Engineered AAVs for Non-Invasive Functional Transgene Expression in Rodent and Non-Human Primate Central and Peripheral Nervous Systems

Gene therapy offers promise in addressing neuropathologies associated with the central and peripheral nervous systems (CNS, PNS). However, genetic access remains difficult, reflecting the need for development of effective and non-invasive gene delivery vectors across species. To that end, we evolved adeno-associated viral (AAV) capsid, serotype-9, in mouse models, and validated two capsids, AAV-MaCPNS1 and AAV-MaCPNS2, across rodent species (mice and rats) and non-human primate (NHP) species (marmosets and rhesus macaques). Intravenous administration of either AAV efficiently transduced the PNS in rodents, and both the PNS and CNS in NHPs. Furthermore, we used AAV-MaCPNS1 in mice to systemically deliver: (1) the neuronal sensor GCaMP8s to record calcium signal dynamics in nodose ganglia and evaluate vagal function in a gastric assay, and (2) the neuronal actuator DREADD to dorsal root ganglia and mediate pain. This conclusively demonstrates the translatability of these two systemic AAVs across four species, and their functional utility.