Adenoviral gene transfer in arteries of hypercholesterolemic nonhuman primates.
Arterial gene transfer with adenoviral vectors is a promising approach for the treatment and prevention of vascular disorders. However, in small animals such as rats and rabbits adenoviral vectors can have deleterious effects on the artery wall. The effects of adenovirus in primate arteries have not been studied. AdRSVn-LacZ, a replication-defective adenoviral vector, was delivered to the left brachial arteries of six hypercholesterolemic cynomolgus monkeys; right brachial arteries received vehicle only. Serum was collected before gene transfer and at vessel harvest 9 or 10 days later. Recombinant gene expression was present in occasional endothelial cells of transduced arteries, and all animals generated neutralizing antibodies. In transduced arteries, immunostaining revealed a fourfold increase in intimal and medial macrophage accumulation (p < 0.05); intimal cellularity was also significantly increased (twofold; p < 0.05). T cell density and total cellular proliferation (determined by bromodeoxyuridine labeling) were unaffected. In hypercholesterolemic nonhuman primates, adenoviral vectors increase vessel wall inflammation and promote the progression of early atherosclerotic lesions. The long-term consequences of these observations remain unclear; however, a better understanding of host responses to specific vector systems appears necessary for the development of safe and effective approaches to human vascular gene therapy.
Schneider
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Gladstone Institute of Cardiovascular Disease, Department of Surgery, University of California, San Francisco 94143, USA.
Fly
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Dichek
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Geary
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D000256:Adenoviridae; D000818:Animals; D000917:Antibody Formation; D001916:Brachial Artery / Q000473:pathology*; D002455:Cell Division; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D006937:Hypercholesterolemia / Q000473:pathology / Q000628:therapy*; D008252:Macaca fascicularis; D008264:Macrophages / Q000473:pathology; D011817:Rabbits; D051381:Rats; D013601:T-Lymphocytes / Q000473:pathology; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D001616:beta-Galactosidase