Retargeting FX binding-ablated HAdV-5 to vascular cells by inclusion of the RGD-4C

peptide in hexon hypervariable region 7 and the HI loop (original) (raw)

Robertson, Stacy, Parker, Alan L., Clarke, Carolyn, Duffy, Margaret R., Alba, Raul, Nicklin, Stuart A. ORCID: https://orcid.org/0000-0002-9691-6210 and Baker, Andrew H.(2016) Retargeting FX binding-ablated HAdV-5 to vascular cells by inclusion of the RGD-4C peptide in hexon hypervariable region 7 and the HI loop.Journal of General Virology, 97(8), pp. 1911-1916. (doi: 10.1099/jgv.0.000505) (PMID:27189759) (PMCID:PMC5156330)

Abstract

Recent studies have generated interest in the function of human adenovirus serotype 5 (HAdV-5) hexon: factor X (FX) binding and subsequent hepatocyte transduction and interaction with the immune system. Here, we retargeted adenovirus serotype 5 vectors, ablated for FX interaction, by replacing amino acids in hexon HVR7 with RGD-4C or inserting the peptide into the fibre HI loop. These genetic modifications in the capsid were compatible with virus assembly, and could efficiently retarget transduction of the vector via the αvβ3/5 integrin-mediated pathway, but did not alter immune recognition by pre-existing human neutralizing anti-HAdV-5 antibodies or by natural antibodies in mouse serum. Thus, FX-binding-ablated HAdV-5 can be retargeted but remain sensitive to immune-mediated attack. These findings further refine HAdV-5-based vectors for human gene therapy and inform future vector development.

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Funder and Project Information

1

Improved gene therapy via genetic modification of the adenovirus capsid to ablate interaction with blood coagulation factor X

Andrew Baker

BB/I53297X/1

RI CARDIOVASCULAR & MEDICAL SCIENCES

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