# Precision therapeutics of inflammatory bowel disease guided by Boolean logic

> **NIH NIH UH3** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $355,500

## Abstract

ABSTRACT
Disruption of the gut barrier has been implicated in the pathogenesis of multiple chronic illnesses that are
characterized by chronic gastrointestinal inflammation. One such illness is inflammatory bowel disease (IBD), a
complex, multi-factorial, autoimmune disorder of the gut in which diverse components (microbes, genetics,
environment and immune response) intersect in elusive ways and culminate in overt disease 1. It is also
heterogeneous with complex sub-disease phenotypes (i.e., strictures, fistula, abscesses, and colitis-associated
cancers). Currently, patients are offered inflammation-reducing therapies that have only a ~30-40% response-
rate, and 40% of responders become refractory to treatment within one year 2. Little to nothing has emerged that
can fundamentally tackle the most widely recognized indicator/predictor of disease relapse, response and
remission 3-8, i.e., a compromised epithelial barrier. Among the reasons cited are- 1) incomplete understanding
of host-microbe interactions in the gut, and 2) our theoretical inability to pinpoint such a fundamental, actionable
and effective target to drive a complex and nebulous process of gut barrier permeability.
 Preliminary studies using publicly available transcriptomic datasets from adult and pediatric patients with
IBD and a set of unbiased novel computational approaches (Boolean implication relationships and Boolean
Implication Networks) have pinpointed a novel target, whose activation is predicted to enhance a bona-fide
barrier-protective pathway, and thereby, restore the gut barrier across the two subtypes of IBD, despite disease
heterogeneity. Expression pharmacology studies using a companion biomarker in FFPE human tissues
confirmed that the barrier-protective pathway orchestrated by this target is silenced in patients with IBD. Using
a potent and highly specific drug that was previously developed for another indication and found to be safe in
Phase I trials on healthy human adults, preliminary evidence has been obtained which shows that activation of
the target is necessary and sufficient to trigger the barrier-protective pathway, and for the protection of the
epithelial barrier in mice (chemical-induced colitis models) and in murine and human organoid-monolayers
challenged with live microbes; it also restored the leaky gut barrier observed in IBD patient-derived organoids.
 This proposal seeks to validate the repurposing of this potent and specific drug for activating a novel
barrier-protective target, the first of its kind, in the treatment of adult and pediatric IBD. Our specific Aims during
the 3-y UG3 phase are all geared towards target validation: obtaining proof-of-mechanism in healthy murine and
human colon-derived organoids (Aim 1); preclinical proof-of-principle studies using murine models of colitis (Aim
2); and expression pharmacology and proof-of-concept Phase `0' trials in patient-derived organoids (pediatric
and adults; Aim 3). Successful demonstration of...

## Key facts

- **NIH application ID:** 10709716
- **Project number:** 4UH3TR003355-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Pradipta Ghosh
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $355,500
- **Award type:** 4N
- **Project period:** 2020-08-28 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10709716

## Citation

> US National Institutes of Health, RePORTER application 10709716, Precision therapeutics of inflammatory bowel disease guided by Boolean logic (4UH3TR003355-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10709716. Licensed CC0.

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