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.

穿越灵长类动物的血脑屏障是基因传递到大脑的主要障碍。腺相关病毒 (AAV) 有望实现从血流到大脑的稳健、非侵入性基因传递。然而，与啮齿类动物不同，在非人类灵长类动物中，很少有神经性 AAV 能够有效地穿过血脑屏障。在这里，我们报告了 AAV.CAP-Mac，这是一种通过在成年狨猴和新生猕猴中筛选而发现的工程变体，它提高了多种非人类灵长类动物（狨猴、恒河猴和绿猴）大脑中的传递效率。 CAP-Mac 在旧大陆灵长类动物中具有神经元偏向性，在成年恒河猴中表现出广泛的趋向性，在成年狨猴中具有脉管系统偏向性。我们演示了单次静脉注射 CAP-Mac 的应用，以提供功能性 GCaMP，用于跨多个大脑区域的离体钙成像，或使用荧光报告基因混合物，在整个猕猴大脑中进行类似 Brainbow 的标记，从而避免了种系操作的需要。旧大陆灵长类动物。因此，CAP-Mac 被证明具有在非人类灵长类动物大脑中进行非侵入性系统基因转移的潜力。