steffan§,
- J. Lawrence Marsh¶,
- Leslie M. Thompson§,
- Cathryn M. Lewis*,
- Paul A. Marks‖, and
- Gillian P. Bates*,**
- *Medical and Molecular Genetics, Guy's, King's and St. Thomas' School of Medicine, King's College London, Eighth Floor Guy's Tower, Guy's Hospital, London SE1 9RT, United Kingdom; †Aton Pharma, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591-6717; ‡School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, United Kingdom; §Department of Psychiatry and Human Behavior, University of California, Gillespie 2121, Irvine, CA 92697-4260; ¶Department of Developmental and Cell Biology, University of California, 4244 McGaugh Hall, Irvine, CA 92697-2300; and ‖Cell Biology Program, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10021
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Contributed by Paul A. Marks
Abstract
Huntington's disease (HD) is an inherited, progressive neurological disorder that is caused by a CAG/polyglutamine repeat expansion and for which there is no effective therapy. Recent evidence indicates that transcriptional dysregulation may contribute to the molecular pathogenesis of this disease. Supporting this view, administration of histone deacetylase (HDAC) inhibitors has been shown to rescue lethality and photoreceptor neurodegeneration in a Drosophila model of polyglutamine disease. To further explore the therapeutic potential of HDAC inhibitors, we have conducted preclinical trials with suberoylanilide hydroxamic acid (SAHA), a potent HDAC inhibitor, in the R6/2 HD mouse model. We show that SAHA crosses the blood–brain barrier and increases histone acetylation in the brain. We found that SAHA could be administered orally in drinking water when complexed with cyclodextrins. SAHA dramatically improved the motor impairment in R6/2 mice, clearly validating the pursuit of this class of compounds as HD therapeutics.
Footnotes
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↵ ** To whom correspondence should be addressed. E-mail: gillian.bates{at}kcl.ac.uk.
- Abbreviations:
- HD,
- Huntington's disease;
- SAHA,
- suberoylanilide hydroxamic acid;
- HDAC,
- histone deacetylase;
- polyQ,
- polyglutamine;
- HOP-β-CD,
- 2-hydroxypropyl-β-cyclodextrin
- Copyright © 2003, The National Academy of Sciences
