Epidermal growth factor targeting of bacteriophage to the choroid plexus for gene delivery to the central nervous system via cerebrospinal fluid


Because the choroid plexus normally controls the production and composition of cerebrospinal fluid and, as such, its many functions of the central nervous system, we investigated whether ligand-mediated targeting could deliver genes to its secretory epithelium. We show here that when bacteriophages are targeted with epidermal growth factor, they acquire the ability to enter choroid epithelial cells grown in vitro as cell cultures, ex vivo as tissue explants or in vivo by intracerebroventricular injection. The binding and internalization of these particles activate EGF receptors on targeted cells, and the dose- and time-dependent internalization of particles is inhibited by the presence of excess ligand. When the phage genome is further reengineered to contain like green fluorescent protein or firefly luciferase under control of the cytomegalovirus promoter, gene expression is detectable in the choroid plexus and ependymal epithelium by immunohistochemistry or by noninvasive imaging, respectively. Taken together, these data support the hypothesis that reengineered ligand-mediated gene delivery should be considered a viable strategy to increase the specificity of gene delivery to the central nervous system and bypass the blood-brain barrier so as to exploit the biological effectiveness of the choroid plexus as a portal of entry into the brain.

Publication DOI: https://doi.org/10.1016/j.brainres.2010.08.044
Divisions: College of Health & Life Sciences > Aston Medical School
Funding Information: Research supported by the BBSRC grant BB/C50466X/1 (AMG); National Institutes of Health grants EY018479 (AB), GM078421 (AB), and HL73396 (BE); and the CDMRP BC073891 (AB). The authors wish to thank Ms Emelie Amburn, Ms Tran Ngyuen, and Ms Shuman Sun at UC
Additional Information: © 2010, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Uncontrolled Keywords: Cerebrospinal fluid,Endocytosis,Epidermal growth factor,Epithelial cell,Gene delivery,Phage,Neuroscience(all),Molecular Biology,Clinical Neurology,Developmental Biology
Publication ISSN: 0006-8993
Last Modified: 08 Jan 2024 09:03
Date Deposited: 19 Mar 2019 13:25
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
https://www.sci ... 8263?via%3Dihub (Publisher URL)
PURE Output Type: Article
Published Date: 2010-11-04
Authors: Gonzalez, Ana Maria
Leadbeater, Wendy (ORCID Profile 0000-0003-3141-9421)
Podvin, Sonia
Borboa, Alexandra
Burg, Michael
Sawada, Ritsuko
Rayner, James
Sims, Karen
Terasaki, Tetsuya
Johanson, Conrad
Stopa, Edward
Eliceiri, Brian
Baird, Andrew

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