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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Biodistribution and retargeting of FX-binding ablated adenovirus serotype 5 vectors
Blood, Volume 116, No. 15, Year 2010
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Description
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 macrophagedepleted 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. © 2010 by The American Society of Hematology.
Authors & Co-Authors
Bradshaw, Angela C.
United Kingdom, Glasgow
College of Medical, Veterinary & Life Sciences
Waddington, Simon N.
United Kingdom, London
Ucl Medical School
Buckley, Suzanne M.K.
United Kingdom, London
Ucl Medical School
Parker, Alan L.
United Kingdom, Glasgow
College of Medical, Veterinary & Life Sciences
Lieber, André
United States, Seattle
University of Washington
Van-Rooijen, Nico
Netherlands, Amsterdam
Amsterdam Umc - Vrije Universiteit Amsterdam
McVey, John H.
United Kingdom, London
Thrombosis Research Institute
Nicklin, Stuart A.
United Kingdom, Glasgow
College of Medical, Veterinary & Life Sciences
Baker, Andrew H.
United Kingdom, Glasgow
College of Medical, Veterinary & Life Sciences
Statistics
Citations: 97
Authors: 9
Affiliations: 6
Identifiers
Doi:
10.1182/blood-2009-12-260026
ISSN:
00064971