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

Gene Therapy volume 28, pages 435–446 (2021)Cite this article

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Abstract

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.

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Fig. 1: Overview of injection routes.
Fig. 2: Vector distribution and GFP expression following various cerebral administration routes of AAV5-GFP in rats.
Fig. 3: GFP expression throughout the rat brain following intrastriatal (IStr), intracerebroventricular (ICV), or intrathecal (IT) administration of AAV5-GFP.
Fig. 4: GFP expression in cortex and striatum in rat brain following intrastriatal (IStr), intracerebroventricular (ICV), or intrathecal (IT) administration of AAV5-GFP.
Fig. 5: GFP expression in the hippocampal area in rat brain intrastriatal (IStr), intracerebroventricular (ICV), or intrathecal (IT) administration of AAV5-GFP.
Fig. 6: GFP staining in the midbrain area and cerebellum in rat brain following intrastriatal (IS), intracerebroventricular (ICV), or intrathecal (IT) administration of AAV5-GFP.
Fig. 7: GFP staining in the spinal cord and the dorsal root ganglion of intracerebroventricular (ICV) and intrathecal (IT) administered AAV5 rats.

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Acknowledgements

The authors would like thank E. Broug and E. Sawyer for critically reviewing this manuscript.

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Author notes

  1. B. Blits

    Present address: Blits Biopharma Consultancy and DegenRx BV, Amsterdam, the Netherlands

  2. These authors contributed equally: K. L. Pietersz, R. M. Martier

Authors and Affiliations

  1. Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands

    K. L. Pietersz, R. M. Martier, M. S. Baatje, J. M. Liefhebber, C. C. Brouwers, S. M. Pouw, L. Fokkert, J. Lubelski, H. Petry, S. J. van Deventer, P. Konstantinova & B. Blits

  2. Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Faculty of Science, Radboud University, Nijmegen, the Netherlands

    K. L. Pietersz & G. J. M. Martens

  3. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands

    R. M. Martier & S. J. van Deventer

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Pietersz, K.L., Martier, R.M., Baatje, M.S. et al. Transduction patterns in the CNS following various routes of AAV-5-mediated gene delivery. Gene Ther 28, 435–446 (2021). https://doi.org/10.1038/s41434-020-0178-0

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