Nature Nanotechnology ( IF 40.523 ) Pub Date : 2023-07-10 , DOI:
10.1038/s41565-023-01419-xMiguelRChuapoco,NicholasCFlytzanis,NickGoeden,JChristopherOcteau,KristinaMRoxas,KenYChan,JonScherrer,JanetWinchester,RoyJBlackburn,LillianJCampos,KwunNokMimiMan,JunqingSun,XinhongChen,ArthurLefevre,VikramPalSingh,CynthiaMArokiaraj,TimothyFShay,JuliaVendemiatti,MinJJang,JohnKMich,YemeserachBishaw,BryanBGore,VictoriaOmstead,NazTaskin,NatalieWeed,BoazPLevi,JonathanTTing,CoryTMiller,BenjaminEDeverman,JamesPickel,LinTian,AndrewSFox,VivianaGradinaru
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.