A Gut-Restricted Small-Molecule Therapeutic for a Novel Target to Treat Inflammatory Bowel Disease
Abstract
A group of chronic intestinal diseases characterized by inflammation of the large and small intestine known as inflammatory bowel disease (IBD) affects over 3.1 million people in the United States. This is ~1% of the population and IBD cases occur among Soldiers at a similar rate. Importantly, because of the severity and symptoms of this disease, mission capability along with unit readiness and cohesion can be compromised by Soldiers with IBD. Patients with IBD often require intensive and expensive medical interventions. A major problem in IBD is injury repair of the inner lining of the intestine. However, current medical treatment approaches for moderate to severe disease are dominated by biologic agents that target a consequence of IBD, inflammation, and not the root cause. As a result, all biologics have failed to maintain the disappearance of the symptoms of IBD for a majority of the patients to date. Furthermore, nearly all biologic medicines are administered by injection (intravenously or subcutaneously), which limits accessibility and medication adherence. To address these problems, we identified PAI-1 (plasminogen activator inhibitor-1) as a novel target for IBD therapy. We created an inhibitor compound to PAI-1 that can be delivered orally, is gut restricted, and showed efficacy in chemical-induced animal models of IBD. We plan to perform studies that will allow us to further develop this compound into a drug. A major focus will be to test if the compound is toxic or has unanticipated effects. We also have a plan in place to identify and develop a back-up compound if our current lead fails in these tests. If successful, our novel drug would provide an oral therapeutic option with a favorable safety profile and efficacy that improves IBD within the individual. Successful therapy of IBD will also likely affect overall unit readiness. This proposal aligns with PRMRP areas of research interest (IBD research strategies that target epithelial health and function, including patients who are refractory to standard care) and also useful in a dual-capacity to benefit the civilian population while also addressing a military need. Overall, with a minimal side effect profile and gut-restricted efficacy for our proposed new drug, Service Members would be able to maintain deployability and be retained on active-duty service with overall improvement in medical readiness.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210675
Entities
People
- Thaddeus S. Stappenbeck
Organizations
- Cleveland Clinic
- United States Army