The relevance of coagulation factor X protection of adenoviruses in human sera

Duffy, M.R., Doszpoly, A., Turner, G., Nicklin, S.A. and Baker, A.H. (2016) The relevance of coagulation factor X protection of adenoviruses in human sera. Gene Therapy, 23(7), pp. 592-596. (doi:10.1038/gt.2016.32) (PMID:27014840) (PMCID:PMC4940928)

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Abstract

Intravenous delivery of adenoviruses is the optimal route for many gene therapy applications. Once in the blood, coagulation factor X (FX) binds to the adenovirus capsid and protects the virion from natural antibody and classical complement-mediated neutralisation in mice. However, to date, no studies have examined the relevance of this FX/viral immune protective mechanism in human samples. In this study, we assessed the effects of blocking FX on adenovirus type 5 (Ad5) activity in the presence of human serum. FX prevented human IgM binding directly to the virus. In individual human sera samples (n=25), approximately half of those screened inhibited adenovirus transduction only when the Ad5–FX interaction was blocked, demonstrating that FX protected the virus from neutralising components in a large proportion of human sera. In contrast, the remainder of sera tested had no inhibitory effects on Ad5 transduction and FX armament was not required for effective gene transfer. In human sera in which FX had a protective role, Ad5 induced lower levels of complement activation in the presence of FX. We therefore demonstrate for the first time the importance of Ad–FX protection in human samples and highlight subject variability and species-specific differences as key considerations for adenoviral gene therapy.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nicklin, Professor Stuart and Baker, Professor Andrew and Duffy, Ms Margaret and Doszpoly, Dr Andor
Authors: Duffy, M.R., Doszpoly, A., Turner, G., Nicklin, S.A., and Baker, A.H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Gene Therapy
Publisher:Nature Publishing Group
ISSN:0969-7128
ISSN (Online):1476-5462
Published Online:25 March 2016
Copyright Holders:Copyright © 2016 Macmillan Publishers Limited
First Published:First published in Gene Therapy 23(7): 592-596
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
583362BHF Chair of Translational Cardiovascular SciencesAndrew BakerBritish Heart Foundation (BHF)SS/CH/11/228733RI CARDIOVASCULAR & MEDICAL SCIENCES
519431Interrogation and manipulation of miRNA in acute vascular injuryAndrew BakerBritish Heart Foundation (BHF)RG/09/005/27915RI CARDIOVASCULAR & MEDICAL SCIENCES
570791ADVANCE - ADenoViruses as novel clinical treatmentsAndrew BakerEuropean Commission (EC)PITN-GA-2011-29RI CARDIOVASCULAR & MEDICAL SCIENCES