Une approche biologique pour le traitement des maladies inflammatoires de l'intestin
Contrer l'inflammation dans les maladies inflammatoires de l'intestin avec une ectonucleotidase et/ou un antagoniste du récepteur P2Y6
Inflammatory bowel disease (IBD), mainly ulcerative colitis and Crohn’s disease, are chronic and debilitating diseases of the gastrointestinal tract which affect 1 in every 150 Canadians and an increasing number of children. It has been proposed that the chronic inflammation underlying IBD results from an abnormal activation of mucosal immunity stimulated by danger signals (alarmins) or damage associated molecular pattern (DAMP) molecules.
The laboratory of Prof Sévigny studies the roles and functions of extracellular nucleotides in intestine mucosal inflammation underlying IBD. Once released in the intestine, nucleotides such as ATP, ADP and UDP can selectively activate G-protein coupled metabotropic P2Y receptors or ligand-gated ionotropic P2X receptors. In colonic epithelial cell lines, P2Y6, a receptor activated by UDP, is upregulated by an inflammatory stress and this stimulates IL-8 secretion. P2 receptor activation is terminated by ectonucleotidases, namely nucleoside triphosphate diphosphohydrolases (NTPDases), enzymes that hydrolyze nucleotides and yield extracellular adenosine, a potent anti-inflammatory agent.
The team of Prof Sévigny has also shown that NTPDase8 is the major ectonucleotidase expressed at the apical surface of the mouse intestinal epithelium. Putting in perspective the fact that in the intestinal epithelium, extracellular nucleotides activate P2Y6 can induce and/or amplify an inflammatory response, and that NTPDase8 can control P2Y6 by limiting access to UDP and release adenosine, the research team has used apyrase to mimic the action of NTPDase8 and demonstrated in preliminary experiments that the intra-rectal administration of this enzyme prevented inflammation in the dextran sulfate (DSS) animal model of induced colitis, a model commonly used in IBD research and applicable to human diseases.
Sévigny J and M Salem (2018). Treatment of inflammatory bowel disease with nucleoside triphosphate disphosphorhydrolase, P2Y2 antagonist and/or P2Y6 antagonist. WO2018058246A1. Assignee: Université Laval.
Pelletier J, M Salem, J Lecka, M Fausther, F Bigonnesse, and J Sévigny (2017). Generation and characterization of specific antibodies to the murine and human ectonucleotidase NTPDase8. Front Pharmacol 8: 115. doi: 10.3389/fphar.2017.00115
Salem M, A Tremblay, J Pelletier, B Robaye, and J Sévigny (2018). P2Y6 receptors regulate CXCL10 expression and secretion in mouse intestinal epithelial cells. Front Pharmacol 9: 149. doi: 10.3389/fphar.2018.00149
Feldbrügge L, AC Moss, EU Yee, E Csizmadia, S Mitsuhashi, MS Longhi, B Sandhu, H Stephan, Y Wu, AS Cheifetz, CE Müller, J Sévigny, SC Robson, and ZG Jiang (2017). Expression of ecto-nucleoside triphosphate diphosphohydrolases-2 and -3 in the enteric nervous system affects inflammation in experimental colitis and Crohn's disease. J Crohns Colitis 11: 1113-1123.
NTPDase8 might provide a biologic solution for treating inflammatory bowel diseases. SOVAR and Université Laval seek a partner for co-development of an enteric formulation of NTPDase8 or commercialization of this technology.
The laboratory of Dr Sévigny is fully capable of in vitro and in vivo evaluation of compounds and molecules in cellular and animal models of IBD.