The goal of this project is to develop a novel immunological-directed Live Biotherapeutic Product (LBP) thatleverages natural microbiome pathways to inhibit gut inflammatory processes for the treatment of inflammatorybowel disease (IBD). Over 3 million adults in the U.S. suffer from IBD, an umbrella term encompassing two chronic inflammatory diseases of the gastrointestinal tract: Crohn's disease (CD) and ulcerative colitis (UC)1.IBD is typically diagnosed in the second or third decades of life, is life-long, and there is no cure. Current IBDtreatments can have serious side-effects, and patients become refractory. Novel therapies that are safe andeffective, particularly restoring the intestinal membrane barrier, are needed and would be life changing.Intestinal immune regulatory signals tightly govern healthy gut homeostasis, and their breakdown may result inIBD39. The human microbiome, harboring trillions of bacteria, is a critical regulator of these mechanisms.Commensal bacteria function to maintain intestinal epithelial barrier integrity and regulate innate and adaptiveimmune cell function40. Surface layer proteins (Slps), including SlpA, SlpB, SlpX, and lipoteichoic acid (LTA)interact with pattern recognition receptors (PRR) expressed on innate immune intestinal cells to fine immunityin steady state and diseased conditions41-44. Recently, our research team demonstrated that SlpA is thepredominant anti-inflammatory Slp signal. SlpA binds to the C-type lectin Specific Intracellular adhesionmolecule-3 Grabbing Non-integrin homolog-Related 3 (SIGNR3) receptor expressed on dendritic cells liningthe gut prevents experimentally induced colitis in multiple models15. Oral delivery of SlpA via L. lactis (alsoknown as R-3750 or R110) reduced inflammatory cytokines, strengthened the mucosal membrane barrier, andsupported a healthier microbiota make-up in animal models of gut inflammation64. Notably, the effects andprotection mediated by SlpA were not observed in Signr3-/- mice, suggesting that SlpA interaction with SIGNR3plays a key protective role in regulating the disease condition15.Our goal is to develop R-3750, a SlpA-expressing Lactococcus (L.) lactis strain, as a novel, orally administereddrug that functions as immune therapy to reduce gut inflammation, improve gastrointestinal mucosal barrierfunction, and restore the natural microbiome make-up in IBD patients. L. lactis provides two key advantages asa delivery vehicle for conveying SlpA to the gut: 1) it has already been safely used in human clinical trials inwild type and genetically manipulated forms16, 45 19 and 2) it does not express any native Slps but can beengineered to selectively overexpress SlpA. This Fast-Track SBIR application is focused on obtaining humanvalidation for R-3750 by completing a first-in-human Phase 1 proof-of-concept clinical trial. The Specific Aimsare: 1) prepare and file an IND with the FDA, 2) complete capsule manufacturing to support the clinical study,3) perform the Phase 1 clinical trial, 4) analyze samples from the patients for key pharmacodynamic responsesand clinical biomarkers, and 5) prepare GMP scale up production processes for Phase 2 drug manufacturing.
Public Health Relevance Statement: Project Narrative Over 3 million adults in the U.S. suffer from inflammatory bowel disease (IBD). This project aims to develop clinical proof-of-concept for a novel oral immune therapy, R-3750, which delivers SlpA to the intestinal tract to reestablish gut immune homeostasis. SlpA reduces gut inflammation, reestablishes gut mucosal barrier function, induces positive maintenance of the gastrointestinal microbiome, and eliminates symptoms of experimental colitis. Based upon these properties, commercialization of R-3750 could provide an important new IBD treatment that is oral-based, safer than current drug options, and potentially lower cost.
Project Terms: <21+ years old> | | | | | | 