Stent-Based Delivery of Tissue Inhibitor of Metalloproteinase-3 Adenovirus Inhibits Neointimal Formation in Porcine Coronary Arteries

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Abstract
Background— Stent-based antiproliferative therapy appears to decrease in-stent restenosis. However, alternative approaches might produce equivalent efficacy with better long-term safety. In previous work, an adenovirus capable of expressing the tissue inhibitor of metalloproteinase-3 (RAdTIMP-3) inhibited neointima formation in cell cultures and porcine saphenous vein grafts. RAdTIMP-3 decreased smooth muscle cell migration, stabilized the extracellular matrix, and uniquely promoted apoptosis. The current study developed eluting stent technology to deliver RAdTIMP-3 during stenting of pig coronary arteries. Methods and Results— Binding of virus to and elution from stents and transduction of pig coronary arteries were confirmed using β-galactosidase as a reporter gene in vitro and in vivo. Deployment of RAdTIMP-3–coated stents increased apoptosis and reduced neointimal cell density, but did not increase inflammation or proliferation compared with β-galactosidase–expressing adenovirus (RAdlacZ). Neointimal ... We developed eluting-stent technology to deliver an adenovirus capable of TIMP-3 overexpression and investigated its effect on restenosis. The technology resulted in effective in vitro and in vivo transduction. TIMP-3 overexpression increased apoptosis and reduced neointimal formation. Our results demonstrate for the first time to our knowledge the feasibility of adenovirus-eluting stent technology.

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