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

E Hockly; V M Richon; B Woodman; D L Smith; X B Zhou; E Rosa; K Sathasivam; S Ghazi-Noori; A Mahal; P A S Lowden; J S Steffan; J L Marsh; L M Thompson; C M Lewis; P A Marks; G P Bates

doi:10.1073/pnas.0437870100

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

E Hockly, V M Richon, B Woodman, D L Smith, X B Zhou, E Rosa, K Sathasivam, S Ghazi-Noori, A Mahal, P A S Lowden, J S Steffan, J L Marsh, L M Thompson, C M Lewis, P A Marks, G P Bates

Medical & Molecular Genetics

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774 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2041 - 2046
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	100
Issue number	4
DOIs	https://doi.org/10.1073/pnas.0437870100
Publication status	Published - 18 Feb 2003

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Hockly, E., Richon, V. M., Woodman, B., Smith, D. L., Zhou, X. B., Rosa, E., Sathasivam, K., Ghazi-Noori, S., Mahal, A., Lowden, P. A. S., Steffan, J. S., Marsh, J. L., Thompson, L. M., Lewis, C. M., Marks, P. A., & 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), 2041 - 2046. https://doi.org/10.1073/pnas.0437870100

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

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.",

author = "E Hockly and Richon, {V M} and B Woodman and Smith, {D L} and Zhou, {X B} and E Rosa and K Sathasivam and S Ghazi-Noori and A Mahal and Lowden, {P A S} and Steffan, {J S} and Marsh, {J L} and Thompson, {L M} and Lewis, {C M} and Marks, {P A} and Bates, {G P}",

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doi = "10.1073/pnas.0437870100",

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Hockly, E, Richon, VM, Woodman, B, Smith, DL, Zhou, XB, Rosa, E, Sathasivam, K , Ghazi-Noori, S , Mahal, A, Lowden, PAS, Steffan, JS, Marsh, JL, Thompson, LM, Lewis, CM, Marks, PA & Bates, GP 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, vol. 100, no. 4, pp. 2041 - 2046. https://doi.org/10.1073/pnas.0437870100

Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. / Hockly, E; Richon, V M; Woodman, B et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 4, 18.02.2003, p. 2041 - 2046.

Research output: Contribution to journal › Article › peer-review

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AU - Richon, V M

AU - Woodman, B

AU - Smith, D L

AU - Zhou, X B

AU - Rosa, E

AU - Sathasivam, K

AU - Ghazi-Noori, S

AU - Mahal, A

AU - Lowden, P A S

AU - Steffan, J S

AU - Marsh, J L

AU - Thompson, L M

AU - Lewis, C M

AU - Marks, P A

AU - Bates, G P

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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ER -

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

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