Our approach is based on the mobilization of neural progenitor cells of the enteric nervous system already present in the affected tissue and their differentiation into neurons to repopulate the affected region of the colon.
In 2020, Dr. Pilon’s group discovered that a brief, localized exposure to human recombinant GDNF permanently induces the formation of a new enteric nervous system in the affected portion of the colon in various Hirschsprung mouse models, thereby preventing the premature death of a significant number of these mice (Soret, Pilon and colleagues, Gastroenterology, 2020).
Detailed characterization of Hirschsprung mice has shown that GDNF penetrates the abnormally permeable colon of these mice and accumulates in the intestinal wall. Additionally, GDNF treatment led to increased endogenous GDNF and RET levels in the colon of these mice, an observation of particular interest as many cases of Hirschsprung disease exhibit reduced RET expression.
GDNF treatment of Hirschsprung mice results in a significant increase in the number of enteric nervous system ganglia by postnatal day 20 and this effect persists into adulthood.
Interestingly, the formation of new neurons following GDNF treatment was observed in cultured surgical colon tissue specimens from children with Hirschsprung disease, with a more pronounced response observed for samples from younger patients. These observations offer the hope that the enteric nervous system can be reconstructed following exposure to trophic factors postnatally, and represent a very promising breakthrough for the treatment of Hirschsprung disease.