Adeno-associated viral vectors in neurogastroenterology: a novel versatile preclinical toolbox and a first step towards gene therapy.

The enteric nervous system (ENS) is an extensive nervous system in the gut wall that governs crucial gastrointestinal functions including motility, secretion and blood supply. Furthermore, the ENS interacts with the immune system to keep a delicate balance between fending of pathogens and keeping tolerance towards unharmful microbiota. Defects in the ENS can lead to potentially fatal diseases such as Hirschsprung's disease, in which a failure of ENS development leads to severe constipation in newborns. Subtler defects in ENS functioning can lead to functional bowel diseases, often associated with motility disorders. To study the impact of specific proteins or genes in these diseases, the generation and breeding of genetically altered animals is often required. This is time- consuming, labor-intensive and expensive. Moreover, ethical concerns may rise if the genetic alteration leads to breeding of permanently diseased animals. This project investigates the validity of adeno-associated viral vectors (AAV) as a tool to genetically alter cell types of interest, or specifically label them for advanced microscopical evaluation. AAV have shown proven merit in research in the central nervous system, but have been undervalued in the domain of neurogastroenterology. This project develops strategies in which AAV can be used not only to investigate genetic defects, but also to correct them, which is a necessary basis for (individualized) gene therapy approaches in ENS disorders.

Keywords:GASTROINTESTINAL PATHOLOGIES, ENTERIC NERVOUS SYSTEM, GASTRO-INTESTINAL MOTILITY, ADENO ASSOCIATED VIRUS

Disciplines:Systems biology, Gastro-enterology and hepatology, Morphological sciences