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Transcellular targeting of fiber- and hexon-modified adenovirus vectors across the brain microvascular endothelial cells in vitro

Laakkonen, Johanna P.; Engler, Tatjana; Romero, Ignacio A; Weksler, Babette; Couraud, Pierre-Olivier; Kreppel, Florian and Kochanek, Stefan (2012). Transcellular targeting of fiber- and hexon-modified adenovirus vectors across the brain microvascular endothelial cells in vitro. PLoS ONE, 7(9) e45977.

DOI (Digital Object Identifier) Link: https://doi.org/10.1371/journal.pone.0045977
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Abstract

In central nervous system (CNS)-directed gene therapy, efficient targeting of brain parenchyma through the vascular route is prevented by the endothelium and the epithelium of the blood-brain and the blood-cerebrospinal fluid barriers, respectively. In this study, we evaluated the feasibility of the combined genetic and chemical adenovirus capsid modification technology to enable transcellular delivery of targeted adenovirus (Ad) vectors across the blood-brain barrier (BBB) in vitro models. As a proof-of-principle ligand, maleimide-activated full-length human transferrin (hTf) was covalently attached to cysteine-modified Ad serotype 5 vectors either to its fiber or hexon protein. In transcytosis experiments, hTf-coupled vectors were shown to be redirected across the BBB models, the transcytosis activity of the vectors being dependent on the location of the capsid modification and the in vitro model used. The transduction efficiency of hTf-targeted vectors decreased significantly in confluent, polarized cells, indicating that the intracellular route of the vectors differed between unpolarized and polarized cells. After transcellular delivery the majority of the hTf-modified vectors remained intact and partly capable of gene transfer. Altogether, our results demonstrate that i) covalent attachment of a ligand to Ad capsid can mediate transcellular targeting across the cerebral endothelium in vitro, ii) the attachment site of the ligand influences its transcytosis efficiency and iii) combined genetic/chemical modification of Ad vector can be used as a versatile platform for the development of Ad vectors for transcellular targeting.

Item Type: Journal Item
Copyright Holders: 2012 The Authors
ISSN: 1932-6203
Project Funding Details:
Funded Project NameProject IDFunding Body
Not Set130242Academy of Finland
Not Set00107022Finnish Cultural Foundation
NoE ClinigeneLSHB-CT-2006-018933EU
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 36412
Depositing User: Ignacio A Romero
Date Deposited: 30 Jan 2013 14:57
Last Modified: 07 Dec 2018 10:13
URI: http://oro.open.ac.uk/id/eprint/36412
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