Principal Investigator:
Nicolas Pilon
Université du Québec à Montréal – UQAM
Co-investigators
Lekha Sleno
Université du Québec à Montréal –
UQAM
Project of $1 500 000 over 3 years
- Supported by CQDM through: Ministère de l’Économie, de l’Innovation et de l’Énergie du Québec (MEIE)
- And by a co-funding partner: Neurenati
Challenge
Hirschsprung disease (HSCR) is a deadly congenital malformation where the enteric nervous system (ENS) is missing from the colon. Because the ENS controls gastrointestinal motility, the ENS-devoid segment remains constantly contracted, resulting in obstruction by fecal material (megacolon). The ENS also controls other gastrointestinal functions, explaining why children with HSCR have high risk [MR1] of developing fatal systemic infection by gut-resident microbes. Current treatment consists of painful surgical removal of the ENS-devoid segment followed by re-connection of innervated colon to the anus. Unfortunately, many children have
post-surgical complications like stool leakage and life-threatening inflammation, often leading to hospital re-admission and repeat surgery.
Solution
Based on recently published results by Prof. Pilon’s team, a non-surgical regenerative medicine approach might now be possible for children with HSCR. Specifically, they found that a protein called GDNF can induce the formation of a new ENS in the colon of three HSCR mouse models. The induced ENS significantly improves gastrointestinal functions, delaying death of many of these HSCR mice. New data now show that a small
molecule normally produced by gut-resident microbes as well as another neurotrophic factor can both enhance the effect of GDNF treatment, not only on the ENS but also on other components of the gastrointestinal ecosystem. Moreover, via a collaboration with the team of Prof. Sleno, they found that specific proteins and metabolites present in the colon wall could serve as biomarkers predictive of a positive response to GDNF treatment.
Achievements/Impact
This collaborative research project with a Quebec company, Neurenati, will elucidate mechanism of action of GDNF and molecules that increase the therapeutical potential. Also, the research team will define pharmacokinetic properties of GDNF, which will help to develop an optimal formulation for clinical assays.
This project will be led by a multidisciplinary team that will use a wide array of new and innovative technologies and approaches. This research will help propel Quebec as a leader in the field of rare disease research.
