Mitigation of Radiation-Induced Pulmonary Injury with Nrf2 activator

描述(由申请人提供)：核事故受害者的轶事经验表明，在高级支持性护理下，个人可能会在急性辐射综合征(造血和胃肠综合征)中幸存下来，但最终会死于放射性肺炎/纤维化造成的呼吸窘迫。此时，还没有FDA批准S治疗放射性肺炎/纤维化。因此，该项目的目标是利用约翰·霍普金斯大学(JHU)开发的Nrf2激活剂--三氟甲基-2‘-甲氧基酮(TMC)，最终开发一种安全、有效、实用和广泛可用的医学对策来减轻和/或治疗放射性肺损伤。Nrf2激活剂作为一种医学对策的理论基础源于十年的研究表明，增强Nrf2信号将通过上调包括几乎所有细胞抗氧化剂在内的广泛细胞保护防御来抑制氧化应激、细胞凋亡、异常免疫反应和炎症(放射性肺损伤涉及的四个关键病理过程)。这里提出的研究将集中在中医药的进一步发展上。这项建议的目的是使TMC在GLP指南下对啮齿动物和非人类灵长类动物进行关键的疗效研究，以便根据动物规则申请研究性新药(IND)和FDA批准。该提案包括七个具体的里程碑，并确定了确定这些里程碑成功与否的基准。具体地说，这些研究旨在确定TMC的最大耐受量(MTD)、组织和血浆PK，建立基于该化合物机理的药效学分析，并确定TMC治疗的最佳剂量、治疗持续时间和开始治疗的机会窗口，以优化治疗效果并最大限度地提高生存率。

DESCRIPTION (provided by applicant): Anecdotal experience with nuclear accident victims has shown that with superior supportive care, individuals may survive the acute radiation syndromes (hematopoietic and gastrointestinal syndromes), but ultimately succumb to respiratory distress due to radiation pneumonitis/fibrosis as a delayed effect. At this time there s no FDA approved treatment for radiation pneumonitis/fibrosis. Therefore, the goal of this project is to finalize the development of a safe, effective, practical, and widely available medical countermeasure to mitigate and/or treat radiation-induced pulmonary injury by utilizing a Nrf2 activator, trifluoromethyl-2'-methoxychalone (TMC) developed at Johns Hopkins University (JHU). The rationale for Nrf2 activator as a medical countermeasure arises from a decade of research demonstrating that augmenting Nrf2 signaling will inhibit oxidative stress, apoptosis, aberrant immune response, and inflammation (the 4 key pathologic processes involved in radiation-induced pulmonary injury) by upregulating a broad spectrum of cytoprotective defenses including nearly all cellular antioxidants. The studies proposed here will be focused on further development of TCM. The objective of this proposal is to bring TMC towards pivotal efficacy studies under GLP guidelines in rodent and non-human primates for Investigational New Drug (IND) application and FDA approval under the Animal Rule. The proposal comprises seven specific Milestones and defines benchmarks for determining their success. Specifically, the studies are designed to determine the maximum tolerated dose (MTD), tissue and plasma PK, establish a pharmacodynamics assay based on the mechanism of the compound, and to define the optimal dose, treatment duration, and window of opportunity for initiation of TMC treatment to optimize therapeutic efficacy and maximally improve survival.