Stent-based delivery of tissue inhibitor of metalloproteinase-3 adenovirus inhibits neointimal formation in porcine coronary arteries

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 beta-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 beta-galactosidase - expressing adenovirus (RAdlacZ). Neointimal area after 28 days was significantly reduced to 1.27 +/- 0.19 mm(2) with RAdTIMP-3 versus 2.61 +/- 0.31 mm(2) with RAdlacZ stents ( P < 0.001) and 2.12 +/- 0.20 mm(2) with bare stents ( P < 0.005). Conclusions - Our results demonstrate for the first time to our knowledge the feasibility of adenovirus-coated stent technology and highlight the potential of TIMP-3 to produce significant inhibition of in-stent neointima formation.