Adenoviral gene therapy has shown promise in both preclinical and clinical settings, but several hurdles need to be overcome before it can reach its full therapeutic potential. One such hurdle is the need for targeting the right cell type, while avoiding liver uptake and hence side effects. This review will focus on transductional targeting strategies, in which the adenoviral particle is physically targeted to specific surface receptors expressed on the target cell. This can be achieved by using either bifunctional adaper molecules, which bind to the adenoviral particle on one side and to the targeted receptor on the other, or genetic targeting strategies. Adapter molecules comprise both chemically conjugated targeting moieties and recombinant fusion proteins, the latter having the advantage of being a homogeneous population. Genetic retargeting strategies include fiber or fiber knob chimerism, genetic incorporation of targeting ligands in the fiber or other capsid locales, or a combination of both (‘complex mosaics’). Since sequestration of virions in the liver presents a major problem for the therapeutic utility of adenoviral gene therapy after systemic administration, blockade of liver uptake has become an increased area of investigation. Strategies encompass blockade of the adenovirus interaction with its cognate receptor CAR, by either using the soluble ectodomain of CAR, or ablation of CAR-interacting amino acid residues in the fiber knob. In addition, inhibition of interaction with additional adenovirus receptors, such as integrins or heparan sulphate proteoglycans, hold promise for decreasing liver uptake and hence adenoviral toxicity.
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