Investigation of the mechanisms of H-ARS mitigation by the orally administrated GI-ARS mitigator LR-IFN-beta - Abstract We have developed a genetically modified second-generation probiotic for the localized delivery of a known mitigator to the GI tract in order to reduce damage and regenerate tissue after exposure to ionizing radiation. Mitigating the effects of ionizing radiation exposure is critical for improving survival in the event of a radiological or nuclear (RAD-NUC) incident, where exposure could lead to hematopoietic or gastrointestinal (GI) acute radiation syndrome (ARS). While Neupogen and Neulasta have been granted label extensions by the FDA to treat casualties of a RAD-NUC incident, these drugs do not prevent GI-ARS-related mortality. There currently are no FDA-approved mitigators for GI-ARS. To address this critical need, we have engineered Limosilactobacillus reuteri to produce the therapeutic cytokine INF-β and target the mitigator to the small intestines to recover intestinal stem cells, regenerate the radiation-sensitive intestinal crypts, and dramatically improve survival from 0–10% to 70–80% after exposure to both GI-ARS and H-ARS-inducing radiation doses. This is a new strategy for therapeutic drug delivery, using a probiotic that can be administered orally, facilitating its use in the context of a resource-limited mass casualty scenario. In addition to mitigating acute injury following a RAD-NUC incident, this approach is also applicable to radioprotection of the intestine during abdominal radiotherapy. Symptoms of GI toxicity affect 60–80% of the >300,000 patients that receive pelvic or abdominal radiation therapy per year. This project is based on an entirely new concept that addresses the fundamental major limitations associated with delivery of any potential radiation mitigator of GI syndrome, including (i) non-invasive administration, (ii) targeted delivery of the therapeutic, (iii) maintained bioavailability of the therapeutic at efficacious dose, (iv) trivially scalable to produce, and (v) no need for formulation. The goal of this project is to develop an FDA-approved mitigator for radiation-induced hematopoietic and GI injury. As part of this overall effort, we propose critical studies to begin to characterize the mechanism by which this orally administrated GI-ARS countermeasure is able to mitigate radiation toxicity in the bone marrow for animals exposed to total body irradiation.
