A more recent version of this article appeared on April 1, 2005

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:754.)
© 2005 American Heart Association, Inc.

Vascular Biology

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

Thomas W. Johnson; Yin Xiong Wu; Christian Herdeg; Andreas Baumbach; Andrew C. Newby; Karl R. Karsch; Martin Oberhoff

From Bristol Heart Institute (T.W.J., Y.X.W., A.B., A.C.N., K.R.K., M.O.), University of Bristol, Bristol, UK; and the Department of Cardiology (C.H.), University of Tübingen, Tübingen, Germany.

Correspondence to Professor Karl R. Karsch, Bristol Heart Institute, University of Bristol, Bristol, UK, BS2 8HW. E-mail K.R.Karsch{at}bristol.ac.uk

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 ß-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 ß-galactosidase–expressing adenovirus (RAdlacZ). Neointimal area after 28 days was significantly reduced to 1.27±0.19 mm² with RAdTIMP-3 versus 2.61±0.31 mm² with RAdlacZ stents (P<0.001) and 2.12±0.20 mm² 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.

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.

Key Words: gene therapy • metalloproteinases • restenosis • stents • viruses

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