Enteric Nervous System Transduction of Different AAV Serotypes Following Intravenous Injection

Functional gastrointestinal disorders (FGID) affect 1 in 4 Americans and are likely caused by dysfunction of the enteric nervous system (ENS). The chronic nature of FGID suggests gene therapy is a promising form of treatment and can be used to treat diseases such as Hirschrprung’s disease. In this study, we characterized transduction efficiency and distribution in the mouse myenteric plexus following intravenous (IV) injection of adeno-associated viral vectors (AAV) expressing green fluorescent protein (GFP). Neonatal (P1) mice were injected with AAV9 in the temporal vein and juvenile mice (P21) were injected in the tail vein. Mice were euthanized at 60-90 days of age, and the myenteric plexus was examined. Immunohistochemical labeling of the myenteric plexus revealed GFP presence along the entire GI tract in injected mice. Neuronal transduction ranged from 21-57% depending on vector dose and GI region analyzed. GFP co-localized with interneurons, excitatory and sensory myenteric neurons while GFP expression was absent in VIP, nNOS and glial cells. Neonate IV injections with AAV1, 5, and 6 containing GFP produced little to no transgene expression in the myenteric plexus. However, AAV8 showed significantly higher neuronal transduction compared to AAV9 injected mice. Collectively, these data demonstrate that enteric neurons are efficiently transduced by AAV8 and AAV9 following IV delivery. Thus, AAV8 and AAV9 can be used as possible treatments for ENS dysfunction by the expression of a transgene.College of Arts and SciencesOffice of Undergraduate ResearchNo embargoAcademic Major: Neuroscienc