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.


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 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.
Johnson
Thomas W
TW
Bristol Heart Institute, University of Bristol, Bristol, UK.
Wu
Yin Xiong
YX
Herdeg
Christian
C
Baumbach
Andreas
A
Newby
Andrew C
AC
Karsch
Karl R
KR
Oberhoff
Martin
M
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D020099:Coated Materials, Biocompatible; D023903:Coronary Restenosis / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000473:pathology*; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D066298:In Vitro Techniques; D015607:Stents; D013552:Swine; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*; D017539:Tunica Intima / Q000473:pathology; D014657:Vasculitis / Q000473:pathology
D020099:Coated Materials, Biocompatible; D019717:Tissue Inhibitor of Metalloproteinase-3