SBIR-STTR Award

We have developed genetically modified second-generation probiotics for the localized delivery of known mitigators 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 Lactobacillus reuteri to produce therapeutic cytokines (IL-22 or INF-?) and target these mitigators 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 GI-ARS-inducing radiation doses. This is a new strategy for therapeutic drug delivery, using a probiotic can be administered orally, facilitating its use in the context of a resource-limited mass casualty scenario. In addition to mitigating 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 GI injury. We propose critical studies to characterize the maximum effective dose, establish the rate of clearance from the body, and address safety by examining the effect of the drugs on the intestinal microbiome. In parallel, we will meet with the FDA to develop a strategy for IND approval that will guide subsequent studies. Successful completion of this work will place these probiotic drugs on a strong path towards eventual FDA approval. Public Health Relevance Statement Project Narrative Mitigating normal tissue toxicity after exposure to ionizing radiation is critical to reduce mortality and morbidity, both for patients that receive pelvic or abdominal radiation therapy, and in the context of a RAD-NUC incident. We have developed second-generation probiotics engineered to express the therapeutic cytokines IL-22 or INF-? that have been shown to increase survival from 0–10% to 70–80%. The goal of this project is to continue to optimize and characterize these probiotic drugs for pivotal IND-enabling pre-clinical studies, which, if successful, will lead to the only FDA-approved radiation mitigators for GI toxicity.

Project Terms:
Abdomen ; Abdominal ; Oral Administration ; Oral Drug Administration ; intraoral drug delivery ; Affect ; Animals ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Clinical Research ; Clinical Study ; gastrointestinal system ; Ailmentary System ; Alimentary System ; Digestive System ; Gastrointestinal Body System ; Gastrointestinal Organ System ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Investigational Drugs ; Investigational New Drugs ; Engineering ; Environment ; Ethics ; ethical ; Feedback ; Interferon-beta ; Endogenous Interferon Beta ; Fibroblast Interferon ; IFN-Beta ; IFN-β ; IFNb ; Interferon-β ; Natural Interferon Beta ; Natural human interferon beta ; Gastrointestinal Agents ; Gastrointestinal Drugs ; Gastrointestinal tract structure ; Alimentary Canal ; Digestive Tract ; GI Tract ; Gastrointestinal Tract ; alimentary tract ; digestive canal ; Goals ; Grant ; Healthcare Systems ; Health Care Systems ; Small Intestines ; small bowel ; Intestines ; Intestinal ; bowel ; Ions ; Kinetics ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Marketing ; Metabolic Clearance Rate ; clearance rate ; Morbidity - disease rate ; Morbidity ; mortality ; Mus ; Mice ; Mice Mammals ; Murine ; Patients ; Pelvis ; Pelvic ; Pelvic Region ; Quality of life ; QOL ; Radiation Protection ; Radioprotection ; Radioprotective ; radio-protection ; radio-protective ; Radiation Tolerance ; Radiation Sensitivity ; Radiosensitivity ; radio-sensitivity ; radiosensitive ; Ionizing radiation ; Ionizing Electromagnetic Radiation ; Radiation-Ionizing Total ; ionizing output ; Radiobiology ; Radiation Biology ; Radiology Specialty ; General Radiology ; Radiology ; Radiation therapy ; Radiotherapeutics ; Radiotherapy ; radiation treatment ; radio-therapy ; treatment with radiation ; Natural regeneration ; Regeneration ; regenerate ; Research Personnel ; Investigators ; Researchers ; Resources ; Research Resources ; Safety ; stem cells ; Progenitor Cells ; Syndrome ; Technology ; Work ; cytokine ; Generations ; Measures ; Drug Delivery Systems ; Drug Delivery ; Gastrointestinal Injury ; New Drug Approvals ; Chimeric Proteins ; Chimera Protein ; Fusion Protein ; Investigational New Drug Application ; Injury ; injuries ; base ; Label ; improved ; Site ; Acute ; Clinical ; Filgrastim ; Neupogen ; filgrastrim ; Evaluation ; Hematopoietic ; hemopoietic ; Individual ; nonhuman primate ; non-human primate ; European ; Radiation Toxicity ; Acute Radiation Syndrome ; Radiotoxicity ; radiation poisoning ; Therapeutic ; L reuteri ; L. reuteri ; Lactobacillus reuteri ; Exposure to ; Normal Tissue ; Normal tissue morphology ; gastrointestinal symptom ; Event ; Oral ; Clinic ; gastrointestinal ; Nuclear ; Drug Formulations ; Probiotics ; Radiation Dose ; Radiation Dose Unit ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Toxicities ; Toxic effect ; Radiation ; drug development ; IL-22 ; interleukin-22 ; Filgrastim SD-01 ; Neulasta ; PEG SD-01 ; PEG-rmetHuG-CSF ; SD-01 ; SD-01 sustained duration G-CSF ; polyethylene glycol-conjugated filgrastim SD-01 ; Pegfilgrastim ; irradiation ; Address ; Dose ; Data ; Translational Research ; Translational Science ; translation research ; Development ; developmental ; tissue regeneration ; regenerate new tissue ; regenerate tissue ; regenerating damaged tissue ; regenerating tissue ; tissue renewal ; tissue specific regeneration ; preclinical study ; pre-clinical study ; microbiome ; intestinal crypt ; design ; designing ; Outcome ; targeted delivery ; site targeted delivery ; manufacturing process ; innovation ; innovate ; innovative ; mouse model ; murine model ; high risk ; novel therapeutic intervention ; new therapeutic approach ; new therapeutic intervention ; new therapeutic strategies ; new therapy approaches ; novel therapeutic approach ; novel therapeutic strategies ; novel therapy approach ; FDA approved ; gut microbiota ; GI microbiota ; Gastrointestinal microbiota ; enteric microbial community ; enteric microbiota ; gastrointestinal microbial flora ; gut commensal ; gut community ; gut flora ; gut microbe community ; gut microbial community ; gut microbial composition ; gut microbial consortia ; gut microbiotic ; gut microflora ; intestinal flora ; intestinal microbes ; intestinal microbiota ; intestinal microflora ; intestinal tract microflora ; mass casualty ; Food and Drug Administration Drug Approval ; FDA Drug Approval ; gut microbiome ; GI microbiome ; digestive tract microbiome ; enteric microbiome ; gastrointestinal microbiome ; gut-associated microbiome ; intestinal biome ; intestinal microbiome ; Formulation ; persistent symptom ; chronic symptom ; acute symptom ; Radiation exposure ; radiation mitigator ; radiological mitigator ; radiomitigator ; experimental study ; experiment ; experimental research ; therapeutic cytokines ; Engineered Probiotics ; Modified Probiotics ; Probiotic Engineering ; radiation delivery ; medication safety ; drug safety ; pharmaceutical safety ;

