Transplant Vascular Sclerosis (TVS) is an accelerated form of arteriosclerosis that is responsible for significant number of cases of chronic rejection in solid organ transplantation procedures. The incidence of TVS is approximately 15% of patients per year, leading to a prevalence of up to 60% of patients surviving at least 5 years. Among the risk factors identified for chronic rejection through TVS is infection by human cytomegalovirus (H)(CMV), an endemic herpesvirus carried by more than 60% of the U.S. population. (H)CMV infection does not cause noticeable acute disease in healthy individuals, but is implicated in several forms of chronic vascular disease. Recent work by Virogenomics' founding scientists has shown the CMV infection of arterial, but not venous, smooth muscle cells (SMC) results in significant cellular migration in vitro. Migration is dependent of expression of a specific one of the four chemokine receptors encoded by either rodent or human CMV. Virogenomics is testing the hypothesis that blocking the expression or function of US28, the human (HCMV) form of the gene can reduce or eliminate TVS in HCMV infected transplant patients. In this Phase I application we propose to test the effect of antisense molecules on the expression of r33, the rat CMV version of the receptor, 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 for TVS and eventually to initiate a drug discovery program to identify small molecule blocking human US28 function, with the ultimate goal of developing human therapeutics for the viral component of TVS.
Successful completion of this Phase I project will lead directly into Phase II animal model studies to determine whether antisense interention at the cell surface receptor level can reduce the negative effects of CMV on transplant vascular sclerosis in vivo. The commercial application will either be an antisense drug candidate or a validated assay system that will make it possible to screen for small molecule drug candidates or antibodies that work through this mechanism.
