Mitigation of Ionizing Irradiation-Induced Intestinal Damage by Second-Generation Probiotics LR-IL-22 and LR-IFN-β

第二代益生菌 LR-IL-22 和 LR-IFN-β 减轻电离辐射引起的肠道损伤

• 批准号: 10380676
• 负责人: JOEL S GREENBERGER
• 金额: $ 30万
• 依托单位: CHROMOLOGIC, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380676
• 关键词: Abdomen; Acute; Address; Affect; Animal Model; Animals; Biological Availability; Chimeric Proteins; Clinic; Clinical; Clinical Research; Data; Development; Dose; Drug Delivery Systems; Drug Formulations; Engineered Probiotics; Engineering; Environment; Ethics; European; Evaluation; Event; Exposure to; FDA approved; Feedback; Filgrastim; Food and Drug Administration Drug Approval; Formulation; Gastrointestinal Agents; Gastrointestinal Injury; Gastrointestinal tract structure; Generations; Goals; Grant; Healthcare Systems; Hematopoietic; Individual; Injury; Interferon-beta; Intestines; Investigational Drugs; Investigational New Drug Application; Ionizing radiation; Ions; Kinetics; Label; Lactobacillus reuteri; Lead; Marketing; Measures; Metabolic Clearance Rate; Morbidity - disease rate; Mus; Natural regeneration; New Drug Approvals; Normal tissue morphology; Nuclear; Oral; Oral Administration; Outcome; Patients; Pegfilgrastim; Pelvis; Persons; Pharmaceutical Preparations; Probiotics; Quality of life; Radiation; Radiation Dose Unit; Radiation Protection; Radiation Tolerance; Radiation Toxicity; Radiation exposure; Radiation therapy; Radiobiology; Radiology Specialty; Research Personnel; Resources; Safety; Site; Small Intestines; Syndrome; Technology; Therapeutic; Toxic effect; Translational Research; Work; acute symptom; base; cytokine; design; drug development; experimental study; gastrointestinal; gastrointestinal symptom; gastrointestinal system; gut microbiome; gut microbiota; high risk; improved; innovation; interleukin-22; intestinal crypt; irradiation; manufacturing process; mass casualty; medication safety; microbiome; mortality; mouse model; nonhuman primate; novel therapeutic intervention; persistent symptom; preclinical study; radiation delivery; radiation mitigator; stem cells; targeted delivery; therapeutic cytokines; tissue regeneration

Abstract 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-β) 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.

摘要