Development of BIO 300 for mitigation and/or treatment of radiation pneumonitis and fibrosis

开发用于缓解和/或治疗放射性肺炎和纤维化的 BIO 300

• 批准号: 10845829
• 负责人: Isabel Lauren Jackson
• 金额: $ 38.47万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-16 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10845829
• 关键词: Development; BIO; 300; mitigation; treatment

Project Summary/Abstract – Project 4 Radiation Pneumonitis/Fibrosis There is a critical, unmet need to develop medical countermeasures (MCM) for the mitigation of the delayed effects of acute radiation exposure (DEARE), namely radiation pneumonitis/fibrosis, in victims successfully treated for acute radiation sickness following a radiological or nuclear incident. The overall objective of project 4 is to complete activities necessary to bring BIO 300 (“BIO 300”) nanosuspension (Humanetics Corporation, Edina, MN) towards approval under the U.S. Food and Drug Administration (FDA) Animal Rule regulatory pathway for the indication to increase survival in individuals acutely exposed to pulmonary-toxic doses of radiation [e.g. delayed effects of acute radiation-exposure (DEARE)-lung]. Our published data indicates BIO 300 (400 mg/kg, QD, oral gavage) confers a significant improvement in survival from DEARE-lung when treatment is started 24 hours after exposure to life-threatening doses of radiation and continued for six weeks (5). Further, clinical data demonstrate an excellent safety profile when BIO 300 is administered as a daily oral regimen (500 - 1500 mg) over a minimum duration of six weeks. Project 4 is highly interactive with the other Projects and Cores within the INTERACT Consortium. Studies in Aim 1 are designed to optimize the BIO 300 dosing regimen to maximize the likelihood of survival from DEARE-lung. Higher drug exposure has been observed in murine and non-human primate models when BIO 300 is administered by intramuscular (IM) injection versus oral administration. Therefore, IM administration may further improve the therapeutic benefit of BIO 300 on 220-day survival and mitigation of lung damage beyond that observed with oral dosing. Specific Aim 2 will be conducted in collaboration with Core B-Multispecies Efficacy and Pharmacometric Modeling. Experiments in this aim are designed to identify and validate plasma-based pharmacodynamic (PD) biomarkers associated with BIO 300 mediated ERb activation and downstream effects on cellular senescence in rodents and NHP. A systems biology approach incorporating pharmacometric modeling will be utilized, and will incorporate known BIO 300-mediated effects on PD biomarkers in cancer patients undergoing clinical radiation therapy to relate the proposed mechanism of action of BIO 300 in animal models to the presumed mechanism in humans. The role of cellular senescence in DEARE-lung is further explored in Aim 3 through the testing of senolytic agents alone or in combination with BIO 300. Further, Aim 3 will address knowledge gaps relevant to the pathophysiological mechanisms underlying ARS evolving towards DEARE and testing of novel senolytic agents (BCL-xL-P) through strong collaborations with Projects 1, 2, and 3. Power calculations and statistical analysis for Project 4 will be performed by the biostatistician in Core A - Administrative Core. The proposed Aims are only achievable through a cooperative research agreement, as proposed by the INTERACT Consortium, whose members bring together expertise in every major area required to probe the complex biological processes orchestrating radiation damage in lung tissue and discover new biomarkers for tissue injury and recovery.

项目摘要/摘要 – 项目 4 放射性肺炎/纤维化 制定医疗对策 (MCM) 来缓解这种情况是一个至关重要的、尚未得到满足的需求。 急性辐射暴露（DEARE）对受害者的延迟影响，即放射性肺炎/纤维化 放射性或核事故后成功治疗急性放射病。总体目标 项目 4 的目的是完成将 BIO 300（“BIO 300”）纳米悬浮液（Humanetics Corporation（明尼苏达州埃迪纳）即将获得美国食品和药物管理局 (FDA) 动物规则的批准 提高急性暴露于肺毒性剂量的个体的生存率的调节途径 辐射[例如急性辐射暴露（DEARE）肺的延迟效应]。我们公布的数据表明 BIO 300（400 mg/kg，QD，口服强饲）可显着改善 DEARE-lung 的存活率 接受危及生命的辐射剂量后 24 小时开始治疗，并持续六周 （5）。此外，临床数据表明，每日口服 BIO 300 具有出色的安全性。 治疗方案（500 - 1500 mg）至少持续六周。 项目 4 与 INTERACT 联盟内的其他项目和核心具有高度互动性。研究 目标 1 旨在优化 BIO 300 给药方案，以最大限度地提高 DEARE-lung 患者的生存可能性。当 BIO 300 存在时，在小鼠和非人类灵长类动物模型中观察到较高的药物暴露 通过肌内 (IM) 注射与口服给药进行比较。因此，IM 管理可以进一步 提高 BIO 300 对 220 天生存率的治疗效果并减轻肺损伤 通过口服给药观察。具体目标 2 将与 Core B-Multispecies Efficacy 合作进行 和药理学建模。此目的的实验旨在识别和验证基于等离子体的 与 BIO 300 介导的 ERb 激活和下游效应相关的药效 (PD) 生物标志物 啮齿动物和 NHP 细胞衰老的影响。结合药理学的系统生物学方法 将利用模型，并将结合已知的 BIO 300 介导的对癌症 PD 生物标志物的影响 接受临床放射治疗的患者将 BIO 300 在动物中的作用机制联系起来 人类假定机制的模型。细胞衰老在 DEARE-lung 中的作用进一步 通过测试单独的 senolytic 药物或与 BIO 300 组合，在目标 3 中进行了探索。此外，目标 3 将解决与 ARS 发展的病理生理机制相关的知识差距 DEARE 和通过与项目 1、2 和项目的强有力合作测试新型 senolytic 药物 (BCL-xL-P) 3. 项目 4 的功效计算和统计分析将由核心 A 的生物统计学家进行 - 行政核心。拟议的目标只能通过合作研究协议才能实现，因为 由 INTERACT 联盟提出，其成员汇集了所需的每个主要领域的专业知识 探索肺组织辐射损伤的复杂生物过程并发现新的 组织损伤和恢复的生物标志物。