A METHOD FOR TREATING HCMV IN VASCULAR DISEASE

Cardiovascular disease remains the most common cause of death in the United States. While atherosclerosis accounts for the majority of these deaths, other vasculopathies such as restenosis after coronary angioplasty, and transplant vascular sclerosis (TVS), the hallmark lesion of chronic solid organ graft rejection, cause significant morbidity and mortality. Clinical studies have directly associated human cytomegalovirus (HCMV) with the acceleration of TVS and vascular restenosis foliowing angioplasty and there is anecdotal evidence for an association with atherosclerosis. Recent work by Virogenomics' founding scientists has shown that HCMV infection of arterial, but not venous, smooth muscle cells (SMC) results in significant cellular migration in vitro. Migration was found to be dependent on expression of one of the four HCMV encoded chemokine receptors, US28, and the presence of the chemokines RANTES or MCP-1. Virogenomics is testing the hypothesis that blocking the expression or function of US28 can relieve the negative effects of HCMV on vascular disease. In this Phase I application we propose to test the effect of antisense molecules on the expression of US28 and its mouse cognate, m33, and furthermore, to test whether antisense treatment can block SMC migration in vitro. The Phase II goals will extend this antisense strategy into animal models and eventually to initiate a drug discovery program to identify small molecules blocking US28 function, with the ultimate goal of developing human therapeutics for the viral component of vascular disease.