Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates

Xinhong Chen, Damien A. Wolfe, Dhanesh Sivadasan Bindu, Mengying Zhang, Naz Taskin, David Goertsen, Timothy F. Shay, Erin E. Sullivan, Sheng-Fu Huang, Sripriya Ravindra Kumar, Cynthia M. Arokiaraj, Viktor M. Plattner, Lillian J. Campos, John K. Mich, Deja Monet, Victoria Ngo, Xiaozhe Ding, Victoria Omstead, Natalie Weed, Yeme Bishaw, Bryan B. Gore, Ed S. Lein, Athena Akrami, Cory Miller, Boaz P. Levi, Annika Keller, Jonathan T. Ting, Andrew S. Fox, Cagla Eroglu and Viviana Gradinaru ()
Additional contact information
Xinhong Chen: California Institute of Technology
Damien A. Wolfe: California Institute of Technology
Dhanesh Sivadasan Bindu: Duke University Medical Center
Mengying Zhang: California Institute of Technology
Naz Taskin: Allen Institute for Brain Science
David Goertsen: California Institute of Technology
Timothy F. Shay: California Institute of Technology
Erin E. Sullivan: California Institute of Technology
Sheng-Fu Huang: Zürich University Hospital, University of Zürich
Sripriya Ravindra Kumar: California Institute of Technology
Cynthia M. Arokiaraj: California Institute of Technology
Viktor M. Plattner: University College London
Lillian J. Campos: University of California, Davis
John K. Mich: Allen Institute for Brain Science
Deja Monet: Allen Institute for Brain Science
Victoria Ngo: University of California San Diego
Xiaozhe Ding: California Institute of Technology
Victoria Omstead: Allen Institute for Brain Science
Natalie Weed: Allen Institute for Brain Science
Yeme Bishaw: Allen Institute for Brain Science
Bryan B. Gore: Allen Institute for Brain Science
Ed S. Lein: Allen Institute for Brain Science
Athena Akrami: University College London
Cory Miller: University of California San Diego
Boaz P. Levi: Allen Institute for Brain Science
Annika Keller: Zürich University Hospital, University of Zürich
Jonathan T. Ting: Allen Institute for Brain Science
Andrew S. Fox: University of California, Davis
Cagla Eroglu: Duke University Medical Center
Viviana Gradinaru: California Institute of Technology

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Delivering genes to and across the brain vasculature efficiently and specifically across species remains a critical challenge for addressing neurological diseases. We have evolved adeno-associated virus (AAV9) capsids into vectors that transduce brain endothelial cells specifically and efficiently following systemic administration in wild-type mice with diverse genetic backgrounds, and in rats. These AAVs also exhibit superior transduction of the CNS across non-human primates (marmosets and rhesus macaques), and in ex vivo human brain slices, although the endothelial tropism is not conserved across species. The capsid modifications translate from AAV9 to other serotypes such as AAV1 and AAV-DJ, enabling serotype switching for sequential AAV administration in mice. We demonstrate that the endothelial-specific mouse capsids can be used to genetically engineer the blood-brain barrier by transforming the mouse brain vasculature into a functional biofactory. We apply this approach to Hevin knockout mice, where AAV-X1-mediated ectopic expression of the synaptogenic protein Sparcl1/Hevin in brain endothelial cells rescued synaptic deficits.

Date: 2023
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DOI: 10.1038/s41467-023-38582-7

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