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Inflammopharmacology

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01-04-2020 | Chronic Inflammatory Bowel Disease | Original Article

VPR-254: an inhibitor of ROR-gamma T with potential utility for the treatment of inflammatory bowel disease

Authors: Leo R. Fitzpatrick, Jeff Small, Robert O’Connell, George Talbott, Gordon Alton, Jim Zapf

Published in: Inflammopharmacology | Issue 2/2020

Abstract

Introduction

Retinoic Acid Related Orphan Nuclear Receptor gamma T (RORγT) is a lineage specifying transcription factor for IL-17 expressing cells, which may contribute to the pathogenesis of Inflammatory Bowel Disease (IBD). VPR-254 is a selective in vitro inhibitor of RORγT.

Aims

The main goals of our study were twofold: (1) To determine if ex vivo treatment with VPR-254 reduced relevant cytokine (IL-17 and IL-21) secretion from colonic strips of mice with colitis; (2) To determine if treatment of mice with VPR-254 attenuated parameters of colitis, using three murine IBD models.

Methods

VPR-254 was evaluated ex vivo in a colonic strip assay, using tissue from mice with Dextran sulfate sodium (DSS)-induced colitis. In vivo, VPR-254 was evaluated for efficacy in DSS, Trintirobenzenesulfonic acid (TNBS) and Anti-CD40 antibody-induced murine models of colitis.

Results

VPR-254 reduced the production of key pro-inflammatory cytokines (e.g., IL-17) in ex vivo and in vivo models of colitis. This small molecule inhibitor of RORγT also improved various morphometric and histological parameters associated with three diverse murine models of IBD.

Conclusion

Our results support the concept that an inhibitor of ROR-gamma T may have potential utility for the treatment of IBD.

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Title: VPR-254: an inhibitor of ROR-gamma T with potential utility for the treatment of inflammatory bowel disease
Authors: Leo R. Fitzpatrick
Jeff Small
Robert O’Connell
George Talbott
Gordon Alton
Jim Zapf
Publication date: 01-04-2020
Publisher: Springer International Publishing
Keywords: Chronic Inflammatory Bowel Disease
Cytokines
Published in: Inflammopharmacology / Issue 2/2020
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-019-00643-z

At a glance: The STEP trials

Springer Medicine

VPR-254: an inhibitor of ROR-gamma T with potential utility for the treatment of inflammatory bowel disease

Abstract

Introduction

Aims

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Introduction

Aims

Methods

Results

Conclusion

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