Engineering Tryptophan Metabolism to treat chronic inflammatory diseases – TrypENGINE

Chronic inflammatory diseases, including inflammatory bowel diseases (IBD) and rheumatoid arthritis (RA) are immune-related disorders characterized by inappropriate inflammation. Their incidence has increased dramatically in Western countries in recent decades, supporting a role for environmental factors. Current therapies are only partially efficient and are mostly based on immunosuppressants that are associated with side effects, including infection and neoplasia. New therapeutic strategies with innovative and more precise targets are thus urgently needed.
We identified an alteration of tryptophan metabolism in both IBD and RA and its role in pathogenesis. We notably pointed out the role of overproduction of pro-inflammatory metabolites to the expense of a decreased production of anti-inflammatory ones. By administrating a specific enzyme (that we produced and purified), which is downregulated in inflammatory contexts, we were able to counteract the tryptophan metabolism alterations and induce therapeutic effects in colitis and RA models.
The aims of the present project are to better characterize the effect of this therapeutic enzyme in pathological settings in order to develop it as a new therapeutic candidate. For this purpose, we will (i) evaluate the efficacy of the newly identified therapeutic enzyme in several colitis and (ii) RA models, and (iii) decipher the mechanisms involved in the therapeutic effects in inflammatory conditions.