P137 LOCAL CRAC CHANNEL BLOCKADE TREATS COLITIS IN MICE. (7th February 2019)

• Record Type: Journal Article
• Authors: Skupsky, Jonathan; Hwang, Michael; Zavala, Angel; Nakasaki, Manando; Sabui, Subrata; Said, Hamid; Cahalan, Michael; Newman, Andrew; Ransom, John; Greenberg, Milton L
• Is Part Of: Inflammatory bowel diseases. Volume 25(2019)Supplement 1
• Page Start: S64
• Page End: S64
• Publication Date: 2019-02-07
• Subjects: Inflammatory bowel diseases -- Periodicals; Colitis, Ulcerative -- Periodicals; Crohn Disease -- Periodicals; Inflammatory Bowel Diseases -- Periodicals; 616.344
• DOI: 10.1093/ibd/izy393.153
• Languages: English
• ISSNs: 1078-0998

Abstract

Abstract: The Ca 2+ release activated Ca 2+ (CRAC) channel is an exciting new pharmacological target for the treatment of Inflammatory Bowel Disease (IBD) because it is upstream in the inflammatory cascade and absolutely necessary for immune responses. Calcium-selective CRAC channels become activated when T cells recognize antigen and allow calcium influx to the cytoplasm leading to increased NF-κB and NFAT-mediated gene expression driving inflammation. We have developed VV2003 which is a small molecule that blocks the CRAC channel and can be delivered orally. It has limited epithelial permeability allowing VV2003 to function locally at the site of inflammation with little risk for systemic complications. Following oral administration in healthy and colitic mice, VV2003 demonstrates low systemic absorption while maintaining therapeutic levels in the colon tissue for greater than 12 hours. In rat pharmacokinetic studies, VV2003 demonstrates low percent bioavailability and rapid clearance. The drug candidate diffuses into the intestinal mucosa and submucosa where it ameliorates inflammation without systemic activity. We have tested VV2003 in the DSS and Adoptive Transfer mouse models for colitis and have seen improvements in multiple endpoints including: disease activity index, fecal calprotectin and histologic scores. Notably, it is non-inferior to several systemically-active treatments which are currently the standard of care. We find that the CRAC channel is upregulated in biopsy samples from patients with IBD, and VV2003 suppresses inflammatory cytokines from PBMCs in-vitro. Importantly, there have been no signs of toxicity in any of our experiments. Overall, these data demonstrate that VV2003 has potential to become a novel next-generation oral therapy for colitis because it effectively limits leukocyte function in-vitro and in-vivo and is expected to have local delivery to the sites of pathology with minimal off target effects. In the near future, we plan to begin clinical trials to determine if VV2003 will be effective in treating patients with IBD. This project is supported by: VA CDA 5IK2BX003518, NIH NCATS TR001415; NIH NIAID R43AI134205.