Optimized Glycopolymer-Mimicking Polysaccharide to Provide Barrier Function and Restore Gastrointestinal Integrity and Homeostasis in Inflammatory Bowel Diseases
Abstract
Inflammatory bowel disease (IBD) is an umbrella term used to describe disorders that involve chronic inflammation of the digestive tract, manifesting in severe diarrhea, abdominal pain, fatigue, and weight loss. Types of IBD include ulcerative colitis (UC), which causes long-lasting inflammation and ulcers in the innermost lining of the large intestine and rectum, and Crohn’s disease (CD), which is characterized by inflammation of the lining of the digestive tract. Although they are separate conditions, they share common features of intestinal inflammation, gut barrier injury, and ulceration. In the inflamed gut characteristic of UC and CD, the damaged gastrointestinal (GI) tract results in dysfunction of the mucosal barrier, allowing penetration of both good and bad microbes, as well as intestinal and cellular debris, onto and through the intestinal cell wall. In a previous PRMRP effort, a lead candidate was refined from a class of newly developed, targeted molecules designed to replace the natural immune functions of the GI surface and help to repair damaged, multilayered intestinal barrier in IBD. In a murine model, the lead candidate demonstrated characteristics that were most effective in restoring the innate barrier function that is lost in a damaged intestine and correlated with the properties of a healthy gut. The current effort is designed to complete the necessary steps to advance the lead candidate into phase 1 clinical trials. Here, we propose toxicology and manufacturing studies to meet the U.S. Food and Drug Administration’s (FDA’s) requirement that the safety of the drug be demonstrated in two species and that the drug be manufactured in a controlled and reproducible environment. Additional efforts to understand the most effective dose administration and how the drug passes through the GI tract will help to support the drug’s clinical development. Further, experts in IBD drug development will analyze the data resulting from the studies proposed here to design the clinical studies needed to demonstrate safety and efficacy in humans. This team of experts will also compile and complete the necessary documentation to complete and file an Investigational New Drug (IND) application to the FDA to allow for initiation of the clinical studies. This proposal addresses the FY21 PRMRP Topic Area of Inflammatory Bowel Diseases, specifically Areas of Encouragement including studies directed toward understanding how acute infections may trigger chronic bowel diseases with acute and sub-acute inflammatory bowel disease, studies that leverage microbiome-oriented and immunological approaches to prevent or treat IBD, and research on treatment strategies for patients with inflammatory bowel disease, including those that target epithelial health and function and patients who are refractory to standard of care. Current standard-of-care drugs are administered systemically and designed to block a particular component of the inflammatory response; consequently, the immune system is suppressed systemically but underlying tissue damage or barrier function of the mucosal GI surface is not addressed. Advances through this proposal may yield a therapeutic that can be administered to patients prophylactically to manage the chronic and unpredictable nature of the disease. Should the observations from the preclinical efforts around the current drug under development translate into the clinic, IBD patient care and quality of life for these individuals could be dramatically improved. As development efforts transition from acute interventions to chronic treatment of IBD, the community will better learn the appropriate modalities of use for this new class of drugs and provide treatment alternatives for patients of this debilitating disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210869
Entities
People
- Shenda M. Baker
Organizations
- Synedgen (United States)
- United States Army