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放射性腹膜炎/纤维化 有一个关键的，未得到满足的需要，发展医疗对策（MCM），以减轻 急性辐射照射（DEARE）的延迟效应，即受害者的放射性肺炎/纤维化 在辐射或核事故后成功治疗急性辐射病。总体目标 项目4的目的是完成将BIO 300（“BIO 300”）纳米混悬液（Humanetics） 公司，明尼苏达州，利弗莫尔），以获得美国食品和药物管理局（FDA）动物法规的批准 急性暴露于肺毒性剂量的个体中增加存活率的适应症的调节途径 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， 300（400 mg/kg，QD，经口灌胃）在以下情况下显著改善DEARE-肺的存活率： 在暴露于危及生命剂量的辐射后24小时开始治疗，并持续6周 （五）、此外，临床数据表明，当BIO 300作为每日口服给药时， 方案（500 - 1500 mg），至少持续6周。 项目4与INTERACT联盟内的其他项目和核心高度互动。研究 目的1中的设计旨在优化BIO 300给药方案，以最大限度地提高从DEARE中存活的可能性- 肺。在小鼠和非人灵长类动物模型中观察到，当BIO 300 通过肌内（IM）注射相对于口服施用施用。因此，IM施用可进一步 提高BIO 300对220天生存期的治疗获益，并减轻超过220天的肺损伤 经口给药观察。具体目标2将与核心B-多种属有效性合作进行 药理学建模。在这个目标的实验是为了识别和验证等离子体为基础的 与BIO 300介导的ERb活化和下游效应相关的药效学（PD）生物标志物 对啮齿动物和NHP细胞衰老的影响。结合药物计量学的系统生物学方法 将使用建模，并将纳入已知的BIO 300介导的对癌症中PD生物标志物的影响 接受临床放射治疗的患者，以说明BIO 300在动物中的拟议作用机制 在人类中的假定机制的模型。细胞衰老在DEARE-肺中的作用是进一步的 在目的3中通过单独或与BIO 300组合的衰老清除剂的测试进行了探索。目标3 将解决与ARS演变为 通过与项目1、2和3的密切合作，DEARE和新型衰老清除剂（BCL-xL-P）的测试 3.项目4的把握度计算和统计分析将由核心A中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实现， 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 探索复杂的生物过程协调肺组织的辐射损伤，并发现新的 用于组织损伤和恢复的生物标志物。