GDNF-based therapy for Hirschsprung disease
Hirschsprung disease (HSCR) is a deadly birth defect affecting 1/5000 children. These children are missing innervation from the enteric nervous system (ENS), resulting in severe constipation and a high risk of bacterial translocation into blood causing premature death. Surgery to remove ENS-devoid bowel is generally life-saving but many children with HSCR continue to have severe problems after surgery. Ideally, a “regenerative medicine” approach that causes the ENS to form in post-natal aganglionic bowel would prevent the need for surgery.
This projects builds on our amazing discovery that postnatal administration of the GDNF protein, which normally stimulates ENS formation during prenatal development, prolongs survival of HSCR mouse models by inducing the formation of a new ENS. Yet, some mice are less responsive than others, suggesting that there is room for improvement. The goal of this project is to identify new molecules that could improve GDNF-based therapy. Identifying the optimal conditions in mice is key before embarking on human clinical trials, which is the goal of our collaboration with Aligo Innovation.