The feasibility of Ad vector-mediated gene transfer in vitro posed the question of the efficiency of this vector system in vivo. Because Ad gene transfer vectors are made from human adenoviruses, there was no a priori reason to believe they would infect rodents or other model animals. Some early studies used cotton rats because this species had been shown previously to be permissive for replication of human adenoviruses (52-54). For example, intratracheal administration of a replication-deficient virus expressing the reporter gene p-galac-tosidase to cotton rats resulted in expression of p-galactosi-dase in the airway epithelium (55). Numerous other animals have been used to demonstrate efficient adenovirus vector-mediated gene transfer, including rats, mice, pigs, rabbits, and nonhuman primates. From these studies, a number of general conclusions can be drawn. Importantly, many tissues can be infected based on the route of administration. As expected from the tropism of Ad5, the transgene delivered to the respiratory epithelium is readily expressed after intranasal or intra-tracheal administration. But intravenous injection into rodents results primarily in transgene expression in the liver and spleen (56-58). It is not known if the hepatocytes or hepatic endothelium account for this tropism as, surprisingly, the preference for liver does not correspond to the distribution of the CAR receptor among organs (13). Direct injection into the peritoneum (34), kidney (59), pancreas (60), cerebral spinal fluid (61), skeletal muscle (62), brain (63), cardiac muscle (64), coronary artery (65), and many other tissues results in local expression of the transgene. However, the absolute efficiency of gene transfer and expression and leakage to other organs has seldom been calculated, and it is often unclear if therapeutic levels of transgene expression can be achieved.
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