Gut Symbiont Lipid A Family: Structures and Immunomodulation in IBD
Abstract
Objectives and Rationale: Inflammatory bowel diseases (IBD) are a major disorder with significant disease burdens. Over the last three decades, the number of people with IBD has increased from 3.7 million (1990) to 6.8 million (2017) globally. The U.S. has the highest prevalence rate (464.5 per 100,000) and notably, among U.S. military Veterans, the increase in the prevalence of IBDs has been even more significant. Still, current therapeutic options for IBDs largely rely on non-specific immunosuppressive agents. The side effects of these drugs are particularly problematic in patients with an elevated risk of infection and trauma, such as active Service Members. Development of therapeutics with better specificity and less toxicity is imperative. Expansion on Our Prior Department of Defense (DOD)-sponsored work (Gut Symbiotic Lipid A Family: Structures and Immunomodulation in IBD, W81XWH1910625): Many non-genetic factors are associated with IBD. It is clear that gut commensal microbiota make critical contributions to host immune development as well as modulation of inflammatory responses. Unfortunately, developing therapeutic leads from the microbiome has proven challenging because the work of discovery requires a unique combination of in-depth expertise in microbiology, immunology, and chemistry. Based on our extensive past studies, supported by the DOD, of gut symbiotic microbiota and modulation of the immune system, we now propose to investigate the unique therapeutic leads we have discovered that originate from human symbiotic microbes. We have performed discovery research studies using several prototypic synthetic molecules that are structural analogs of the Bacteroides lipid A. We have conducted these studies in cellular and animal models. We have successfully identified a specific analog (tetraacylated lipid A) as a dominant immunoregulatory structure. We are now proposing to expand our investigation to the preclinical level by studying the therapeutic efficacy of synthetic and biogenic analogs of tetraacylated lipid A in human cells as well as humanized animal models. Relevance to Topic Area: Fiscal Year 2022 (FY22) Peer Reviewed Medical Research Program (PRMRP) Topic Area—Inflammatory Bowel Disease; FY22 PRMRP- Strategic Goal—1) Foundational Study—This project is relevant to the therapeutic potential of the microbiome on immune-mediated disease (Inflammatory Bowel Disease); 2) Treatment—We plan to develop and test new treatments and/or refine existing treatment strategies to minimize toxicity, and to mitigate the inflammatory and/or allergic disease state. Our proposed program for preclinical development, level 3, precisely fits the Topic Area of IBD and the Strategic Goal of both a foundational study and treatment development. The foundation being built by our program is to identify and define naturally existing immunomodulatory molecules from the microbiome. There is now very good evidence that many molecules with immunomodulatory capacity exist in the microbiome, but few have yet been harnessed and mechanistically explored. The specific molecule of interest in our program offers significant potential for treatment of patients for IBD. Ultimate Applicability of Work: Upon successful execution of the proposal, we expect to demonstrate potent protection by the target molecules against inflammation in human cells and humanized colitis model systems. These studies are required before moving onto level 4 clinical development. This therapy would be beneficial for patients with Crohn’s disease as well as those with ulcerative colitis. One major advantage of using these lipid As for therapy is that they are analogs of the naturally occurring molecule found in the healthy intestine and therefore likely to be less toxic than current therapies. They only activate immune cells in the intestine and are not absorbed into the blood. In the current proposal, we will preclinically expand our discovery work and further exp
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310226
Entities
People
- Dennis L Kasper
Organizations
- Harvard University
- United States Army