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., 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:	04 Jun 2017 04:42
URI:	http://orca.cf.ac.uk/id/eprint/43272

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