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

摘要 我们已经开发出转基因的第二代益生菌，用于已知的 在暴露于电离辐射后，胃肠道的缓解剂可以减少损伤并使组织再生。 减轻电离辐射暴露的影响对于在发生放射性损伤时提高存活率至关重要。 或核（RAD-NUC）事件，其中暴露可能导致造血或胃肠道（GI）急性 放射综合征（ARS）。虽然Neupogen和Neulasta已获得FDA的标签扩展， 治疗RAD-NUC事件的伤亡，这些药物不能预防GI-ARS相关的死亡。目前， 没有FDA批准的GI-ARS缓解剂。为了满足这一关键需求，我们设计了乳酸菌 reuteri产生治疗性细胞因子（IL-22或INF-β），并将这些缓解剂靶向小肠， 恢复肠道干细胞，再生辐射敏感的肠隐窝，并显着改善 暴露于GI-ARS诱导辐射剂量后，存活率从0-10%提高到70-80%。这是一个新的战略， 使用益生菌的治疗药物递送可以口服施用， 资源有限的大规模伤亡场景除了减轻RAD-NUC事件后的伤害外， 该方法也适用于腹部放射治疗期间肠的放射防护。症状 GI毒性影响60-80%的> 300，000接受盆腔或腹部放射治疗的患者， 年这个项目是基于一个全新的概念，解决了基本的主要限制 与递送GI综合征的任何潜在辐射缓解剂相关，包括（i）非侵入性 施用，（ii）治疗剂的靶向递送，（iii）维持治疗剂的生物利用度， 以有效剂量，（iv）可轻微放大生产，和（v）不需要配制。这个目标 项目是开发一种FDA批准的辐射诱导胃肠道损伤缓解剂。我们建议进行批判性研究， 表征最大有效剂量，确定从体内清除的速率，并通过以下方式解决安全性问题 检查药物对肠道微生物组的影响。与此同时，我们将与FDA会面， 指导后续研究的IND批准策略。这项工作的顺利完成将使 这些益生菌药物正在朝着最终获得FDA批准的方向前进。

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.