# A Novel Synthetically Engineered Oral Immunotherapy for Treating Ulcerative Colitis

> **NIH NIH SB1** · RISE THERAPEUTICS, LLC · 2024 · $673,379

## Abstract

Project Summary
The goal of this project is to develop a novel synthetic biology-based cellular medicine that leverages natural
microbiome pathways to inhibit gut inflammatory processes for the treatment of inflammatory bowel 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 IBD
treatments can have serious side-effects, and patients become refractory. Novel therapies that are safe and
effective, 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 in
IBD40. 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 adaptive
immune cell function41. 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 immunity
in steady state and diseased conditions42-45. Our research team demonstrated that SlpA is the predominant
anti-inflammatory Slp signal. SlpA binds to the C-type lectin Specific Intracellular adhesion molecule-3
Grabbing Non-integrin homolog-Related 3 (SIGNR3) receptor expressed on dendritic cells lining the gut
prevents experimentally induced colitis in multiple models15. Oral delivery of SlpA via L. lactis (also known as
R-3750 or R110) reduced inflammatory cytokines, strengthened the mucosal membrane barrier, and supported
a healthier microbiota make-up in animal models of gut inflammation20. Notably, the effects and protection
mediated by SlpA were not observed in Signr3-/- mice, suggesting that SlpA interaction with SIGNR3 plays a
key protective role in regulating the disease condition15. New data from our Phase 1 clinical trial in patients
suffering from ulcerative colitis (NCT05666960) showed that R-3750 was safe and yielded promising biomarker
data and clinical outcome results demonstrating clinical proof-of-concept.
Our goal is to develop R-3750, a synthetic biology engineered SlpA-expressing Lactococcus (L.) lactis strain,
as a novel, orally administered drug that functions as immune therapy to reduce gut inflammation, improve
gastrointestinal mucosal barrier function, and restore the natural microbiome make-up in IBD patients. This
CRP application is intended to build upon our prior product development success and advance R-3750 into
Phase 2 clinical testing. The specific aims are: 1) establish 250L scale GMP manufacturing infrastructure, 2)
develop 250L scale process for R-3750 clinical manufacturing, 3) perform clinical GMP manufacturing of...

## Key facts

- **NIH application ID:** 11007154
- **Project number:** 1SB1DK141356-01
- **Recipient organization:** RISE THERAPEUTICS, LLC
- **Principal Investigator:** Gary Fanger
- **Activity code:** SB1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $673,379
- **Award type:** 1
- **Project period:** 2024-09-16 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11007154

## Citation

> US National Institutes of Health, RePORTER application 11007154, A Novel Synthetically Engineered Oral Immunotherapy for Treating Ulcerative Colitis (1SB1DK141356-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11007154. Licensed CC0.

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