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Project

Molecular characterization of pathophysiologic pathways in IBD and its therapeutic potential

Inflammatory bowel diseases (IBD), with Crohn’s disease (CD) and ulcerative colitis (UC) as the two most prevalent phenotypes, span a disease spectrum of lifelong, idiopathic conditions characterized by chronic inflammation of the gut with diarrhea and abdominal pain. Although its exact pathophysiology remains elusive, IBD is believed to be caused by an aberrant mucosal immune responses towards intestinal microorganisms in genetically predisposed individuals. During the last years, new pathophysiologic pathways have been uncovered and since there still is an unmet therapeutic need in IBD, this knowledge is currently being applied by pharmaceutical companies to develop compounds that target these pathways. Therefore, in the first part of this project we aimed to contribute to the therapeutic development for IBD patients by performing a preclinical efficacy experiment in mice for a new experimental JAK1-specific inhibitor (GLPG0634/filgotinib) that has been developed by Galapagos NV. Since the efficacy of filgotinib was already shown in a chemically induced murine colitis model (DSS), we performed these experiments in the T cell transfer model of colitis which is an adaptive/T cell-driven model. Daily oral administration of filgotinib resulted in a significant reduction in body weight loss and histological inflammation scores. Our data, together with the data obtained from the chronic DSS model, provide convincing preclinical evidence for the application of filgotinib in IBD and meanwhile a large phase 3 program is ongoing.

Other new therapeutic strategies, are in the research pipeline or reaching registration. This means that, in the future, the range of therapies will drastically expand. Furthermore, a well-known characteristic of IBD is the large inter-patient variability in disease course and severity, which has consequences for the type, the dose and frequency of treatment. We believe that the IBD treatment paradigm should change towards a more personalized approach that is based on targeting the underlying pathophysiologic pathways that drive the disease in a given patient. The second part of this PhD project investigated the contribution of three IBD-associated pathways (ER stress, autophagy and inflammasomes) in specific patient-subgroups at different levels. First of all, we developed a novel cell culture system that allows short term expansion of patient/biopsy-derived intestinal epithelial monolayers. We confirmed that these monolayers had an epithelial character and a normal apical-basolateral polarization. In this model we showed that the number of risk alleles in ER stress and/or autophagy leads to an increased BIP induction after thapsigargin treatment indicating functional alterations in the epithelial ER stress response. These readouts might in the future be used as an indication for ER stress reducing therapies such as TUDCA. Furthermore, we believe that this patient-derived intestinal epithelial cell culture approach has more potential applications such as co-culturing with other cell types and/or investigating patient-specific responses to pharmaceuticals or even microbes.

Finally, we investigated the inflammasome, ER stress and autophagy at a transcriptional level in the mucosa of patients and healthy controls who were included in two well-characterized whole genome gene expression microarray cohorts. We found a strong upregulation of two dsDNA-responsive inflammasome sensors AIM2 and IFI16 in patients with active disease when compared to patients with inactive disease or healthy controls. We are one of the first groups to identify the potential involvement of both inflammasome sensors which are now subject of investigation as a disease activity marker (IFI16) and a key player in intestinal homeostasis (AIM2). We also found a strong upregulation of several ER stress genes and a downregulation of autophagy genes that was associated with increased disease activity. When disease was controlled normalization was observed for most of these genes, yet some (KDELR3, XBP1, MAP1LC3A and CHMP4B) remained dysregulated, indicating that these pathways are not entirely restored to their normal levels upon remission. Finally, we found a gene expression signature in these pathways that could aid in predicting the response to anti-TNF treatment caused by an altered ER stress or autophagy status. Although preliminary, these data hint towards the application of ER stress reducing or autophagy stimulating therapy in patients who show, already at baseline, dysregulated gene expression patterns.

In conclusion, the promising filgotinib data demonstrate that we live in a time of increasing therapeutic diversity for IBD. In this PhD thesis we furthermore set the first steps towards a personalized pathway-based approach for treating this multifactorial disease spectrum. 

Date:1 Oct 2013 →  16 Nov 2017
Keywords:Inflammatory Bowel Disease
Disciplines:Endocrinology and metabolic diseases, Gastro-enterology and hepatology, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences
Project type:PhD project