Biodistribution and retargeting of FX-binding ablated adenovirus serotype 5 vectors

Alba, Raul, Bradshaw, Angela C., Coughlan, Lynda, Denby, Laura, McDonald, Robert A., Waddington, Simon N., Buckley, Suzanne M. K., Greig, Jenny A., Parker, Alan L. ORCID: https://orcid.org/0000-0002-9302-1761, Miller, Ashley M., Wang, Hongjie, Lieber, Andre, van Rooijen, Nico, McVey, John H,, Nicklin, Stuart A. and Baker, Andrew H. 2010. Biodistribution and retargeting of FX-binding ablated adenovirus serotype 5 vectors. Blood 116 (15) , pp. 2656-2664. 10.1182/blood-2009-12-260026

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Abstract

A major limitation for adenoviral transduction in vivo is the profound liver tropism of adenovirus type 5 (Ad5). Recently, we demonstrated that coagulation factor X (FX) binds to Ad5-hexon protein at high affinity to mediate hepatocyte transduction after intravascular delivery. We developed novel genetically FX-binding ablated Ad5 vectors with lower liver transduction. Here, we demonstrate that FX-binding ablated Ad5 predominantly localize to the liver and spleen 1 hour after injection; however, they had highly reduced liver transduction in both control and macrophage-depleted mice compared with Ad5. At high doses in macrophage-depleted mice, FX-binding ablated vectors transduced the spleen more efficiently than Ad5. Immunohistochemical studies demonstrated transgene colocalization with CD11c+, ER-TR7+, and MAdCAM-1+ cells in the splenic marginal zone. Systemic inflammatory profiles were broadly similar between FX-binding ablated Ad5 and Ad5 at low and intermediate doses, although higher levels of several inflammatory proteins were observed at the highest dose of FX-binding ablated Ad5. Subsequently, we generated a FX-binding ablated virus containing a high affinity Ad35 fiber that mediated a significant improvement in lung/liver ratio in macrophage-depleted CD46+ mice compared with controls. Therefore, this study documents the biodistribution and reports the retargeting capacity of FX binding-ablated Ad5 vectors in vitro and in vivo.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QR Microbiology > QR180 Immunology R Medicine > RC Internal medicine
Publisher:	American Society of Hematology
ISSN:	0006-4971
Last Modified:	24 Oct 2022 10:09
URI:	https://orca.cardiff.ac.uk/id/eprint/43272

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