Grant: Project Grant

Hirschsprung disease (HSCR) is a potentially fatal congenital malformation where the enteric nervous system (ENS) is missing from the end of the bowel. Because the ENS controls patterns of intestinal contraction and relaxation, the segment without neurons remains constantly contracted, resulting in blockage and accumulation of fecal material (megacolon). The ENS also controls several other intestinal functions, explaining why children with HSCR have vomiting, growth failure and a high risk of dying from systemic bacterial infection. HSCR affects 1 in 5000 newborn infants and current treatment consists of painful surgical removal of the segment that lacks enteric neurons followed by re-connection of innervated bowel to the anus. Unfortunately, many children continue to have problems after HSCR surgery including life-threatening bowel inflammation (enterocolitis), stool leakage, constipation, bowel perforation, hospital re-admission and repeat surgery. A therapy that could really cure HSCR children is clearly warranted. Based on our recently published results, we believe that a non-surgical regenerative medicine approach to treatment might now be possible for children with HSCR. Specifically, we found that a protein called GDNF can induce the formation of new neurons in the bowel of three HSCR mouse models as well as in human colon removed from children with HSCR as part of their routine care. Induced neurons significantly improve bowel function, delaying death of our HSCR mouse models. New preliminary data further show that a small molecule normally produced by gut-resident microbes enhances GDNF impact. During the next 5 years, we will elucidate the mode of action of GDNF and the newly identified microbial molecule at both molecular and cellular levels. These studies should lead to future human clinical trials that could provide valuable alternative treatments for children with HSCR and perhaps other intestinal motility disorders.