Percutaneous gene therapy using recombinant adenoviruses encoding human herpes simplex virus thymidine kinase, human PAI-1, and human NOS3 in balloon-injured porcine coronary arteries

Local intracoronary delivery of recombinant adenoviruses expressing anti-mi gratory or anti-proliferative proteins including human constitutive endothe lial nitric oxide synthase (NOS3), plasminogen activator inhibitor 1 (PAI-1 ), or herpesvirus thymidine kinase (TK) (combined with ganciclovir) was use d to prevent neointimal formation in porcine coronary arteries. After ballo on injury of the left anterior descending (LAD) coronary artery, animals re ceived an intramural injection of adenovirus (1.5 X 10(9) PFU) carrying eit her the NOS3 cDNA (AdCMVNOS3, n = 12), the PAI-1 cDNA (AdCMVPAI-1, n = 12), the TK cDNA (AdMLPItk, n = 12), or no cDNA (AdpL+, n = 12). After 28 days, morphometric analysis was performed on coronary sections from all segments demonstrating injury. The internal elastic lamina (IEL) fracture length no rmalized to the IEL perimeter (initial injury) and the neointimal area norm alized to the vessel area (response to injury) were used to generate linear regression lines and calculate an index of stenosis for the respective tre atment groups. The response to injury was significantly smaller in AdCMVNOS 3- and AdMLPItk-infected animals than in AdpL+-infected animals (slopes = 0 .86 +/- 0.05 and 0.69 +/- 0.07 versus 1.11 +/- 0.06, p < 0.005 and p < 0.00 01, respectively) but not in AdCMVPAI-1-infected animals (slope = 1.26 +/- 0.04, p = 0.04). No viral shedding was observed and there was no acute syst emic toxicity after gene transfer. An increase in neutralizing antibody tit ers against Ad vectors was observed without any detectable response to the transgene products (NOS3, PAI-1). Local gene transfer of NOS3 and TK may ho ld promise as a safe and effective adjunctive treatment to reduce neointima l formation after percutaneous coronary intervention in humans.