One Health: Translational and Reverse Translational Modeling of Inflammatory Bowel Disease using an advanced Boolean Network
Violeta Balbás-Martínez (1), Karin Allenspach (2), Dawn Kingsbury (2), Albert E. Jergens (2), Iñaki F. Troconiz (1)* and J.P. Mochel (2)*
(1) Pharmacometrics & Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, University of Navarra, Pamplona, Spain; (2) Iowa State University College of Veterinary Medicine, Ames, United States of America. (* : co-last authors)
Objectives: Recent literature [1,2] suggests that the purinergic receptor P2X7 is a relevant target for treating inflammatory bowel disease (IBD). IBD is a highly prevalent chronic intestinal disorder in both humans and dogs, such as clinical trials with naturally occurring cases of canine IBD are particularly relevant to study the efficacy and safety of P2X7 receptor antagonists (P2X7A). A model-based approach was used to predict the effect of a candidate non-competitive P2X7A on biomarkers known to be associated with chronic intestinal inflammation (IL1b, IL18) and tissue damage (i.e. Matrix Metalloproteinases, MMPs), as well as to guide dose selection for an upcoming clinical trial in IBD dogs.
Methods: A semi-quantitative Systems Pharmacology (SP) model, based on Boolean equations of IBD (including 43 nodes and 240 interactions), and implemented in the SP platform SPIDDOR [3], was used to simulate the effect of the candidate P2X7A. Simulations were performed assuming chronic response to 3 different microbial antigens (Lipopolysaccharide, Muramyl dipeptide and Peptidoglycan), and a direct effect of P2X7 antagonism on the inflammasome. Results were expressed as relative percent change from control for an increasing fraction of P2X7 being antagonized (from 25% to 100%, with 25% increments).
Results: In silico simulations showed a reduction by ca. half of IL1b and IL18 systemic levels when antagonizing 50% of P2X7, with only moderate effect on MMPs. A more substantial decrease in MMPs (>20%) can be expected with 75% and higher blockade of the target receptor.
Conclusions: Assuming that MMPs levels are associated with clinical activity, the selected dose of the P2X7A candidate should antagonize at least 75% of the target receptor. This approach has apparent translational medical impacts due to similarities in the pathophysiology of IBD between humans and dogs.
References:
[1] Arulkumaran N, Unwin RJ, Tam FW. A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases. Expert Opin Investig Drugs. 2011 Jul;20(7):897-915.
[2] Eser A, Colombel JF, Rutgeerts P, Vermeire S, Vogelsang H, Braddock M, Persson T, Reinisch W. Safety and Efficacy of an Oral Inhibitor of the Purinergic Receptor P2X7 in Adult Patients with Moderately to Severely Active Crohn's Disease: A Randomized Placebo-controlled, Double-blind, Phase IIa Study. Inflamm Bowel Dis. 2015 Oct;21(10):2247-53.
[3] Irurzun-Arana I, Pastor JM, Trocóniz IF, Gómez-Mantilla JD. Advanced Boolean modeling of biological networks applied to systems pharmacology. Bioinformatics. 2017 Jan 10. pii: btw747.
