GENE-TRANSFER INTO NORMAL AND ATHEROSCLEROTIC HUMAN BLOOD-VESSELS

Gene transfer to blood vessels is a promising new approach to the trea tment of the vascular diseases, but the feasibility of gene transfer t o adult human vessels has not been explored. We introduced an adenovir us vector encoding a marker gene human placental alkaline phosphatase :into normal and atherosclerotic human vessels in organ culture. In th e normal vessels, recombinant gene was expressed preferentially in the endothelial cells (approximate to 100%), intimal smooth muscle cells (1.3+/-0.4%, 1.4+/-1.0%, and 3.8+/-0.8% in the internal mammary arteri es, saphenous veins, and normal coronary arteries, respectively), and various adventitial cells. Advanced, complicated atherosclerotic plaqu es demonstrated a similar efficiency of recombinant gene expression (3 .1+/-0.5.% and 3.8+/-0.3% of nonendothelial intimal cells in the coron ary artery and carotid artery plaques, respectively). Of these intimal cells, macrophages and smooth muscle cells expressed a transgene, ide ntifying them as targets for gene transfer. Areas of plaque rupture an d thrombus are sites of predilection for expression of recombinant gen es. Collagenase and elastase treatment increased the percentage of tra nsgenic alkaline phosphatase-positive cells 7 times (P<0.001), suggest ing that the pattern of gene expression was affected by the amount of surrounding extracellular matrix. These studies demonstrate the feasib ility of gene transfer to human blood vessels. However, these studies also highlight important barriers to adenoviral gene delivery to the a ctual normal and atherosclerotic human vessels of clinical interest.