Systemic gene delivery transduces the enteric nervous system of guinea pigs and cynomolgus macaques

• Published in: Gene therapy Vol. 24; no. 10; pp. 640 - 648
• Main Authors: Gombash, S E, Cowley, C J, Fitzgerald, J A, Lepak, C A, Neides, M G, Hook, K, Todd, L J, Wang, G-D, Mueller, C, Kaspar, B K, Bielefeld, E C, Fischer, A J, Wood, J D, Foust, K D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2017; Nature Publishing Group
• Subjects: 14/35; 42/34; 631/1647/2300; 631/378/1959; 631/378/1959/1315/1951; 631/378/87; 692/700/565/201; 82/51; 82/80; Anatomy; Animal tissues; Animals; Biomedical and Life Sciences; Biomedicine; Cell Biology; Dependovirus - genetics; Digestive system; Dorsal root ganglia; Dosage and administration; Enteric nervous system; Enteric Nervous System - metabolism; Expression vectors; Female; Ganglia, Spinal - cytology; Ganglia, Spinal - metabolism; Gastrointestinal tract; Gene Expression; Gene Therapy; Gene transfer; Gene Transfer Techniques; Genetic modification; Genetic Therapy - methods; Genetic Vectors - genetics; Genetics; Genome editing; Green fluorescent protein; Green fluorescent proteins; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Guinea Pigs; Human Genetics; Information processing; Injection; Injections, Intravenous; Intravenous administration; Intravenous injections; Large intestine; Macaca fascicularis; Macaques; Male; Motor nuclei; Nanotechnology; Neonates; Nervous system; Neurons; Neurons - metabolism; Optics; original-article; Phosphates; Primates; Rats; Rodents; Stomach; Vagus Nerve - metabolism; Guinea
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2017.72

Characterization of adeno-associated viral vector (AAV) mediated gene delivery to the enteric nervous system (ENS) was recently described in mice and rats. In these proof-of-concept experiments, we show that intravenous injections of clinically relevant AAVs can transduce the ENS in guinea pigs and non-human primates. Neonatal guinea pigs were given intravenous injections of either AAV8 or AAV9 vectors that contained a green fluorescent protein (GFP) expression cassette or phosphate-buffered saline. Piglets were euthanized three weeks post injection and tissues were harvested for immunofluorescent analysis. GFP expression was detected in myenteric and submucosal neurons along the length of the gastrointestinal tract in AAV8 injected guinea pigs. GFP-positive neurons were found in dorsal motor nucleus of the vagus and dorsal root ganglia. Less transduction occurred in AAV9-treated tissues. Gastrointestinal tissues were analyzed from young cynomolgus macaques that received systemic injection of AAV9 GFP. GFP expression was detected in myenteric neurons of the stomach, small and large intestine. These data demonstrate that ENS gene delivery translates to larger species. This work develops tools for the field of neurogastroenterology to explore gut physiology and anatomy using emerging technologies such as optogenetics and gene editing. It also provides a basis to develop novel therapies for chronic gut disorders.