Nous Biosciences Inc

Combination of Formulated Dolcanatide, a Guanylate Cyclase-c Agonist, With Formulated Atiprimod, a Jak-stat Inhibitor, for Treatment of Murine Colitis. - Abstract: Pathogenesis of Inflammatory Bowel Disease (IBD) Is Typically Initiated by the Disruption of Intestinal Barrier Functions (ibf), Causing Imbalance in Gut Microbiome, Leading to Dysregulation in Mucosal Immune Responses, and Eventually to Development of Ulcerative Colitis (UC) or Crohn’s Disease (CD). Existing Therapies for Ibd Are Not Entirely Satisfactory Due to Limited Effectiveness as Those Are Primarily Anti-inflammatory or Immunomodulatory Agents That Are Designed to Control Gastrointestinal (GI) Inflammation. Guanylyl Cyclase-c (GC-C) Is Activated Upon Binding of Guanylin (GN) or Uroguanylin (ug), Resulting in Stimulation in Cyclic GMP (CGMP) Production to Stimulate Fluid Secretion in Proximal Intestine to Normalize Bowel Movement. Beyond Fluid Secretion in Proximal Intestine, Activation of GC-C Signaling by Ug or GN Also Regulates Ibf, Epithelial Cells Homeostasis (gi Renewal Process). Pi’s Group Was the First to Show That Transcript Levels of Both Ug and GN Are Reduced Dramatically in Human Colon Polyps and Adenocarcinomas, and That the Dietary Supplementation With Human Ug Not Only Inhibited Polyp Formation, But Also Delayed Their Progression to Adenocarcinomas in Apc+/min Mice. Subsequently, Pi and Several Other Researchers Have Shown That Disruption in GC-C Signaling, Due to Near Universal Loss of GN and Ug, Leads to Ibd and Colorectal Cancer (CRC). Thus, Oral Treatment With GC-C Agonist to Overcome This Deficiency Represents a Promising Novel Approach for Treatment of Uc & CRC. Indeed, Orally Administered Dolcanatide (dol), a Superior Analog of Ug and a Stable Agonist of GC-C, Ameliorated Gi Inflammation in Both Chemical-induced, Spontaneous Models of Colitis, and Inflammation-induced CRC in Mice. These Animal Studies Showed Inverted U (BELL) Shaped Therapeutic Responses, Raising a Possibility That the Higher Oral Dose of Dol Might Lead to Excessive Fluid Secretion in the Proximal Intestine, Resulting in ‘wash Out’ of Dol Before It Could Reach the Target Site Colon. Thus, Fluid Secretion in Proximal Intestine Could Reduce Its’ Therapeutic Effect. in Addition, GC-C Signaling Is Also Disrupted by the Cytokine-mediated Activation of Jak-stat Signaling in Gi Inflammatory Diseases. Thus, Combination of Dol With Atiprimod (ati), a Phase 2 Clinically Validated Inhibitor of Cytokines Mediated Activation of Jak-stat Signaling, Might Produce Superior Therapeutic Effects. Pi Developed an Oral Formulation of Drug-loaded Chitosan Microspheres (MSF) That Were Sequentially Coated With Time- and Ph-dependent Polymers to Bypass Proximal Intestine Such That the Loaded Drugs Are Released in Distal Intestine to Colon Regions. This Sbir Phase 1 Grant Is to Evaluate Msf-dol Either Alone or in Combination With Msf-ati on Severity of Colitis in Acute and Chronic Models of Dss-induced Murine Colitis. Colon Tissues and Blood Samples Will Be Collected to Assess Treatment Effects on GC-C and Jak-stat Signaling and on Cytokine Profiles. Successful Completion of These Studies Is Expected to Advance the Msf-dol Either Alone or in Combination With Msf-ati for Further Evaluations in the Spontaneous and Genetic Models of Uc, and in Non-clinical Ind-enabling Studies, as Part of the Planned Sbir Phase 2 Grant.