UEGJournal Abstracts 2021 - 42

GPX4 activity. In CD patients, dietary PUFA intake correlates with longitudinal
disease activity, and ~50% of CD patients displayed an inflammatory
serum signature comprising lipid peroxidation and ER stress.
Conclusion: We demonstrate a critical role for ER stress in PUFA-induced
metabolic enteritis and find that dietary PUFAs may worsen the course of
human CD. As such, we identify a non-toxic dietary constituent as driver of
gut inflammation in human CD, providing a basis for targeted nutritional
therapy.
References: 1. Ng, S. C. et al. Worldwide incidence and prevalence of
inflammatory bowel disease in the 21st century: a systematic review of
population-based studies. Lancet (London, England) 390, 2769-2778,
doi:10.1016/s0140-6736(17)32448-0 (2017).
2. Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic
disorders. Nature 542, 177-185, doi:10.1038/nature21363 (2017).
3. Mayr, L. et al. Dietary lipids fuel GPX4-restricted enteritis resembling
Crohn's
disease. Nature Communications 11,
s41467-020-15646-6 (2020).
Disclosure: Nothing to disclose.
OP048
PRECLINICAL MECHANISTIC INVESTIGATION OF THE FIRST-IN-CLASS
SIK2/SIK3 INHIBITOR GLPG3970 IN AN EXPERIMENTAL MODEL OF IBD
S. Lavazais1, A. Cosson1, D. Merciris1, C. Delachaume1
A. Gigout1, N. Desroy1, D. Amantini1, S. De Vos2
1Galapagos SASU, Romainville, France, 2
Belgium
, L. Perret1
,
Galapagos NV, Mechelen,
Contact E-Mail Address: steve.devos@glpg.com
Introduction: GLPG3970 is a first-in-class oral, selective, small molecule
inhibitor of salt-inducible kinase (SIK) 2 and 3 currently being investigated
in clinical trials of immune-inflammatory diseases, including ulcerative
colitis. Supported by internal research and scientific literature,1-3
selective
SIK2/SIK3 inhibition acts through a dual mechanism of action in inflammatory
conditions, which are characterized by inhibition of pro-inflammatory
mediators coupled with enhanced immunoregulatory functions in
myeloid cells. Dysfunction of regulatory immune cells in the gut accounts
for a compromised intestinal mucosal immune response and is associated
with an imbalance of pro- and anti-inflammatory cytokines. SIK2/
SIK3 inhibition governs a molecular switch in activated myeloid cells and
is associated with inflammatory bowel disease (IBD) genetic risk factors
modulating the EP4-SIK-CRTC3-CREB-IL10 signalling axis.4
Aims & Methods: Our research aimed to investigate the therapeutic potential
and dual mechanism of SIK2/SIK3 inhibition on the cytokine imbalance
between pro- and anti-inflammatory cytokines, and enhancement of
regulatory immune cells in local intestinal tissues by evaluating GLPG3970
in the T-cell transfer model of chronic colitis. The dual activity of GLPG3970
was assessed in LPS-stimulated human macrophage and dendritic cell
(DC) assays, representative of inflammatory gut myeloid cells. The therapeutic
activity of GLPG3970 was evaluated in a murine model of chronic Tcell
driven colitis and recorded by disease activity index (DAI) scoring and
colon histology analysis. To assess the effect on goblet cell health, PAS (Periodic
acid-Schiff) mucin staining and RNAscope®
in situ hybridization of
MUC2 was performed. Translational mechanistic investigations were conducted
in local colon tissues using gene expression analysis and protein
quantification. Lastly, flow cytometry was used to assess the phenotypic
state of macrophage and DC subtypes and the ratio of Treg versus Th17 in
lamina propria mononuclear cells (LPMCs) isolated from colonic tissues.
