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

Ana Maria Gonzalez, Wendy Leadbeater, Sonia Podvin, Alexandra Borboa, Michael Burg, Ritsuko Sawada, James Rayner, Karen Sims, Tetsuya Terasaki, Conrad Johanson, Edward Stopa, Brian Eliceiri, Andrew Baird*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalBrain Research
Volume1359
DOIs
Publication statusPublished - 4 Nov 2010

Bibliographical note

© 2010, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/

Keywords

  • Cerebrospinal fluid
  • Endocytosis
  • Epidermal growth factor
  • Epithelial cell
  • Gene delivery
  • Phage

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    Gonzalez, A. M., Leadbeater, W., Podvin, S., Borboa, A., Burg, M., Sawada, R., Rayner, J., Sims, K., Terasaki, T., Johanson, C., Stopa, E., Eliceiri, B., & Baird, A. (2010). Epidermal growth factor targeting of bacteriophage to the choroid plexus for gene delivery to the central nervous system via cerebrospinal fluid. Brain Research, 1359, 1-13. https://doi.org/10.1016/j.brainres.2010.08.044