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Engineering Viral Vectors for Acoustically Targeted Gene Delivery

Li, Hongyi and Heath, John E and Trippett, James S. and Shapiro, Mikhail G. and Szablowski, Jerzy O. (2021) Engineering Viral Vectors for Acoustically Targeted Gene Delivery. . (Unpublished)

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Targeted gene delivery to the brain is a critical tool for neuroscience research and has significant potential to treat human disease. However, the site-specific delivery of common gene vectors such as adeno-associated viruses (AAVs) is typically performed via invasive injections, limiting their scope of research and clinical applications. Alternatively, focused ultrasound blood-brain-barrier opening (FUS-BBBO), performed noninvasively, enables the site-specific entry of AAVs into the brain from systemic circulation. However, when used in conjunction with natural AAV serotypes, this approach has limited transduction efficiency, requires ultrasound parameters close to tissue damage limits, and results in undesirable transduction of peripheral organs. Here, we use high throughput in vivo selection to engineer new AAV vectors specifically designed for local neuronal transduction at the site of FUS-BBBO. The resulting vectors substantially enhance ultrasound-targeted gene delivery and neuronal tropism while reducing peripheral transduction, providing a more than ten-fold improvement in targeting specificity. In addition to enhancing the only known approach to noninvasively target gene delivery to specific brain regions, these results establish the ability of AAV vectors to be evolved for specific physical delivery mechanisms.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Li, Hongyi0000-0001-6970-0230
Heath, John E0000-0002-5004-2693
Trippett, James S.0000-0003-4883-6547
Shapiro, Mikhail G.0000-0002-0291-4215
Szablowski, Jerzy O.0000-0001-7851-5408
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This version posted July 27, 2021. The authors thank Drs. Benjamin Deverman, Nicholas Flytzanis, Nicholas Goeden, and Viviana Gradinaru, and the CLOVER center at Caltech for helpful discussions. This research was supported by the National Institutes of Health (grant UG3MH120102 to MGS), the Jacobs Institute for Molecular Engineering in Medicine and the Sontag Foundation, and 2019 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation (grant 27737 to JOS). Related work in the Shapiro Lab is supported by the David and Lucille Packard Foundation and the Heritage Medical Research Institute and in Szablowski lab by The G. Harold and Leila Y. Mathers Charitable Foundation. JEH acknowledges support from Rose Hills foundation and Barry Goldwater Scholarship. The authors have declared no competing interest.
Group:Heritage Medical Research Institute, Jacobs Institute for Molecular Engineering for Medicine
Funding AgencyGrant Number
Jacobs Institute for Molecular Engineering for MedicineUNSPECIFIED
Sontag FoundationUNSPECIFIED
Brain and Behavior Research Foundation27737
David and Lucille Packard FoundationUNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
G. Harold and Leila Y. Mathers Charitable FoundationUNSPECIFIED
Rose Hills FoundationUNSPECIFIED
Barry Goldwater ScholarshipUNSPECIFIED
Record Number:CaltechAUTHORS:20210729-152223015
Persistent URL:
Official Citation:Engineering Viral Vectors for Acoustically Targeted Gene Delivery. Hongyi Li, John E. Heath, James S. Trippett, Mikhail G. Shapiro, Jerzy O. Szablowski. bioRxiv 2021.07.26.453904; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110062
Deposited By: Tony Diaz
Deposited On:02 Aug 2021 19:04
Last Modified:16 Nov 2021 19:39

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