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

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 studi...

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Autores principales: Duffy, M R, Doszpoly, A, Turner, G, Nicklin, S A, Baker, A H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940928/
https://www.ncbi.nlm.nih.gov/pubmed/27014840
http://dx.doi.org/10.1038/gt.2016.32
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author Duffy, M R
Doszpoly, A
Turner, G
Nicklin, S A
Baker, A H
author_facet Duffy, M R
Doszpoly, A
Turner, G
Nicklin, S A
Baker, A H
author_sort Duffy, M R
collection PubMed
description 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.
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spelling pubmed-49409282016-07-18 The relevance of coagulation factor X protection of adenoviruses in human sera Duffy, M R Doszpoly, A Turner, G Nicklin, S A Baker, A H Gene Ther Original Article 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. Nature Publishing Group 2016-07 2016-04-14 /pmc/articles/PMC4940928/ /pubmed/27014840 http://dx.doi.org/10.1038/gt.2016.32 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Duffy, M R
Doszpoly, A
Turner, G
Nicklin, S A
Baker, A H
The relevance of coagulation factor X protection of adenoviruses in human sera
title The relevance of coagulation factor X protection of adenoviruses in human sera
title_full The relevance of coagulation factor X protection of adenoviruses in human sera
title_fullStr The relevance of coagulation factor X protection of adenoviruses in human sera
title_full_unstemmed The relevance of coagulation factor X protection of adenoviruses in human sera
title_short The relevance of coagulation factor X protection of adenoviruses in human sera
title_sort relevance of coagulation factor x protection of adenoviruses in human sera
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940928/
https://www.ncbi.nlm.nih.gov/pubmed/27014840
http://dx.doi.org/10.1038/gt.2016.32
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