Expandable metallic stents have been successfully utilized to relieve coronary arterial obstruction During this past year in the United States more then five hundred thousand coronary stents were used. Furthermore, there has been increasing interest in drug delivery stents to prevent restenosis following stent angioplasty. Our laboratory has pioneered the use of stents as platforms for gene delivery systems for arterial wall gene therapy. In this research program, we will address the following hypothesis: Gene therapy for in-stent restenosis and stabilization of vulnerable plaque can be achieved with a gene delivery stent. Our gene delivery stent utilizes antibody-mediated tethering of replication defective adenoviral gene vectors; this results in enhanced site specific ta'ansgene expression, and a highly localized biodistribution restricted to the site of stent deployment.
Aims Aim 1 : Polyaminobisphosphonate-steel interactions with subsequent polyamine and antibody binding: Formulation and Characterization. Bisphosphonate chemosorption will be the basis for a molecular surface modification of the steel stents either directly or with amplifying polyamines, to permit the covalent binding of anti-adenoviral antibodies to amino groups using bifunctional crosslinking, thereby enabling vector tethering.
Aim 2 : Formulation and characterization of the steel-PAABP-antibody gene delivery system: Ceil culture studies. Arterial smooth muscle cell cultures will be used as a model system to investigate the mechanism of gene delivery, fi-galactosidase (LacZ) and Green Fluorescent Protein (GFP) will be used as the reporter genes for these experiments.
Aim 3 : In vivo efficiency and anti-in-stent restenosis efficacy. Pig coronary stent studies will use the optimal formulations based on Aims 1 and 2. Reporter studies (LacZ) will focus on in vivo efficiency and biodistribution of vector. The therapeutic gene will be Fas-Ligand, a pro-apoptotic protein with established efficacy for restenosis. The chief therapeutic endpoint will be extent of inhibition of neointimal formation.
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