Adenoviral Gene Transfer in Arteries of Hypercholesterolemic Nonhuman Primates

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Abstract
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. AdRSVnLacZ, 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. Adenoviral gene transfer is a promising approach for treating vascular disorders, but the effects of adenovirus on primate arteries are unknown. A replication-defective adenoviral vector was delivered to the left brachial arteries of six hypercholesterolemic cynomolgus monkeys; right brachial arteries received vehicle alone. At vessel harvest 9 or 10 days later, recombinant gene expression was present in occasional endothelial cells, and neutralizing antibodies were generated in all animals. In transduced arteries, intimal cellularity and macrophage accumulation increased significantly; T cell density and cellular proliferation were unaffected. In nonhuman primates, adenoviral vectors cause vessel wall inflammation that may promote progression of atherosclerosis.

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