Targeted Therapies for the Treatment of GI-ARS Diarrhea

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 andamp; 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 RxBioandapos;s business platform and strategy: 1) It adds required infor- mation to the drug master files; 2) Opens up new indications for these compounds in the treatment of SED of multiple etiologies postradiotherapy and bacterial, the latter being the second leading cause of death in the developing world to be pursued in phase 2.With the aggressive moves of rogue nations to develop ballistic missiles with nuclear warheads, the potential of nuclear accidents, and the threat of radiation terrorism increase the possibility of exposure to high levels of ionizing radiation. Currently, no FDA approved medical countermeasures available for Gastrointestinal Acute Radiation Syndrome. The proposed work significantly advances the development of a novel gastrointestinal radiation countermeasures by evaluating their efficacy in reducing life- threatening radiation-induced diarrhea. This research will also open up peace-time indications for these drug candidates in the treatment of secretory diarrhea of multiple etiology.