Engineered AAVs for non-invasive gene delivery to rodent and non-human primate nervous systems

• DOI: 10.1016/j.neuron.2022.05.003
• Publication Date: 2022-05-27T14:48:09Z
• Authors: Xinhong Chen; Sripriya Ravindra...; Cameron D. Adams; Daping Yang; Tongtong Wang; Damien A. Wolfe; Cynthia M. Arokiaraj; Victoria Ngo; Lillian J. Campos; Jessica A. Griffiths; Takako Ichiki; Sarkis K. Mazmanian; Peregrine B. Osborne; Janet R. Keast; Cory T. Miller; Andrew S. Fox; Isaac M. Chiu; Viviana Gradinaru
• Keywords: Central Nervous System; 0301 basic medicine; 570; functional modulation; Medical Biotechnology; Genetic Vectors; 610; PNS; non-human primate; Rodentia; cross-species; Transduction; Mice; 03 medical and health sciences; Genetic; Transduction, Genetic; Genetics; Psychology; Animals; 0303 health sciences; Neurology & Neurosurgery; Biomedical and Clinical Sciences; General Neuroscience; Pain Research; Neurosciences; Gene Transfer Techniques; AAV; Gene Therapy; Genetic Therapy; Dependovirus; gene therapy; Macaca mulatta; functional readout; Rats; 3. Good health; Neurological; Biological psychology; Cognitive Sciences; CNS; Biotechnology

Gene therapy offers great promise in addressing neuropathologies associated with the central and peripheral nervous systems (CNS and PNS). However, genetic access remains difficult, reflecting the critical need for the development of effective and non-invasive gene delivery vectors across species. To that end, we evolved adeno-associated virus serotype 9 (AAV9) capsid in mice 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 the following: (1) the neuronal sensor jGCaMP8s to record calcium signal dynamics in nodose ganglia and (2) the neuronal actuator DREADD to dorsal root ganglia to mediate pain. This conclusively demonstrates the translatability of these two systemic AAVs across four species and their functional utility through proof-of-concept studies in mice.