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    Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease

    Hockly, E. and Richon, V.M. and Woodman, B. and Smith, D.L. and Zhou, X.B. and Rosa, E. and Sathasivam, K. and Ghazi-Noori, S. and Mahal, A. and Lowden, Philip and Steffan, J.S. and Marsh, J.L. and Thompson, L.M. and Lewis, C.M. and Marks, P.A. and Bates, G.P. (2003) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proceedings of the National Academy of Sciences of the United States of America 100 (4), pp. 2041-2046. ISSN 0027-8424.

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    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. Huntington's disease (HD) is an inherited progressive neurological disorder caused by a CAG/polyglutamine (polyQ) expansion and is associated with selective cell death and the deposition of polyQ aggregates in the brain (1). Recent studies suggest that transcriptional dysregulation might play a role in HD pathogenesis (2–4) by decreasing several functions including histone acetyltransferase and Sp1 and TAFII130 activity (5–13). Although the molecular basis of transcriptional dysfunction in HD requires further dissection, transcriptional repression is the predominant result of dysregulation. Histone deacetylases (HDACs) work in concert with histone acetyl transferases to modify chromatin and regulate transcription (14). HDAC inhibitors such as trichostatin A and suberoylanilide hydroxamic acid (SAHA) have been shown to act selectively on gene expression and are potent inducers of growth arrest, differentiation, and/or apoptotic cell death of transformed cells in vitro and in vivo (15–18). Recent studies in cell culture, yeast, and Drosophila models of polyQ disease have indicated that HDAC inhibitors might provide a useful class of agents to ameliorate the transcriptional changes in HD (9–11). For example, alleviation of transcriptional repression in Drosophila models either by genetic reduction of Sin3A corepressor activity or through administration of HDAC inhibitors was shown to rescue lethality and photoreceptor neurodegeneration (11). Therapeutic trials in humans are challenging, because of the late onset, variability, and slow progression of HD. Therefore, before testing novel therapeutics in clinical trials, compounds must be rigorously and extensively evaluated in genetic HD mouse models, a wide range of which are now available (19). The R6/2 line (20, 21) has been used the most extensively for preclinical trials (22–25). The early onset of impairment (5–6 weeks), rapid progression of the disease (severely impaired at 12–14 weeks), and reproducibility of the phenotype makes it particularly suitable for this type of study. Here we ask whether the beneficial effects of HDAC inhibitors in Drosophila models of polyQ disease can be reproduced in preclinical mouse trials. We show that SAHA can cross the blood–brain barrier and demonstrate bioactivity in brain tissue. SAHA has an effective concentration of ≈2.5 μM and is relatively insoluble in aqueous solution. We show that when complexed with 2-hydroxypropyl-β-cyclodextrin (HOP-β-CD), we are able to administer SAHA in drinking water and dramatically improve motor impairment in the R6/2 mouse model.

    Metadata

    Item Type: Article
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Depositing User: Sarah Hall
    Date Deposited: 07 May 2019 15:38
    Last Modified: 29 Jul 2019 17:04
    URI: http://eprints.bbk.ac.uk/id/eprint/27431

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