We have developed genetically modified second-generation probiotics for the localized delivery of knownmitigators 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 radiologicalor nuclear (RAD-NUC) incident, where exposure could lead to hematopoietic or gastrointestinal (GI) acuteradiation syndrome (ARS). While Neupogen and Neulasta have been granted label extensions by the FDA totreat casualties of a RAD-NUC incident, these drugs do not prevent GI-ARS-related mortality. There currentlyare no FDA-approved mitigators for GI-ARS. To address this critical need, we have engineered Lactobacillusreuteri to produce therapeutic cytokines (IL-22 or INF-β) and target these mitigators to the small intestines torecover intestinal stem cells, regenerate the radiation-sensitive intestinal crypts, and dramatically improvesurvival from 0-10% to 70-80% after exposure to GI-ARS-inducing radiation doses. This is a new strategy fortherapeutic drug delivery, using a probiotic can be administered orally, facilitating its use in the contextof a resource-limited mass casualty scenario. In addition to mitigating injury following a RAD-NUC incident,this approach is also applicable to radioprotection of the intestine during abdominal radiotherapy. Symptoms ofGI toxicity affect 60-80% of the >300,000 patients that receive pelvic or abdominal radiation therapy peryear. This project is based on an entirely new concept that addresses the fundamental major limitationsassociated with delivery of any potential radiation mitigator of GI syndrome, including (i) non-invasiveadministration, (ii) targeted delivery of the therapeutic, (iii) maintained bioavailability of the therapeuticat efficacious dose, (iv) trivially scalable to produce, and (v) no need for formulation. The goal of thisproject is to develop an FDA-approved mitigator for radiation-induced GI injury. We propose critical studies tocharacterize the maximum effective dose, establish the rate of clearance from the body, and address safety byexamining the effect of the drugs on the intestinal microbiome. In parallel, we will meet with the FDA to developa strategy for IND approval that will guide subsequent studies. Successful completion of this work will placethese probiotic drugs on a strong path towards eventual FDA approval.

Public Health Relevance Statement:
Project Narrative Mitigating normal tissue toxicity after exposure to ionizing radiation is critical to reduce mortality and morbidity, both for patients that receive pelvic or abdominal radiation therapy, and in the context of a RAD-NUC incident. We have developed second-generation probiotics engineered to express the therapeutic cytokines IL-22 or INF-β that have been shown to increase survival from 0-10% to 70-80%. The goal of this project is to continue to optimize and characterize these probiotic drugs for pivotal IND-enabling pre-clinical studies, which, if successful, will lead to the only FDA-approved radiation mitigators for GI toxicity.

Project Terms: