Pre-treatment with elastase improves the efficiency of percutaneous adenovirus-mediated gene transfer to the arterial media.
The endothelium and internal elastic lamina (IEL) appear to be the main barriers to adenovirus-mediated gene transfer to medial smooth muscle cells (SMC). The present randomized study tested whether controlled incubation with elastase enhanced the efficiency of catheter-based gene transfer to medial SMC by adenoviral vectors. After an initial safety dose ranging study, rabbits underwent balloon abrasion of the iliac endothelium followed by local incubation of either elastase (2 x 10(-7) IU over 5 min) or saline using a double balloon catheter (DBC). Then, adenoviral vectors (5 x 10(9) p.f.u.) carrying Cmv-Luc or RSV-beta gal reporter genes were instilled for 30 min. Three days later, the number of medial SMC expressing lacZ was increased in the elastase-treated arteries compared with saline-treated arteries (7.2 +/- 2.5 versus 2.3 +/- 0.9 cells per section, P = 0.003). Likewise, the amount of luciferase protein product was increased (70 +/- 32 versus 36 +/- 15 pg luciferase/mg tissue, P = 0.03). No vessel enlargement, light or electron microscopic evidence of injury or inflammation was seen in elastase-treated arteries up to 7 weeks. Preincubation with elastase increased transduction efficiency of catheter-based gene delivery of replication-defective adenoviral vectors to rabbit iliac arteries without detectable arterial damage.
D000256:Adenoviridae; D000818:Animals; D002404:Catheterization; D004548:Elasticity; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007083:Iliac Artery / Q000033:anatomy & histology / Q000293:injuries; D008156:Luciferases / Q000378:metabolism; D008854:Microscopy, Electron; D009131:Muscle, Smooth, Vascular / Q000033:anatomy & histology / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000008:administration & dosage* / Q000378:metabolism; D010865:Pilot Projects; D011817:Rabbits; D011897:Random Allocation; D001616:beta-Galactosidase / Q000378:metabolism