Chronic (or congestive) heart failure is a clinical syndrome that affects approximately 700,000 individuals yearly in the United States with an annual estimated health care cost of $ 10-40 billion. Heart failure is a progressive disease that ultimately leads to premature death. The expanding number of those afflicted with chronic heart failure and its persistently poor prognosis make it clear that additional novel treatment approaches are necessary. Frequently, heart failure is preceded by cardiac hypertrophy. Underlying the hypertrophic growth of the myocardium and the ensuing progression to heart failure is a characteristic change in gene expression that has been observed in animal models as well as in human patients. Our knowledge of the epigenetic control of such regulatory events suggests that modulating the activity of histone deacetylases, an integral component of chromatin, may become a novel therapeutic approach for the treatment of heart failure. In the present Phase I application, Myogen will seek to determine if known histone deacetylase inhibitors are effective modulators of hypertrophy in vitro and in vivo (proof of concept). In a future Phase II application, Myogen will develop a high throughput screening assay based on specific histone deacetylase isoforms to identify and develop novel lead compounds. In vitro and in vivo secondary assays will be used to validate anti-hypertrophic activity and tissue selectivity of lead compounds. Phase III will focus on medicinal chemistry to optimize lead compounds and on commercial development.
