Histone deacetylase (HDAC) is a class of enzymes that plays a critical role in gene activation and silencing by regulating chromatin structure. Chromatin is formed by the packaging of DNA around histone protein complexes. When the chromatin is tightly coiled, gene transcription is generally turned off, and when uncoiled, gene transcription is generally turned on. These states are highly dynamic and are regulated by modifications of histones including the acetylation of lysine residues at their N-terminal tails in response to the opposing actions of histone acetylases (HATs) and HDACs. Moreover, a number of important transcription factors that regulate gene activation are also regulated by acetylation. HDAC inhibitors, by decreasing the rate of deacteylation and thereby increasing acetylation of histones and transcription factors, cause a change in gene transcription and thereby cellular responses. In cancer cells, HDAC inhibitors increase the expression of tumor suppressors and lead to cessation of cell proliferation and/or cell apoptosis. In neurons in a pathological state, HDAC inhibitors are thought to provide therapeutic benefit by restoring gene transcriptional balance that had gone awry due to pathogenic proteins such as mutant huntington in Huntington’s disease, and also by increasing the expression of neuroprotective genes.
HDAC inhibitors were one of the first potential targets for neurodegeneration that was discovered by EnVivo’s platform technology. EnVivo, in partnership with MethylGene, is developing isozyme-selective small molecular inhibitors of HDACs that are safe and efficacious therapeutics for neurodegenerative diseases such as Huntington’s, Parkinson’s and Alzheimer’s diseases.