Intravenous functional gene transfer throughout the brain of non-human primates using AAV

Miguel R Chuapoco; Nicholas C Flytzanis; Nick Goeden; J Christopher Octeau; Kristina M Roxas; Ken Y Chan; Jon Scherrer; Janet Winchester; Roy J Blackburn; Lillian J Campos; Kwun Nok Mimi Man; Junqing Sun; Xinhong Chen; Arthur Lefevre; Vikram Pal Singh; Cynthia M Arokiaraj; Timothy F Shaya; Julia Vendemiatti; Min J Jang; John Mich; Yeme Bishaw; Bryan Gore; Victoria Omstead; Naz Taskin; Natalie Weed; Jonathan Ting; Cory T Miller; Benjamin E Deverman; James Pickel; Lin Tian; Andrew S Fox; Viviana Gradinaru

doi:10.21203/rs.3.rs-1370972/v1

Intravenous functional gene transfer throughout the brain of non-human primates using AAV

Res Sq [Preprint]. 2023 Jan 13:rs.3.rs-1370972. doi: 10.21203/rs.3.rs-1370972/v1.

Authors

Miguel R Chuapoco¹, Nicholas C Flytzanis^{1

2

3}, Nick Goeden^{1

2

3}, J Christopher Octeau², Kristina M Roxas², Ken Y Chan^{1

4}, Jon Scherrer², Janet Winchester², Roy J Blackburn², Lillian J Campos⁵, Kwun Nok Mimi Man⁵, Junqing Sun⁵, Xinhong Chen¹, Arthur Lefevre⁶, Vikram Pal Singh⁶, Cynthia M Arokiaraj¹, Timothy F Shaya¹, Julia Vendemiatti¹, Min J Jang¹, John Mich⁷, Yeme Bishaw⁷, Bryan Gore⁷, Victoria Omstead⁷, Naz Taskin⁷, Natalie Weed⁷, Jonathan Ting⁷, Cory T Miller⁶, Benjamin E Deverman^{1

4}, James Pickel⁶, Lin Tian^{5

8}, Andrew S Fox^{5

8}, Viviana Gradinaru^{1

8}

Affiliations

¹ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
² Capsida Biotherapeutics, Thousand Oaks, CA 91320, USA.
³ Present address: Capsida Biotherapeutics, Thousand Oaks, CA 91320, USA.
⁴ Present address: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁵ Department of Psychology and the California National Primate Research Center, University of California-Davis, Davis, CA 95616, USA.
⁶ Cortical Systems and Behavior Laboratory, University of California-San Diego, La Jolla, CA 92039, USA.
⁷ Allen Institute for Brain Science, Seattle, WA, 98109, USA.
⁸ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815.

Abstract

Adeno-associated viruses (AAVs) promise robust gene delivery to the brain through non-invasive, intravenous delivery. However, unlike in rodents, few neurotropic AAVs efficiently cross the blood-brain barrier in non-human primates (NHPs). Here we describe AAV.CAP-Mac, an engineered variant identified by screening in adult marmosets and newborn macaques with improved efficiency in the brain of multiple NHP species: marmoset, rhesus macaque, and green monkey. CAP-Mac is neuron-biased in infant Old World primates, exhibits broad tropism in adult rhesus macaques, and is vasculature-biased in adult marmosets. We demonstrate applications of a single, intravenous dose of CAP-Mac to deliver (1) functional GCaMP for ex vivo calcium imaging across multiple brain areas, and (2) a cocktail of fluorescent reporters for Brainbow-like labeling throughout the macaque brain, circumventing the need for germline manipulations in Old World primates. Given its capabilities for systemic gene transfer in NHPs, CAP-Mac promises to help unlock non-invasive access to the brain.

Publication types

Preprint

Abstract

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