# Modulating XIAP for the Treatment of Inflammatory Bowel Disease

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $173,438

## Abstract

PROPOSAL SUMMARY
Inflammatory bowel disease (IBD) is a highly prevalent intestinal disorder for which there is currently no cure.
The current treatment is comprised of anti-TNF therapy which alleviates the symptoms but does not target the
cause of the disease. Mutations in the X-linked Inhibitor of apoptosis protein (XIAP) have been identified in IBD
patients, suggesting that reduced XIAP activity causes IBD. One of the characteristic manifestations in IBD is
excessive death and damage to the intestinal epithelium, which contributes to intestinal inflammation because
of the compromised intestinal epithelial barrier against luminal microbiota. We propose to target the root cause
of IBD by directly restoring XIAP activity to homeostatic levels in patients with IBD. XIAP is the most potent
inhibitor of caspases and apoptosis. Reduced XIAP is associated with increased activation of the inflammasome
pathway of innate immune host defense and the upregulation of inflammatory tumor necrosis factor (TNF) and
interleukin (IL)-1b cytokines, resulting in hyperinflammation, which is also a characteristic of IBD. We predict
that regaining the normal activity of XIAP in IBD would control the excessive cell death of intestinal epithelial
cells and restore the healthy function and homeostatic turnover of the intestinal epithelium. The studies we
propose here will exploit the pro-apoptotic protein ARTS, which negatively regulates XIAP and promotes its
degradation by the Ubiquitin-Proteasome System. We hypothesize that ARTS serves as an important
therapeutic target for IBD by boosting the reduced activity of XIAP back to normal. Working with murine and
human colonic organoids, we will test the idea that reduced activity of XIAP in cells harboring IBD-associated
mutations can be overcome by inhibition of ARTS. Since expression of ARTS is induced in response to stress
and DNA-damage, this may also account for reduced XIAP activity in IBD patients without XIAP mutations. Thus,
strategies to raise XIAP activity may have broad impact beyond cases in which XIAP mutations are implicated
in IBD. Utilizing a complementary approach, we will modulate the activities of ARTS and XIAP using a proprietary
panel of small-molecule “ARTS-antagonists” and “XIAP-agonists” which we have identified. We seek to provide
proof-of-concept that our “ARTS-antagonists” and “XIAP-agonists” will be able to restore to normal the XIAP
function in cells with IBD-associated XIAP mutations as a novel treatment strategy for IBD. We will also test
these small molecules in an animal model of IBD. We have two specific aims: (1) Determine the role of ARTS
in regulating XIAP-induced apoptosis and inflammation in IBD, and (2) Identify the most potent ARTS-antagonist
and XIAP-agonist small molecules that restore XIAP expression and function in IBD models. Our proposal
provides a radical new approach for regulating XIAP by its natural antagonist ARTS, whose therapeutic
exploitation has not yet been investigat...

## Key facts

- **NIH application ID:** 10915575
- **Project number:** 5R21AI178327-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Julie Magarian Blander
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $173,438
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915575

## Citation

> US National Institutes of Health, RePORTER application 10915575, Modulating XIAP for the Treatment of Inflammatory Bowel Disease (5R21AI178327-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10915575. Licensed CC0.

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