Transductional Targeting of Adenoviral Cancer Gene Therapy

Abstract

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.

Biomarkers to identify and isolate senescent cells

“…Changes in the expression of PM proteins can also be detected with transductionally targeted recombinant viruses, which are able to enter only those cells with the appropriate ligand exposed on the PM. This has been accomplished in cancer cells already and readers are referred to an excellent review by Everts and Curiel for more information (Everts and Curiel, 2004). A similar strategy could be used to target senescent cells.…”

Herpes simplex virus 1 (HSV-1) for cancer treatment

“…205 Although the complexities of HSV-1 entry are not fully unraveled, several studies have demonstrated the feasibility of restricting HSV-1 infection to predefined subpopulations of cells (reviewed in Burton et al 13 ). For example, an HSV-1 mutant was engineered in which the heparan sulfate binding domain of gB was abrogated, and N-terminal truncated gC was fused to full-length erythropoietin (EPO).…”

Evolving gene therapy approaches for osteosarcoma using viral vectors: Review

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