Results: GLPG3970 potently inhibited pro-inflammatory cytokines coupled
with enhanced release of IL-10 and pro-resolving proteins in LPSstimulated
human macrophage and DC assays. Treatment with GLPG3970
42
REDUCED EXPRESSION OF GATA6-AS1 LNCRNA IN GUT EPITHELIA
ATTENUATE MITOCHONDRIAL RESPIRATION AND MAY ACCOUNT IN
PART FOR THE EPITHELIAL DYSFUNCTION SEEN IN INFLAMMATORY
BOWEL DISEASE (IBD)
K. Sosnovski1,2
I. Abramovich4
, M. BenShoshan1,2
, E. Gottlieb4
Y. Haberman2,1,5
1
, T. Braun3, E. Glick Saar2
, T. Geiger1,2, I. Barshack1,2
Tel Aviv University, Tel Aviv, Israel, 2
Gan, Israel, 3
Institute, Haifa, Israel, 5
United States
,
, L. Denson5
Sheba Medical Center, Ramat-Gan, Israel, 4
Sheba Medical Center, Ramat
Technion
Cincinnati Children's Hospital, Cincinnati,
Contact E-Mail Address: 1katya3@gmail.com
Introduction: There is an ongoing need to identify new therapeutic targets
for Inflammatory Bowel Diseases (IBD). Long non-coding RNAs (lncRNA)
have cellular regulatory roles and show tissue specific expression, which
make them appealing targets for interventions. Oxidative stress, hypoxia,
and mitochondria dysfunction in gut epithelia was previously linked with
disease pathogenesis.
Aims & Methods: Our aim is to prioritize IBD-associated lncRNAs and explore
their role in epithelial in relation to IBD pathogenesis.
We used transcriptomics of mucosal biopsies identified differential expression
of lncRNA in IBD. RNA pull-down followed by mass-spectrometry
identified lncRNA: Protein interactions. shRNAs technology used to modify
expression of GATA6-AS1 lncRNA. qPCR and western blot were used to
evaluate effects on mRNA and protein levels. The Seahorse XFe Cell Mito
Stress Test was used to detect cellular mitochondrial respiration [Oxygen
Consumption Rate (OCR)].
UEG Journal | Abstract Book
,
1-15,
doi:doi:10.1038/
in the T-cell transfer colitis model resulted in dose-dependent reversal of
disease activity endpoints coinciding with the protection of goblet cell
health and expression of MUC2. The dual mechanism of SIK2/SIK3 inhibition
in intestinal tissues was further demonstrated by gene expression
analysis and protein quantification resulting in reduced expression of proinflammatory
cytokines and enhanced release of IL-10 and pro-resolution
mediators. Flow cytometric analysis of isolated LPMCs from GLPG3970treated
animals revealed robust effects in enhancing immunoregulatory
phenotypes: decrease in pro-inflammatory macrophages (M1) coupled
with increase in regulatory phenotypes (M2); increase in IL-22+
macrophages
(associated with mucosal healing); decrease in the maturation
state of DCs coupled with induction of tolerogenic DC phenotypes; and an
increase in Treg/Th17 ratio.
Conclusion: Our preclinical investigations demonstrate the efficacy of
GLPG3970 in the murine T-cell transfer colitis model and support the dual
mechanism of SIK2/SIK3 inhibition in local inflamed intestinal tissues underpinning
its potential to restore intestinal homeostasis. These data support
GLPG3970 as an attractive novel potential therapeutic option for the
treatment of chronic IBD.
References:
1. Clark K et al. PNAS 2012;109:16986-91.
2. MacKenzie K et al. Immunology 2013;190:565-77.
3. Sundberg TB et al. PNAS 2014;111:12468-73.
4. Wein MN et al. Trends Endocrinol Metab 2018;29:723-35.
Disclosure: SL, AC, DM, CD, LP, AG, ND, DA and SDV are employees of Galapagos.
These
studies were funded by Galapagos NV (Mechelen, Belgium).
Editorial support for the development of this abstract was provided by Antonio
Alvau, PhD, of PharmaGenesis London, London, UK, and funded by
Galapagos NV.
OP049
Tuesday, October 5, 2021
Monday, October 4, 2021
Sunday, October 3, 2021
UEGJournal Abstracts 2021

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