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，在上级支持性治疗下，个体可在急性辐射综合征（造血和胃肠道综合征）中存活，但最终死于辐射性肺炎/纤维化所致的呼吸窘迫，这是一种延迟效应。目前还没有FDA批准的放射性肺炎/纤维化的治疗方法。因此，本项目的目标是最终开发一种安全、有效、实用和广泛可用的医疗对策，以利用约翰霍普金斯大学（JHU）开发的Nrf 2激活剂三氟甲基-2 '-甲氧基查尔酮（TMC）减轻和/或治疗辐射诱导的肺损伤。Nrf 2激活剂作为医学对策的基本原理来自于十年的研究，这些研究表明，增强Nrf 2信号传导将通过上调广谱细胞保护性防御（包括几乎所有的细胞抗氧化剂）来抑制氧化应激、细胞凋亡、异常免疫反应和炎症（辐射诱导的肺损伤中涉及的4个关键病理过程）。本文提出的研究重点是中医药的进一步发展。本提案的目的是根据GLP指导原则，在啮齿动物和非人灵长类动物中开展TMC关键疗效研究，以用于研究性新药（IND）申请和FDA根据动物规则的批准。该提案包括七个具体的里程碑，并确定了确定其成功与否的基准。具体而言，这些研究旨在确定最大耐受剂量（MTD）、组织和血浆PK，建立基于化合物机制的药效学试验，并确定最佳剂量、治疗持续时间和开始TMC治疗的机会窗口，以优化治疗疗效并最大限度地改善生存期。

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.