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HDAC9 Inhibition as a Novel Treatment for Stroke
1Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, United Kingdom.
Insights
A genetic variant in HDAC9 (histone deacetylase 9) is linked to atherosclerotic stroke and heart disease. Inhibiting HDAC9 shows promise as a novel therapeutic strategy for cardiovascular diseases.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Molecular Biology
Background:
- A variant in the HDAC9 gene is identified as a risk factor for large-artery atherosclerotic stroke and coronary artery disease.
- HDAC9 expression is elevated in human atherosclerotic plaques, suggesting a role in disease pathogenesis.
- Reducing HDAC9 protein levels in preclinical models is associated with decreased atherosclerotic disease burden.
Purpose of the Study:
- To explore the pathway from HDAC9 gene discovery to novel therapeutic approaches for atherosclerotic diseases.
- To investigate the potential of HDAC9 inhibition as a treatment strategy for atherosclerotic cardiovascular disease.
Main Methods:
- Review of genetic association studies identifying HDAC9 variants.
- Analysis of preclinical studies (animal and cellular models) investigating HDAC9 function and inhibition.
- Examination of epidemiological data and clinical trial information related to HDAC9 inhibition.
Main Results:
- HDAC9 gene variant identified as a risk factor for atherosclerotic stroke and coronary artery disease.
- Preclinical studies demonstrate that reducing HDAC9 levels mitigates atherosclerosis.
- Sodium valproate, a non-specific HDAC inhibitor, shows preclinical efficacy and epidemiological association with reduced cardiovascular events.
Conclusions:
- HDAC9 inhibition represents a promising novel therapeutic target for atherosclerotic cardiovascular disease.
- Clinical trials are underway to evaluate HDAC9 inhibitors for treating large-artery stroke.
- Further development of specific HDAC9 inhibitors is ongoing for broader cardiovascular applications.
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.
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