title: Stent-based delivery of tissue inhibitor of metalloproteinase-3 adenovirus inhibits neointimal formation in porcine coronary arteries.
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.
  
  
  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.
authors.affiliation: Bristol Heart Institute, University of Bristol, Bristol, UK.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Johnson
authors.forename: Yin Xiong
authors.initials: YX
authors.lastname: Wu
authors.forename: Christian
authors.initials: C
authors.lastname: Herdeg
authors.forename: Andreas
authors.initials: A
authors.lastname: Baumbach
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Newby
authors.forename: Karl R
authors.initials: KR
authors.lastname: Karsch
authors.forename: Martin
authors.initials: M
authors.lastname: Oberhoff
mesh_terms: 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
chemical_list: D020099:Coated Materials, Biocompatible; D019717:Tissue Inhibitor of Metalloproteinase-3