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AAV9-mediated central nervous system-targeted gene delivery via cisterna magna route in mice


Lukashchuk, V and Lewis, KE and Coldicott, I and Grierson, AJ and Azzouz, M, AAV9-mediated central nervous system-targeted gene delivery via cisterna magna route in mice, Molecular Therapy - Methods & Clinical Development, 3 Article 15055. ISSN 2329-0501 (2016) [Refereed Article]


Copyright Statement

Copyright 2016 Official journal of the American Society of Gene & Cell Therapy. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

DOI: doi:10.1038/mtm.2015.55


Current barriers to the use of adeno-associated virus serotype 9 (AAV9) in clinical trials for treating neurological disorders are its high expression in many off-target tissues such as liver and heart, and lack of cell specificity within the central nervous system (CNS) when using ubiquitous promoters such as human cytomegalovirus (CMV) or chicken-β-actin hybrid (CAG). To enhance targeting the transgene expression in CNS cells, self-complementary (sc) AAV9 vectors, scAAV9-GFP vectors carrying neuronal Hb9 and synapsin 1, and nonspecific CMV and CAG promoters were constructed. We demonstrate that synapsin 1 and Hb9 promoters exclusively targeted neurons in vitro, although their strengths were up to 10-fold lower than that of CMV. In vivo analyses of mouse tissue after scAAV9-GFP vector delivery via the cisterna magna revealed a significant advantage of synapsin 1 promoter over both Hb9 variants in targeting neurons throughout the brain, since Hb9 promoters were driving gene expression mainly within the motor-related areas of the brain stem. In summary, this study demonstrates that cisterna magna administration is a safe alternative to intracranial or intracerebroventricular vector delivery route using scAAV9, and introduces a novel utility of the Hb9 promoter for the targeted gene expression for both in vivo and in vitro applications.

Item Details

Item Type:Refereed Article
Keywords:Adeno-associated virus, gene therapy, cisterna magna
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Central nervous system
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Lewis, KE (Dr Katherine Lewis)
ID Code:133950
Year Published:2016
Web of Science® Times Cited:30
Deposited By:Menzies Institute for Medical Research
Deposited On:2019-07-17
Last Modified:2019-08-08
Downloads:17 View Download Statistics

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