Integrins help facilitate immune cell trafficking and are an important receptor family for therapeutic intervention. The α4β7 integrin is an already clinically validated target for the treatment of inflammatory bowel disease (IBD): vedolizumab blocks the interactions between α4β7-expressing lymphocytes and its ligand mucosal addressin cell adhesion molecule-1 (MadCAM-1). In a study to develop and characterise orally bioavailable small-molecule inhibitors of the α4β7 integrin, a number of potent, selective, α4β7 integrin inhibitors were discovered that demonstrate on-target, mechanistic efficacy in 2 animal models of IBD [1]. The lead compound had favourable drug metabolism and pharmacokinetic properties, good oral bioavailability, and probably sufficient exposure in humans to effectively block α4β7-expressing immune cells. The authors therefore claimed this result could lead to an effective and safe monotherapy for IBD, which may also be combined with other IBD drugs.
Another study highlighted a new approach for modulating inflammation in Crohn’s disease (CD) by means of CEACAM5 small peptide [2]. Previously, a small region in CEACAM5 was identified that is able to restore the suppressive activity of CD8+ Treg cells in CD. In the new study, CEACAM5 small peptide activated CD8+ T cells from CD patients and significantly suppressed CD4+ T-cell proliferation [2]. The strongest suppression of proliferation was induced by a new small peptide from the overlapping peptide library containing N71. Peripheral CD8+ T cells increased IL-10 production upon stimulation with the CEACAM5 peptide.
CKD-506 is a selective inhibitor of HDAC6, a stress-inducible gene that is highly expressed in IBD. Molecular mechanisms of CKD-506 were identified [3]. CKD-506 was found to exert anti-inflammatory and anti-colitis effects through regulation of the NF-κB and AP-1 signalling pathway. Therefore, CKD-506 may provide beneficial effects in IBD patients.
Thiomyristoyl is a potent specific inhibitor of the HDAC SIRT2. Thiomyristoyl has shown extensive anticancer activity. A study of its anti-inflammatory properties revealed that thiomyristoyl ameliorates experimental colitis by blocking the differentiation of Th17 cells, which may be associated with the STAT3/IL-6 signal pathway [4]. The authors concluded SIRT2 may represent a potential target for IBD treatment.
- Wong J, et al. ECCO-IBD 2020, DOP64.
- Roda G, et al. ECCO-IBD 2020, DOP66.
- Shin J, et al. ECCO-IBD 2020, DOP67.
- Xu Y, et al. ECCO-IBD 2020, DOP68.
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Table of Contents: ECCO 2020
Featured articles
Gut Microbiome as Treatment Target
Response to faecal microbiota transplantation in UC
Bioactives produced by gut bacteria to modulate immune response
Big Data Analysis
Multi-omics help describe CD phenotypes
The positive impact of genetic data on drug development
Experimental Therapies: Study Results
AMT-101: an oral human IL-10 fusion protein
Phase 2 results of first-in-class TL1A inhibitor
Open-label extension study of risankizumab: final results
Clinical remission after dose escalation of upadacitinib
Short- and Long-Term Treatment Results
Infliximab discontinuation increases relapse risk
Tofacitinib ‘real-world’ effectiveness in active UC
Subcutaneous ustekinumab as maintenance therapy in UC
Subcutaneous vedolizumab maintenance therapy in CD
Vedolizumab treatment persistence and safety
Specific Therapeutic Strategies
Impact of strategies on intestinal resection rate
Early ileocaecal resection in CD patients failing conventional treatment
Biologics before surgery in IBD do not elevate infection risk
Top-down infliximab superior to step-up in children with CD
High versus standard adalimumab in active UC
Head-to-Head Comparison of Treatments
Vedolizumab and anti-TNF therapies: a real-world comparison
Cancer Risk
Increased risk of small bowel cancer in IBD
Increased incidence of colorectal cancer and death in CD
Risk of rectal, anal cancer increased in perianal CD
Glyco-fingerprint as risk factor of UC-associated cancer
Miscellaneous Topics
Resolution of mucosal inflammation has dramatic effect
PICaSSO validated in real-life study
Re-inducing inflammation in organoids from UC patients
Role of immune cells in intestinal fibrosis
Association between meat consumption and IBD risk
CD exclusion diet corrects dysbiosis
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