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In vivo high-throughput screening of novel adeno-associated viral capsids targeting adult neural stem cells in the subventricular zone

Sascha Dehler, Lukas PM Kremer, Santiago Cerrizuela, Thomas Stiehl, Jonas Weinmann, Heike Abendroth, Susanne Kleber, Alexander Laure, Jihad El Andari, Simon Anders, Anna Marciniak-Czochra, View ORCID ProfileDirk Grimm, Ana Martin-Villalba
doi: https://doi.org/10.1101/2021.03.05.434064
Sascha Dehler
1Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Lukas PM Kremer
1Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
5Center for Molecular Biology of Heidelberg University (ZMBH), 69120 Heidelberg, Germany
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Santiago Cerrizuela
1Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Thomas Stiehl
4Institute of Applied Mathematics, Interdisciplinary Center for Scientific Computing and BioQuant, Heidelberg University, 69120 Heidelberg, Germany
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Jonas Weinmann
2Virus-Host Interaction Group, Department of Infectious Diseases/Virology, Heidelberg University Hospital, Cluster of Excellence Cell Networks, BioQuant, 69120 Heidelberg, Germany
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Heike Abendroth
1Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Susanne Kleber
1Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Alexander Laure
1Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Jihad El Andari
2Virus-Host Interaction Group, Department of Infectious Diseases/Virology, Heidelberg University Hospital, Cluster of Excellence Cell Networks, BioQuant, 69120 Heidelberg, Germany
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Simon Anders
5Center for Molecular Biology of Heidelberg University (ZMBH), 69120 Heidelberg, Germany
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Anna Marciniak-Czochra
4Institute of Applied Mathematics, Interdisciplinary Center for Scientific Computing and BioQuant, Heidelberg University, 69120 Heidelberg, Germany
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Dirk Grimm
2Virus-Host Interaction Group, Department of Infectious Diseases/Virology, Heidelberg University Hospital, Cluster of Excellence Cell Networks, BioQuant, 69120 Heidelberg, Germany
3German Center for Infection Research (DZIF) and German Center for Cardiovascular Research (DZHK), partner site Heidelberg, 69120 Heidelberg, Germany
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  • ORCID record for Dirk Grimm
Ana Martin-Villalba
1Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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  • For correspondence: a.martin-villalba@dkfz.de
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Abstract

The adult mammalian brain entails a reservoir of neural stem cells (NSCs) generating glial cells and neurons. However, NSCs become increasingly quiescent with age, which hampers their regenerative capacity. New means are therefore required to genetically modify adult NSCs for re-enabling endogenous brain repair. Recombinant adeno-associated viruses (AAVs) are ideal gene therapy vectors due to an excellent safety profile and high transduction efficiency. We thus conducted a high-throughput screening of 177 intraventricularly injected barcoded AAV variants profiled by RNA sequencing. Quantification of barcoded AAV mRNAs identified two synthetic capsids, AAV9_A2 and AAV1_P5, both of which transduce active and quiescent NSCs. Further optimization of AAV1_P5 by judicious selection of promoter and dose of injected viral genomes enabled labeling of 30-60% of the NSC compartment, which was validated by FACS analyses and single cell RNA sequencing. Importantly, transduced NSC readily produced neurons. The present study identifies AAV variants with a high regional tropism towards the v-SVZ with high efficiency in targeting adult NSCs, thereby paving the way for preclinical testing of regenerative gene therapy.

Competing Interest Statement

D.G. is a co-founder and shareholder of AaviGen GmbH. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 05, 2021.
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In vivo high-throughput screening of novel adeno-associated viral capsids targeting adult neural stem cells in the subventricular zone
Sascha Dehler, Lukas PM Kremer, Santiago Cerrizuela, Thomas Stiehl, Jonas Weinmann, Heike Abendroth, Susanne Kleber, Alexander Laure, Jihad El Andari, Simon Anders, Anna Marciniak-Czochra, Dirk Grimm, Ana Martin-Villalba
bioRxiv 2021.03.05.434064; doi: https://doi.org/10.1101/2021.03.05.434064
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In vivo high-throughput screening of novel adeno-associated viral capsids targeting adult neural stem cells in the subventricular zone
Sascha Dehler, Lukas PM Kremer, Santiago Cerrizuela, Thomas Stiehl, Jonas Weinmann, Heike Abendroth, Susanne Kleber, Alexander Laure, Jihad El Andari, Simon Anders, Anna Marciniak-Czochra, Dirk Grimm, Ana Martin-Villalba
bioRxiv 2021.03.05.434064; doi: https://doi.org/10.1101/2021.03.05.434064

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