Inhibition of neointimal formation after stent placement with adenovirus-mediated gene transfer of IκBα in the hypercholesterolemic rabbit model:: Initial results

PURPOSE: To evaluate the feasibility and efficacy of the local application of a replication-defective adenovirus construct for the expression of the antiinflammatory protein IkappaBalpha, inhibitor of nuclear factor kappaB (NF-kappaB), to reduce neointimal formation after stent placement. MATERIALS AND METHODS: Nitinol stents were implanted in the iliac arteries of hypercholesterolemic rabbits, followed by balloon dilation (30 seconds at 6 atm). Local adenovirus-mediated transfer Of IkappaBalpha (3 mL of 10(9) plaque-forming units per milliliter at 6 atm) was performed and compared with three control groups: stent alone, stent plus local delivery of phosphate-buffered saline (PBS) (3 mL at 6 atm), and stent plus local delivery of control adenovirus coding for green fluorescent protein (GFP) (3 mL of 109 plaque-forming units per milliliter at 6 atm). A multichannel balloon was used for local drug delivery and balloon dilation. Animals were sacrificed I or 4 weeks after treatment. Effective transfection was demonstrated with immunofluorescence staining. Angiographic patency and luminal diameter were evaluated at quantitative angiography. Luminal and neointimal areas were measured on surface-stained ground sections with m ethyl meth acrylate embedding and the cutting-grinding technique. RESULTS: All vessels with stents were patent at angiography. Neointimal area was negligible in all groups1 week after stent placement (range, 0.42-0.52 mm(2); p = .44; analysis of variance). Neointimal formation was demonstrated in all groups 4 weeks after implantation but was significantly reduced with IkappaBalpha treatment compared with treatment with stent alone (by 22%, from 2.80 mm(2) +/- 0.20 to 2.28 mm(2) +/- 0.14, P =.05), stent plus PBS (by 43%, from 3.26 mm(2) +/- 0.25 to 2.28 mm(2) 0.14, P =.005), and stent plus GFP (by 53%, from 2.32 mm(2) 0.19 to 1.51 mm(2) +/- 0.08, P <.005). CONCLUSION: Local adenovirus-mediated IkappaBalpha gene transfer has the potential to reduce intimal hyperplasia after stent placement.