Transduction patterns in the CNS following various routes of AAV-5-mediated gene delivery.

Autor: Pietersz KL; Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands.; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Faculty of Science, Radboud University, Nijmegen, the Netherlands., Martier RM; Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands.; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands., Baatje MS; Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands., Liefhebber JM; Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands., Brouwers CC; Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands., Pouw SM; Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands., Fokkert L; Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands., Lubelski J; Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands., Petry H; Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands., Martens GJM; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Faculty of Science, Radboud University, Nijmegen, the Netherlands., van Deventer SJ; Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands.; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands., Konstantinova P; Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands. P.konstantinova@uniqure.com., Blits B; Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands.; Blits Biopharma Consultancy and DegenRx BV, Amsterdam, the Netherlands.
Jazyk: angličtina
Zdroj: Gene therapy [Gene Ther] 2021 Aug; Vol. 28 (7-8), pp. 435-446. Date of Electronic Publication: 2020 Aug 15.
DOI: 10.1038/s41434-020-0178-0
Abstrakt: Various administration routes of adeno-associated virus (AAV)-based gene therapy have been examined to target the central nervous system to answer the question what the most optimal delivery route is for treatment of the brain with certain indications. In this study, we evaluated AAV5 vector system for its capability to target the central nervous system via intrastriatal, intrathalamic or intracerebroventricular delivery routes in rats. AAV5 is an ideal candidate for gene therapy because of its relatively low level of existing neutralizing antibodies compared to other serotypes, and its broad tissue and cell tropism. Intrastriatal administration of AAV5-GFP resulted in centralized localized vector distribution and expression in the frontal part of the brain. Intrathalamic injection showed transduction and gradient expression from the rostral brain into lumbar spinal cord, while intracerebroventricular administration led to a more evenly, albeit relatively superficially distributed, transduction and expression throughout the central nervous system. To visualize the differences between localized and intra-cerebral spinal fluid administration routes, we compared intrastriatal to intracerebroventricular and intrathecal administration of AAV5-GFP. Together, our results demonstrate that for efficient transgene expression, various administration routes can be applied.
(© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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