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: 10401463
• 负责人: Isabel Lauren Jackson
• 金额: $ 37.43万
• 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/10401463
• 关键词: Acute; Address; Advanced Development; Agreement; Anatomy; Animal Model; Animals; Area; BCL2L1 gene; Biological Process; Blinded; Blood specimen; Bone Marrow; C57L/J Mouse; Cancer Patient; Cell Aging; Cell Death; Cell Survival; Cells; Clinical; Clinical Data; Collaborations; Combined Modality Therapy; Competitive Binding; Complex; DNA Damage; DNA Repair; Data; Development; Disease Progression; Dose; Drug Exposure; Drug Kinetics; Enzyme-Linked Immunosorbent Assay; Estrogen Receptor beta; Evaluation; Exposure to; Fibrosis; Goals; Hour; Human; In Vitro; Individual; Inflammation; Inflammatory Response; Intramuscular; Intramuscular Injections; Knowledge; Life; Lung; Mediating; Medical Imaging; Methods; Modeling; Morbidity - disease rate; Mus; NF-kappa B; Natural History; Nuclear Accidents; Oral; Oral Administration; Outcome; Outcome Measure; Oxidative Stress; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Pharmacology; Plasma; Play; Protac; Publishing; Pulmonary Inflammation; Radiation Accidents; Radiation Dose Unit; Radiation Injuries; Radiation Pneumonitis; Radiation Sicknesses; Radiation Syndromes; Radiation Toxicity; Radiation exposure; Radiation induced damage; Radiation therapy; Randomized; Readiness; Recovery of Function; Regimen; Regulatory Pathway; Research; Rodent; Role; Safety; Signal Transduction; Statistical Data Interpretation; Structure of parenchyma of lung; Supportive care; Suspensions; Syndrome; Systems Biology; Technology; Testing; Therapeutic; Tissues; Treatment Efficacy; United States Food and Drug Administration; Whole-Body Irradiation; animal efficacy; animal rule; base; candidate marker; design; efficacy study; experience; experimental study; functional outcomes; good laboratory practice; improved; indexing; injury recovery; lung injury; medical countermeasure; member; model design; mouse model; nonhuman primate; novel; pharmacodynamic biomarker; pharmacometrics; pneumonitis and fibrosis; radiation countermeasure; senescence; standard of care; survival outcome; tissue biomarkers; transcriptome sequencing

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 有一个迫切的，尚未得到满足的需求，即开发医学对策(MCM)来缓解 急性辐射暴露(DEARE)对受害者的延迟效应，即放射性肺炎/纤维化 在发生放射性或核事故后，成功治疗急性放射病。总体目标 项目4的目的是完成必要的活动，使BIO 300(“BIO 300”)纳米悬浮(人文学) 公司，Edina，MN)根据美国食品和药物管理局(FDA)动物规则获得批准 急性暴露于肺毒性剂量的个体增加存活率的适应症的调节途径 辐射的延迟效应[例如，急性辐射--暴露(DEARE)--肺]。我们公布的数据表明 300(400 mg/kg，qd，口服)可显著提高死肺后的存活率。 治疗在暴露于危及生命的剂量后24小时开始，并持续6周。 (5)。此外，临床数据显示，当bio 300作为每日口服时，具有极好的安全性。 疗程(500-1500毫克)，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 在Aim 1中，旨在优化BIO 300给药方案，以最大限度地提高从DeARE中存活的可能性。 阿龙。在小鼠和非人类灵长类动物模型中观察到，当BIO 300 通过肌肉注射(IM)与口服给药。因此，IM管理可以进一步 提高BIO 300对220天存活期的治疗益处，并减轻除此之外的肺损伤 口服给药观察。具体目标2将与核心B--多物种功效合作进行 和药物计量模型。这一目标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学(PD)生物标志物 关于啮齿类动物和NHP的细胞衰老。结合药物计量学的系统生物学方法 将利用建模，并将结合已知的BIO300对癌症中PD生物标记物的影响 接受临床放射治疗的患者与BIO 300在动物身上的拟议作用机制有关 模型与人类的假定机制相吻合。细胞衰老在肺萎缩中的作用更进一步 在目标3中通过单独或与BIO 300结合测试感受剂进行了探索。更进一步，目标3 将解决与ARS潜在的病理生理机制相关的知识差距 通过与项目1、2和项目的大力合作，开发和测试新型感受剂(BCL-XL-P) 3.项目4的功率计算和统计分析将由核心A的生物统计学家进行-- 管理核心。拟议的目标只有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一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。