Adeno-associated viral vectors for functional intravenous gene transfer throughout the non-human primate brain

• Published in: Nature nanotechnology Vol. 18; no. 10; pp. 1241 - 1251
• Main Authors: Chuapoco, Miguel R., Flytzanis, Nicholas C., Goeden, Nick, Christopher Octeau, J., Roxas, Kristina M., Chan, Ken Y., Scherrer, Jon, Winchester, Janet, Blackburn, Roy J., Campos, Lillian J., Man, Kwun Nok Mimi, Sun, Junqing, Chen, Xinhong, Lefevre, Arthur, Singh, Vikram Pal, Arokiaraj, Cynthia M., Shay, Timothy F., Vendemiatti, Julia, Jang, Min J., Mich, John K., Bishaw, Yemeserach, Gore, Bryan B., Omstead, Victoria, Taskin, Naz, Weed, Natalie, Levi, Boaz P., Ting, Jonathan T., Miller, Cory T., Deverman, Benjamin E., Pickel, James, Tian, Lin, Fox, Andrew S., Gradinaru, Viviana
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2023; Nature Publishing Group
• Subjects: 631/61; 631/61/350; 631/61/350/59; Animals; Blood-brain barrier; Brain; Brain - physiology; Calcium imaging; Callithrix - genetics; Chemistry and Materials Science; Chlorocebus aethiops; Expression vectors; Fluorescence; Gene sequencing; Gene transfer; Gene Transfer Techniques; Genetic Vectors - genetics; Humans; Infant, Newborn; Intravenous administration; Labeling; Macaca mulatta - genetics; Materials Science; Monkeys & apes; Nanotechnology; Nanotechnology and Microengineering; Neuroimaging; Neurons; Primates; Tropism
• ISSN: 1748-3387; 1748-3395
• DOI: 10.1038/s41565-023-01419-x

Crossing the blood–brain barrier in primates is a major obstacle for gene delivery to the brain. Adeno-associated viruses (AAVs) promise robust, non-invasive gene delivery from the bloodstream to the brain. However, unlike in rodents, few neurotropic AAVs efficiently cross the blood–brain barrier in non-human primates. Here we report on AAV.CAP-Mac, an engineered variant identified by screening in adult marmosets and newborn macaques, which has improved delivery efficiency in the brains of multiple non-human primate 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 functional GCaMP for ex vivo calcium imaging across multiple brain areas, or a cocktail of fluorescent reporters for Brainbow-like labelling throughout the macaque brain, circumventing the need for germline manipulations in Old World primates. As such, CAP-Mac is shown to have potential for non-invasive systemic gene transfer in the brains of non-human primates. Crossing the blood–brain barrier in primates is a major obstacle to gene delivery in the brain. Here an adeno-associated virus variant (AAV.CAP-Mac) is identified and demonstrated for crossing the blood–brain barrier and delivering gene sequences to the brain of different non-human primates species.