Leo R Fitzpatrick1,2, Jeff Small3, Robert O'Connell4, George Talbott5, Gordon Alton6, Jim Zapf6. 1. Department of Pharmaceutical and Biomedical Sciences Department, California Northstate University College of Pharmacy, 9700 West Taron Drive, Elk Grove, CA, 95757, USA. lfitzpatrick@cnsu.edu. 2. Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033, USA. lfitzpatrick@cnsu.edu. 3. Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033, USA. 4. Bolder Biopath Incorporated, Boulder, CO, 80301, USA. 5. Department of Pharmaceutical and Biomedical Sciences Department, California Northstate University College of Pharmacy, 9700 West Taron Drive, Elk Grove, CA, 95757, USA. 6. Visionary Pharmaceuticals Incorporated, San Diego, CA, 92121, USA.
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.
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 murineIBD 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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