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

Alba, R. et al. (2010) Biodistribution and retargeting of FX-binding ablated adenovirus serotype 5 vectors. Blood, 14(116), pp. 2656-2664. (doi:10.1182/blood-2009-12-260026)

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Publisher's URL: http://bloodjournal.hematologylibrary.org

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:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Coughlan, Dr Lynda and Nicklin, Professor Stuart and Greig, Ms Jenny and Bradshaw, Dr Angela and Baker, Professor Andrew and Alba, Dr Raul and Denby, Dr Laura and McDonald, Dr Robert and Miller, Dr Ashley and Parker, Dr Alan
Authors: Alba, R., Bradshaw, A. C., Coughlan, L., Denby, L., McDonald, R. A., Waddington, S. N., Buckley, S. M. K., Greig, J. A., Parker, A. L., Miller, A. M., Wang, H., Lieber, A., van Rooijen, N., McVey, J. H., Nicklin, S. A., and Baker, A. H.
Subjects:R Medicine > RC Internal medicine
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
Published Online:07 July 2010
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
519431Interrogation and manipulation of miRNA in acute vascular injuryAndrew BakerBritish Heart Foundation (BHF)RG/09/005/27915RI CARDIOVASCULAR & MEDICAL SCIENCES