# Targeted Therapies for the Treatment of GI-ARS Diarrhea

> **NIH NIH R41** · RXBIO, INC. · 2020 · $252,128

## Abstract

The US population at large, and particularly military personnel and first responders, are at risk of radiation
exposure due to the explosion of a nuclear device, a nuclear reactor accident, and the threat of radiation terror-
ism. There is no radiation medical countermeasure (RCM) drug approved by the FDA that meets the criterion
of a gastrointestinal (GI) radiomitigator – an agent which mitigates the acute GI radiation syndrome (GI-ARS)
when administered after the exposure. Post-irradiation genotoxic stress and cell injury is an unsolved medical
problem. The US Government mandates that a RCM have peace-time indications in the treatment of other
diseases. RxBio Inc., founded by faculty and alumni of the University of Tennessee in 2003, has successfully
developed three lead compounds Rx100, Radioprotectin 1 (RP1), and Radioprotectin 2 (RP2) that are highly
effective in reducing radiation-induced cell death in vitro and in vivo. These compounds are effective radiation
mitigators in murine gastrointestinal acute radiation syndrome (GI-ARS) models and Rx100 has also been
proven effective in a Rhesus model when administered 24h postirradiation with lethal doses of γ-radiation. RID
is also the most common issue experienced by patients undergoing whole body, pelvic, or abdominal radio-
therapy. The objectives of this STTR application are: 1) to assess and rank the anti-diarrheal efficacy of the
three lead drug candidates for use to treat secretory-type diarrheas (SED) of multiple etiologies in addition to
Radiation-induced diarrhea (RID), and 2) elucidate their antidiarrheal mechanism of action required under the
FDA Animal Rule (21 CFR 314.600). In this translational research proposal, we propose studies to fully
satisfy the mechanism of action requirement of the Animal rule for our radiation mitigators we developed with
previous NIAID funding. We propose the following aims:
1. Determine the efficacy of three LPA2 targeting radiation mitigators in blocking the CFTR-linked
transcellular ion transport pathway leading to GI-ARS diarrhea.
Rationale: Rx100, RP1 & 2 are agonists of LPA2. We showed that LPA2 inhibits CFTR-mediated Cl- influx into
the gut lumen followed by secondary paracellular movement of Na+ and H2O leading to diarrhea.
2. Establish the efficacy of our radiation mitigators in blocking the paracellular ion transport path-
way in GI-ARS diarrhea by enhancing adherens-junction (AJ) and tight-junction (TJ) function.
Rationale: LPA2 signaling enhances the gut barrier by reducing paracellular transport via the AJ and TJ.
 Our expected outcomes will include the evaluation of the actions of our three lead compounds as
antidiarrheals thereby providing a better understanding of RID and BARD in GI-ARS.
 Our team brings together the expertise of the Tigyi group in LPA pharmacology/signaling, the Rao
team in gut barrier regulation with the expertise of the RxBio team in drug pharmaceutics. The proposed re-
search will have two major outcomes on RxBio's ...

## Key facts

- **NIH application ID:** 10008169
- **Project number:** 1R41DK125208-01
- **Recipient organization:** RXBIO, INC.
- **Principal Investigator:** GABOR J TIGYI
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $252,128
- **Award type:** 1
- **Project period:** 2020-09-18 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10008169

## Citation

> US National Institutes of Health, RePORTER application 10008169, Targeted Therapies for the Treatment of GI-ARS Diarrhea (1R41DK125208-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10008169. Licensed CC0.

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