# Novel Therapeutic Approaches For Treatment of Intestinal Inflammation

> **NIH NIH R01** · GEORGIA STATE UNIVERSITY · 2020 · $340,875

## Abstract

Summary
The two most common forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis,
affect approximately 1.4 million people in the United States. The etiology of IBD is unclear, yet aberrant innate
and adaptive immune responses directed towards the commensal microbiota are believed to underlie disease
pathogenesis. Numerous pro-inflammatory factors contribute to disease severity and targeting some of these
factors has proven effective in the treatment of IBD patients. TNFα in particular plays a crucial role as a pro-
inflammatory mediator in the pathogenesis of IBD and the anti-TNFα monoclonal antibody, infliximab, is now
successfully used in the clinic to treat human IBD. However, anti-TNFα therapy is only effective in a subset of
IBD patients and concerns remain regarding adverse effects, such as cancer and opportunistic infections. The
observed adverse effects are mainly due to the lack of targeted treatment and the “over dosage” that is usually
inherent to systemic drug administration. More recently, a monoclonal antibody targeting IL-12 and IL-23,
ustekinumab, was shown to be effective in IBD patients, especially those in which anti-TNFα therapy had
previously failed. Thus, treatment of human IBD may be optimized by novel delivery regimens that allow for
targeted, low-dose inhibition of both TNF-α and IL-12/23. We have demonstrated that oral administration of
nanoparticles loaded with TNFα siRNA and encapsulated in an alginate-chitosan hydrogel can be efficiently
targeted to the colon without toxicity and reduce intestinal inflammation in a mouse model. Our exciting
preliminary data demonstrate that specific targeting of nanoparticles containing siRNA to intestinal antigen
presenting cells may enhance the beneficial effects of this novel therapeutic approach. In the course of these
studies, we also discovered that inhibition of pro-inflammatory cytokines can have the unexpected side effect
of inhibiting critical wound-healing factors, such as IL-22. These finding have led us to propose that
nanoparticle-mediated manipulation of TNFα, IL-12/23 and IL-22 limits intestinal inflammation and promotes
wound healing during IBD. These novel strategies aimed at locally inhibiting key pro-inflammatory cytokines
while simultaneously promoting wound healing may contribute to the development of improved therapies for
the treatment of human IBD.

## Key facts

- **NIH application ID:** 9925209
- **Project number:** 5R01DK107739-04
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** Timothy L Denning
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $340,875
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925209

## Citation

> US National Institutes of Health, RePORTER application 9925209, Novel Therapeutic Approaches For Treatment of Intestinal Inflammation (5R01DK107739-04). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9925209. Licensed CC0.

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