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

摘要 我们已经开发了转基因第二代益生菌，用于本地化传递已知的 在暴露于电离辐射后，可将缓释剂用于胃肠道，以减少损伤并使组织再生。 减轻电离辐射暴露的影响对于提高在发生放射性疾病时的存活率至关重要 或核(RAD-NUC)事件，暴露可能导致造血或胃肠道(GI)急性 辐射综合征(ARS)。而Neupogen和Neulasta已被FDA批准延长标签期限 治疗RAD-NUC事件的伤亡，这些药物不能防止与GI-ARS相关的死亡。目前在那里 没有FDA批准的GI-ARS缓释剂。为了满足这一关键需求，我们设计了乳杆菌 Reuri产生治疗性细胞因子(IL-22或INF-β)，并将这些缓释剂靶向小肠 恢复肠道干细胞，再生对辐射敏感的肠道隐窝，并显著改善 在暴露于GI-ARS诱发辐射剂量后，存活率从0-10%到70-80%。这是一种新的战略 使用益生菌的治疗性药物递送可以口服，便于在上下文中使用 在资源有限的大规模伤亡情况下。除了减轻RAD-NUC事件后的伤害外， 这种方法也适用于腹部放射治疗期间肠道的放射防护。症状： 在每年接受盆腔或腹部放射治疗的30万名患者中，胃肠道毒性影响到60%-80% 年。这个项目基于一个全新的概念，解决了根本的主要限制 与提供任何潜在的胃肠道综合征放射缓释剂有关，包括：(I)非侵入性 给药，(Ii)靶向输送治疗性药物，(Iii)维持治疗性药物的生物利用度 在有效剂量下，(Iv)可平凡地按比例生产，以及(V)不需要配方。这样做的目的是 该项目是开发一种FDA批准的用于治疗辐射引起的胃肠道损伤的缓释剂。我们建议进行批判性研究，以 描述最大有效剂量，建立从体内清除的速率，并通过以下方式解决安全问题 检测药物对肠道微生物群的影响。同时，我们将与FDA会面，以制定 指导后续研究的IND批准战略。这项工作的圆满完成将使 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.