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Broad gene expression throughout the mouse and marmoset brain after intravenous delivery of engineered AAV capsids

Flytzanis, Nicholas C. and Goeden, Nick and Goertsen, David and Cummins, Alexander and Pickel, James and Gradinaru, Viviana (2020) Broad gene expression throughout the mouse and marmoset brain after intravenous delivery of engineered AAV capsids. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20200626-103613335

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Abstract

Genetic intervention is increasingly explored as a therapeutic option for debilitating disorders of the central nervous system. The safety and efficacy of gene therapies relies upon expressing a transgene in affected cells while minimizing off-target expression. To achieve organ/cell-type specific targeting after intravenous delivery of viral vectors, we employed a Cre-transgenic-based screening platform for fast and efficient capsid selection, paired with sequential engineering of multiple surface-exposed loops. We identified capsid variants that are enriched in the brain and detargeted from the liver in mice. The improved enrichment in the brain extends to non-human primates, enabling robust, non-invasive gene delivery to the marmoset brain following IV administration. Importantly, the capsids identified display non-overlapping cell-type tropisms within the brain, with one exhibiting high specificity to neurons. The ability to cross the blood–brain barrier with cell-type specificity in rodents and non-human primates enables new avenues for basic research and potential therapeutic interventions unattainable with naturally occurring serotypes.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2020.06.16.152975DOIDiscussion Paper
ORCID:
AuthorORCID
Flytzanis, Nicholas C.0000-0002-7921-9392
Goertsen, David0000-0001-7138-1697
Pickel, James0000-0002-3617-3072
Gradinaru, Viviana0000-0001-5868-348X
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. We thank B. Deverman for helpful discussions on experimental design and implementation. We wish to thank the entire Gradinaru laboratory for helpful discussions. We are grateful to I. Antoshechkin and the Millar and Muriel Jacobs Genetics and Genomics Core at Caltech for assistance with next generation sequencing. We thank M. Smith for helpful discussions and assistance with the bioinformatics pipeline. This work was primarily supported by Defense Advanced Research Projects Agency grant W911NF-17-2-0036 to V.G. and grants from the National Institutes of Health (NIH) to V.G.: Director’s New Innovator DP2NS087949 and PECASE, and BRAIN R01MH117069 and NIH Pioneer DP1OD025535. In addition, this work is funded by the Beckman Institute at Caltech, the Vallee Foundation, and the Moore Foundation. V.G. is a Heritage Principal Investigator supported by the Heritage Medical Research Institute. Data availability: All constructs and tools will be available through Addgene and the Beckman Institute CLOVER center: clover.caltech.edu. The data that support the findings of this study are available from the corresponding author upon request. Competing Interest Statement: The California Institute of Technology has filed and licensed patent applications for the work described in this manuscript with N.C.F., N.G., and V.G. listed as inventors.
Group:Heritage Medical Research Institute
Funders:
Funding AgencyGrant Number
Defense Advanced Research Projects Agency (DARPA)W911NF-17-2-0036
NIHDP2NS087949
NIHR01MH117069
NIHDP1OD025535
Caltech Beckman InstituteUNSPECIFIED
Vallee FoundationUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
Record Number:CaltechAUTHORS:20200626-103613335
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200626-103613335
Official Citation:Broad gene expression throughout the mouse and marmoset brain after intravenous delivery of engineered AAV capsids Nicholas C. Flytzanis, Nick Goeden, David Goertsen, Alexander Cummins, James Pickel, Viviana Gradinaru bioRxiv 2020.06.16.152975; doi: https://doi.org/10.1101/2020.06.16.152975
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104080
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:26 Jun 2020 20:10
Last Modified:26 Jun 2020 20:10

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