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

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Abstract

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.

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Chuapoco, M. R., Flytzanis, N. C., Goeden, N., Christopher Octeau, J., Roxas, K. M., Chan, K. Y., … Gradinaru, V. (2023). Adeno-associated viral vectors for functional intravenous gene transfer throughout the non-human primate brain. Nature Nanotechnology, 18(10), 1241–1251. https://doi.org/10.1038/s41565-023-01419-x

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