Vascular grafts are used in more than 1 million patients each year in the United States (1-3). However, the outcome of vascular graft implantation is often complicated by neointimal buildup at the vascular graft-blood vessel anastomosis. We hypothesize that vascular graft anastomotic obstruction can be prevented through using an antibody-immobilized adenoviral vector localized at the anastomotic site, delivering a gene (the truncated Retinoblastoma protein, Rb94) that will suppress excessive proliferative neointimal activity at the graft-vessel junction. Thus the Aims are: 1) To configure a monoclonal antibody (IgG) with specificity for the adenovirus hexon domain onto a prototype matrix support (collagen lyophilized onto a Dacron vascular graft) using sulfhydral derivatizing reagents, and to use this immobilized antibody as a means of regulating localized viral vector delivery. 2) We will next characterize the delivery system in cell culture with A10 cells, using our therapeutic construct, the retinoblastoma gene, constructed as the truncated and thus longer acting Rb94, carried in an adenoviral vector. 3) During Phase I, based on the above studies, we will perform a series of vascular graft implants in dogs using an established model focusing on limiting anastomotic hyperplasia (neointima). Thus, Phase I will seek to demonstrate feasibility, gene delivery efficiency, initial proof of efficacy, and biodistribution for this strategy for pretreating vascular grafts at the time of surgery in order to improve the anastomotic outcome. A Phase II proposal will work toward using this approach in both preclinical and Phase I human clinical studies.
Improved outcome for the more than one million vascular graft patients treated annually.
