Biodistribution and inflammatory profiles of novel penton and hexon double-mutant serotype 5 adenoviruses

Bradshaw, A. C. , Coughlan, L., Miller, A. M.., Nicklin, S. A. , Baker, A. H., Alba, R. and van Rooijen, N. (2012) Biodistribution and inflammatory profiles of novel penton and hexon double-mutant serotype 5 adenoviruses. Journal of Controlled Release, 164(3), pp. 394-402. (doi:10.1016/j.jconrel.2012.05.025)

Bradshaw, A. C. , Coughlan, L., Miller, A. M.., Nicklin, S. A. , Baker, A. H., Alba, R. and van Rooijen, N. (2012) Biodistribution and inflammatory profiles of novel penton and hexon double-mutant serotype 5 adenoviruses. Journal of Controlled Release, 164(3), pp. 394-402. (doi:10.1016/j.jconrel.2012.05.025)

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Abstract

The use of adenovirus serotype 5 (Ad5) vectors in the clinical setting is severely hampered by the profound liver tropism observed after intravascular delivery coupled with the pronounced inflammatory and innate immune response elicited by these vectors. Liver transduction by circulating Ad5 virions is mediated by a high-affinity interaction between the capsid hexon protein and blood coagulation factor X (FX), whilst penton-α(v)integrin interactions are thought to contribute to the induction of anti-Ad5 inflammatory and innate immune responses. To overcome these limitations, we sought to develop and characterise for the first time novel Ad5 vectors possessing mutations ablating both hexon:FX and penton:integrin interactions. As expected, intravascular administration of the FX binding-ablated Ad5HVR5*HVR7*E451Q vector (AdT*) resulted in significantly reduced liver transduction in vivo compared to Ad5. In macrophage-depleted mice, increased spleen uptake of AdT* was accompanied by an elevation in the levels of several inflammatory mediators. However ablation of the penton RGD motif in the AdT* vector background (AdT*RGE) resulted in a significant 5-fold reduction in spleen uptake and attenuated the antiviral inflammatory response. A reduction in spleen uptake and inflammatory activation was also observed in animals after intravascular administration of Ad5RGE compared to the parental Ad5 vector, with reduced co-localisation of the viral beta-galactosidase transgene with MAdCAM-1+ sinus-lining endothelial cells. Our detailed assessment of these novel adenoviruses indicates that penton base RGE mutation in combination with FX binding-ablation may be a viable strategy to attenuate the undesired liver uptake and pro-inflammatory responses to Ad5 vectors after intravascular delivery

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baker, Professor Andrew and Miller, Dr Ashley and Alba, Dr Raul and Nicklin, Professor Stuart and Bradshaw, Dr Angela and Coughlan, Dr Lynda
Authors: Bradshaw, A. C., Coughlan, L., Miller, A. M.., Nicklin, S. A., Baker, A. H., Alba, R., and van Rooijen, N.
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:Journal of Controlled Release
Publisher:Elsevier
ISSN:0168-3659
ISSN (Online):1873-4995
Published Online:21 May 2012
Copyright Holders:Copyright © 2012 The Authors
First Published:First published in Journal of Controlled Release 164(3);394-402
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
478611Interrogation and manipulation of micro RNA during differentiation of human ES cells to cardiomyocyte and vascular lineagesAndrew BakerBritish Heart Foundation (BHF)PG/08/107/26160RI CARDIOVASCULAR & MEDICAL SCIENCES