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133950 - AAV9-mediated central nervous system-targeted gene delivery.pdf (3.65 MB)
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AAV9-mediated central nervous system-targeted gene delivery via cisterna magna route in mice

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journal contribution
posted on 2023-05-20, 05:38 authored by Lukashchuk, V, Katherine LewisKatherine Lewis, Coldicott, I, Grierson, AJ, Azzouz, M
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.


Publication title

Molecular Therapy - Methods & Clinical Development

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Menzies Institute for Medical Research


Elsevier BV

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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)

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  • Open

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Clinical health not elsewhere classified; Clinical health not elsewhere classified

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