# Designer Probiotics for the treatment of intestinal infection and inflammation

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $733,448

## Abstract

Project Summary
New drug delivery platforms are vitally needed for the targeted delivery of high-specificity therapeutics to sites
of disease in order to maximize therapeutic efficacy while limiting off-target side effects. The majority of efforts
currently underway for the development of such targeted drug delivery systems are focused on the
development of synthetic nanoparticles, materials which are costly to produce, store, and distribute. Here, we
propose to develop cost-effective, self-replicating and flexible, programmable designer probiotics for the
targeted delivery of therapeutics directly to sites of disease. We propose to utilize a synthetic biology approach
to genetically engineer a widely and safely administered probiotic, Escherichia coli Nissle 1917, to express a
nanomachine that can secrete therapeutic payloads into the intestinal milieu. These designer bacteria will be
equipped with a type 3 secretion system modified to secrete proteins into the intestinal lumen rather than their
innate target, the cytosol of mammalian cells. As proof of concept and towards the development of these
designer probiotics as therapeutics, we will engineer these designer probiotics to secrete a new class of well-
documented therapeutic biomolecules of exquisite specificity, single domain antibodies, also referred to as
VHH. We will focus on the delivery of VHH multimers that exhibit profound neutralizing activity, VHH-based
neutralizing agents (VNAs), which inhibit the activity of essential bacterial toxins or proinflammatory cytokines.
Furthermore, we will investigate the potential of these strains as novel therapeutic paradigms for the treatment
of both intestinal infections and inflammation disorders. Specifically, we will investigate the efficacy of these
strains in the prevention of treatment of Clostridium difficile infections (CDI), hemolytic uremic syndrome (HUS)
and inflammatory bowel disease (IBD). We appreciate that there might be some concern regarding the
administration of genetically modified bacteria as therapeutics. However, as we enter the `era of the
microbiome,' it seems extremely likely that such interventions are to become an integral component of the
armamentarium utilized to treat infections and inflammatory disorders, particularly those rooted in the
gastrointestinal tract, especially because of the high likelihood that such agents can overcome many issues
associated with the wide-spread usages of antibiotics and systemic immunosuppressive agents. While efforts
here are specifically devoted towards the development of these designer probiotics for the treatment of CDI,
HUS, and IBD, once established as a therapeutic paradigm, this designer probiotic platform can be extended
to treat a variety of intestinal based diseases. For example, the designer probiotics could be programmed to
deliver a variety of protein-based therapeutic payloads, including cytokines, such as IL-10, that suppress
intestinal inflammation or VNAs designed to...

## Key facts

- **NIH application ID:** 10004029
- **Project number:** 5R01DK113599-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Wendy S. Garrett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $733,448
- **Award type:** 5
- **Project period:** 2016-09-23 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004029

## Citation

> US National Institutes of Health, RePORTER application 10004029, Designer Probiotics for the treatment of intestinal infection and inflammation (5R01DK113599-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10004029. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*