ADENOVIRUS-MEDIATED GENE-TRANSFER TO LOWER-LIMB ARTERY OF PATIENTS WITH CHRONIC CRITICAL LEG ISCHEMIA

Arterial gene transfer offers a promising new approach for the treatme nt of vascular disorders, However, no data are available about the gen e transfer efficiency in human arteries in vivo. The aim of this study was to evaluate the safety and feasibility of catheter-mediated adeno viral gene transfer in human peripheral arteries, Ten patients (8 fema les, 2 males, mean age 80 +/- 8 years) suffering from chronic critical leg ischemia with a prior decision for amputation were recruited in t he study, Gene transfer was performed in eight patients in conjunction with a conventional percutaneous transluminal angioplasty, using a pe rfusion coil balloon catheter, Two patients served as controls, Increa sing concentrations of replication-deficient adenoviruses (titers from 1 x 10(8) to 3 x 10(10) PFU) containing a nuclear-targeted beta-galac tosidase marker gene were administered into the arteries over 10 min v ia the catheter, Amputations were performed 20 to 51 hr after the proc edures and gene transfer efficiency was evaluated in the transduced ar teries using X-Gal staining for beta-galactosidase activity, beta-Gala ctosidase gene transfer was well tolerated and no adverse tissue respo nses or systemic complications were observed in any of the patients, G ene transfer was successful in six of the eight patients, Gene transfe r efficiency varied between 0.04 and 5.0% of all arterial cells, Trans gene expression was detected in smooth muscle cells, endothelial cells , and macrophages and in tunica adventitia. However, transgene activit y was not evenly distributed in the arterial wall and no transgene act ivity was found beneath advanced atherosclerotic lesions, The safety a nd feasibility of in vivo gene transfer by adenoviral vectors to human peripheral arteries were established, Although improvements are still required in gene transfer efficiency, these findings suggest that ade noviruses can be used to deliver therapeutically active genes into hum an arteries.