Transcriptional dysregulation has emerged as a core pathologic feature of
Huntington's disease (HD), one of several triplet-repeat disorders characterized by movement deficits and
cognitive dysfunction. Although the mechanisms contributing to the gene expression deficits remain unknown, therapeutic strategies have aimed to improve transcriptional output via modulation of
chromatin structure. Recent studies have demonstrated
therapeutic effects of commercially available
histone deacetylase (
HDAC) inhibitors in several HD models; however, the therapeutic value of these compounds is limited by their toxic effects. Here, beneficial effects of a novel pimelic diphenylamide
HDAC inhibitor, HDACi 4b, in an HD mouse model are reported. Chronic
oral administration of HDACi 4b, beginning after the onset of motor deficits, significantly improved motor performance, overall appearance, and
body weight of symptomatic R6/2(300Q) transgenic mice. These effects were associated with significant attenuation of gross brain-size decline and striatal
atrophy. Microarray studies revealed that HDACi 4b treatment ameliorated, in part, alterations in gene expression caused by the presence of mutant
huntingtin protein in the striatum, cortex, and cerebellum of R6/2(300Q) transgenic mice. For selected genes, HDACi 4b treatment reversed
histone H3 hypoacetylation observed in the presence of mutant huntingtin, in association with correction of
mRNA expression levels. These findings suggest that HDACi 4b, and possibly related
HDAC inhibitors, may offer clinical benefit for HD patients and provide a novel set of potential
biomarkers for clinical assessment.