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

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.

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. Shay, Julia Vendemiatti, Min J. Jang, John K. Mich, Yemeserach Bishaw, Bryan B. Gore, Victoria Omstead, Naz Taskin, Natalie Weed, Boaz P. Levi, Jonathan T. Ting, Cory T. Miller, Benjamin E. Deverman, James Pickel, Lin Tian, Andrew S. Fox, Viviana Gradinaru