Gene transfer into normal and atherosclerotic human blood vessels.
Gene transfer to blood vessels is a promising new approach to the treatment of the vascular diseases, but the feasibility of gene transfer to adult human vessels has not been explored. We introduced an adenovirus vector encoding a marker gene human placental alkaline phosphatase into normal and atherosclerotic human vessels in organ culture. In the normal vessels, recombinant gene was expressed preferentially in the endothelial cells (approximately 100%), intimal smooth muscle cells (1.3+/-0.4%, 1.4+/-1.0%, and 3.8+/-0.8% in the internal mammary arteries, saphenous veins, and normal coronary arteries, respectively), and various adventitial cells. Advanced, complicated atherosclerotic plaques demonstrated a similar efficiency of recombinant gene expression (3.1+/-0.5% and 3.8+/-0.3% of nonendothelial intimal cells in the coronary artery and carotid artery plaques, respectively). Of these intimal cells, macrophages and smooth muscle cells expressed a transgene, identifying them as targets for gene transfer. Areas of plaque rupture and thrombus are sites of predilection for expression of recombinant genes. Collagenase and elastase treatment increased the percentage of transgenic alkaline phosphatase-positive cells 7 times (P<0.001), suggesting that the pattern of gene expression was affected by the amount of surrounding extracellular matrix. These studies demonstrate the feasibility of gene transfer to human blood vessels. However, these studies also highlight important barriers to adenoviral gene delivery to the actual normal and atherosclerotic human vessels of clinical interest.
Rekhter
M D
MD
Department of Pathology, University of Michigan, Ann Arbor, USA.
Simari
R D
RD
Work
C W
CW
Nabel
G J
GJ
Nabel
E G
EG
Gordon
D
D
D000256:Adenoviridae; D000328:Adult; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001161:Arteriosclerosis / Q000473:pathology / Q000628:therapy*; D001808:Blood Vessels; D004274:DNA, Recombinant / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology; D015870:Gene Expression; D018014:Gene Transfer Techniques / Q000009:adverse effects*; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D009924:Organ Culture Techniques; D010920:Placenta / Q000201:enzymology; D011817:Rabbits; D019076:Transgenes; D014657:Vasculitis / Q000209:etiology
D004274:DNA, Recombinant; D007527:Isoenzymes; D000469:Alkaline Phosphatase