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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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
Glasgow Author(s) Enlighten ID:Baker, Professor Andrew and Miller, Dr Ashley and Greig, Ms Jenny and Alba, Dr Raul and McDonald, Dr Robert and Nicklin, Professor Stuart and Bradshaw, Dr Angela and Denby, Dr Laura and Parker, Dr Alan and Coughlan, Dr Lynda
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 > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Blood
Publisher:American Society of Hematology
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