HDAC9 Inhibition as a Novel Treatment for Stroke

Abstract

The identification of a variant in the HDAC9 gene as a risk factor for large-artery atherosclerotic stroke, and subsequently coronary artery disease, has opened novel treatment pathways for stroke and more widely atherosclerotic disease. This article describes the pathway from gene discovery to novel therapeutic approaches that are now entering man. HDAC9 expression is elevated in human atherosclerotic plaque, while in animal and cellular models, reducing HDAC9 (histone deacetylase 9) protein is associated with reduced disease. Several mechanisms have been proposed to account for the association between HDAC9 and atherosclerosis including alterations in the inflammatory response and cholesterol efflux and endothelial-mesenchymal transition. The association raises the possibility that inhibiting HDAC9 may provide a novel treatment approach for atherosclerotic cardiovascular disease. This is supported by intervention studies demonstrating HDAC9 inhibition reduces atherosclerosis in animal and cellular models. Indirect data support such an approach in man. The antiseizure drug sodium valproate, which has nonspecific HDAC inhibitory properties, both inhibits atherosclerosis in animal models and is epidemiologically associated with reduced stroke and myocardial infarction risk in man. It is now being trailed in phase 2 studies in large-artery stroke, while more specific HDAC9 inhibitors are being developed.