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

基本信息

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
项目类别：
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

项目摘要

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辐射肺炎/纤维化有一个至关重要的需要开发医学对策（MCM）来减轻医疗对策（MCM）急性辐射暴露的延迟作用（Deare），即受害者肺炎/纤维化的辐射肺炎/纤维化放射线或核事件后成功治疗了急性辐射病。总体目标项目4的完成是为了完成Bio 300（“ Bio 300”）纳米uspension（人文材料）所需的完成活动美国食品药品监督管理局（FDA）动物规则批准的公司调节途径，以提高急性暴露于肺毒剂剂量的个体的存活率辐射[例如急性辐射暴露（Deare）-Lung]的延迟作用。我们已发布的数据表明生物 300（400毫克/千克，QD，口服饲料）承认，当Deare-Lung的生存率显着提高接触威胁生命的辐射后24小时开始治疗，持续六个星期（5）。此外，临床数据表明，当生物300作为每日口服时，临床数据表明了出色的安全性在最低六周的最低持续时间内，方案（500-1500 mg）。项目4与交互联盟内的其他项目和核心相互互动。研究在AIM 1中，旨在优化生物300剂量方案，以最大程度地提高Deare-生存的可能性肺。当Bio 300 IS时，在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肉内（IM）注射与口服给药。因此，IM管理可能会进一步提高生物300对220天生存的治疗益处，并减轻肺部损伤观察到口服给药。具体目标2将与核心B-Multispecies功效合作进行和药物计量模型。此目标中的实验旨在识别和验证基于等离子体的基于等离子体与BIO 300介导的ERB激活和下游效应相关的药效（PD）生物标志物在啮齿动物和NHP中的细胞感应上。系统生物学方法纳入了药物测量将使用建模，并将纳入对癌症PD生物标志物的已知生物300介导的影响接受临床放射治疗的患者与动物中生物300的作用机理有关模型的人类假定机制。细胞敏感在Deare-ung中的作用进一步通过单独或与Bio 300结合测试AIM 3中的探索。此外，AIM 3 将解决与ARS为基础的病理生理机制相关的知识差距，通过与项目1、2和 3。项目4的功率计算和统计分析将由生物统计学家在核心A中进行。行政核心。拟议的目标只能通过合作研究协议来实现，因为互动财团提出的，其成员在所需的每个主要领域中汇集了专业知识探测复杂的生物学过程，策划了肺组织中的辐射损伤并发现新的组织损伤和恢复的生物标志物。