KL4 Surfactant to Mitigate Radiation-Induced Lung Injury

KL4 表面活性剂可减轻辐射引起的肺损伤

• 批准号: 8393586
• 负责人: Robert Segal
• 金额: $ 30万
• 依托单位: DISCOVERY LABORATORIES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-21 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393586
• 关键词: 8-Oxo-2' -Deoxyguanosine; Acute; Acute Lung Injury; Aerosols; Alveolar; Animal Experiments; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Architecture; Area; Biochemical; Biological; Biological Markers; Bioshield; Biotechnology; Blood; Breathing; Businesses; C57BL/6 Mouse; Capillary Permeability; Cells; Chemicals; Chest; Chronic; Clinical; Cytokine Activation; Data; Devices; Dose; Drug Approval; Effectiveness; Evaluation; Exposure to; Fibrosis; Funding Mechanisms; Goals; Health; Histopathology; Hour; Hydroxyproline; Immune; Immune response; Individual; Inflammatory; Inflammatory Response; Injury; Ionizing radiation; Laboratories; Lead; Lipid Peroxidation; Liquid substance; Lung; Medical; Membrane; Newborn Respiratory Distress Syndrome; Nuclear; Nuclear Reactor Accidents; Oxidants; Oxidative Stress; Pathway interactions; Patients; Pennsylvania; Peptides; Pharmaceutical Preparations; Phase; Plasma Proteins; Pneumonia; Prevention; Production; Property; Protein Analysis; Proteins; Public Health; Publishing; Pulmonary Fibrosis; Pulmonary Surfactants; Pulse Oximetry; Radiation; Radiation Injuries; Radiation Pneumonitis; Radioactive; Resistance; Respiration; Respiratory physiology; Role; Safety; Series; Small Business Innovation Research Grant; Source; Structure of parenchyma of lung; Technology; Testing; Therapeutic; Time; Tissues; base; cytokine; design; dirty bomb; experience; falls; irradiation; lung injury; macrophage; migration; mouse model; neutrophil; novel strategies; particle; pre-clinical; prevent; research study; surfactant; treatment strategy

DESCRIPTION (provided by applicant): The threat of exposure to ionizing radiation from a nuclear reactor accident, nuclear attack, or deliberate terrorist actions including the detonation of "dirty bombs" is a significant public healh concern. The lung is particularly susceptible to ionizing radiation injury from external sources or inhalation of radioactive particles from radioactive fall-out. Radiation pneumonopathy can manifest with an acute radiation pneumonitis and/or delayed effects of acute radiation exposure (DEARE) leading to progressive, often fatal pulmonary fibrosis. Medical countermeasures (MCMs) to mitigate radiation-pneumonopathy are needed; the ideal treatment is one that can be given in a mass-casualty situation many hours post-exposure, as prior warning is unlikely. Discovery Laboratories, Inc., a biotechnology company (small business concern) is evaluating its proprietary peptide-based synthetic KL4 surfactant (lucinactant) as a broad-spectrum, multi-use MCM against chemical, biological, radiological and nuclear threat agents targeting the lung. Given KL4 surfactant's lung-protective and immune-modulatory properties, ability to be delivered as an aerosol to spontaneously breathing subjects, and its robustness (resistance to inactivation by plasma proteins and oxidants present in the inflamed lung), the drug is an ideal MCM test candidate to treat radiation pneumonopathy. Moreover, the extensive preclinical and clinical safety/efficacy experience with KL4 surfactant (>1000 treated patients), and its potential FDA approval in early 2012 for prevention of neonatal RDS should facilitate the regulatory approval of the drug as a MCM. Exogenous surfactants have not been evaluated for treating radiation pneumonopathy. Our objectives are to evaluate KL4 surfactant as a novel approach to mitigate radiation pneumonopathy in the well characterized C57BL/6 mouse model. Discovery Labs will be collaborating with Dr. Christofidou-Solomidou at Univ. of Pennsylvania, who is well published in the area, and who has collaborated and previously published with Dr. Segal (PI) on KL4 surfactant to mitigating acute lung injury in C57BL/6 mouse models. We hypothesize that KL4 surfactant, when delivered to the lung 24 hours post high-dose radiation, will mitigate radiation pneumonopathy. The Specific Aims are test in the C57BL/6 thoracic-radiation mouse model whether KL4 surfactant delivered for 2 weeks beginning 24 hours post irradiation can reduce: 1) acute radiation pneumonitis (protein leak, neutrophil/macrophage migration, cytokine production) observed at day 21 post exposure; 2) the delayed subacute inflammatory response and altered lung architecture/fibrosis (including histopathology, hydroxyproline content, and indicators of oxidative stress), observed at week 18 post exposure. These proof- of-concept experiments should determine whether KL4 surfactant should be further evaluated (alone or with other mitigating agents), which could be supported by a SBIR Phase II funding mechanism. The long-term objective is to obtain FDA approval of KL4 surfactant as a MCM for radiation pneumonopathy, and its inclusion in the Strategic National Stockpile for treating radiation exposure, an important goal of Project Bioshield. PUBLIC HEALTH RELEVANCE: Exposure to ionizing radiation and inhalation of radioactive particles from nuclear reactor accidents or deliberate terrorist actions is a particular health concern, since acute lung damage, or delayed, often fatal lung scaring can occur in exposed individuals and unprotected rescue workers. Discovery Laboratories, Inc., a biotechnology company is proposing to test its proprietary synthetic KL4 surfactant technology as a medical countermeasure (MCM) to treat radiation-induced lung injury. KL4 surfactant's lung-protective and anti- inflammatory properties make it an ideal broad-spectrum, multi-use MCM candidate. The proposed proof-of- concept animal experiments should determine whether KL4 surfactant should be further evaluated and ultimately approved as a MCM to be included in the Strategic National Stockpile for treating radiation exposure, an important goal of Project Bioshield.

描述（由申请人提供）： 暴露于核反应堆事故、核攻击或蓄意的恐怖主义行动（包括引爆“脏弹”）的电离辐射的威胁是一个重大的公共卫生问题。肺特别容易受到来自外部来源的电离辐射损伤， 吸入来自放射性沉降物的放射性粒子。放射性肺炎可以表现为急性放射性肺炎和/或急性放射暴露的延迟效应（DEARE），导致进行性的，通常是致命的肺纤维化。需要采取医学对策来减轻放射性肺病;理想的治疗方法是在大规模伤亡情况下，在受照后数小时内就可以进行，因为事先警告是不可能的。 Discovery Laboratories，Inc.，一家生物技术公司（小型企业）正在评估其专有的基于肽的合成KL 4表面活性剂（Lucinactant）作为广谱、多用途MCM，以对抗针对肺部的化学、生物、放射和核威胁剂。鉴于KL 4表面活性剂的肺保护和免疫调节特性，能够以气雾剂形式递送至自主呼吸受试者，以及其稳健性（对炎症肺中存在的血浆蛋白和氧化剂灭活的抗性），该药物是治疗放射性肺病的理想MCM测试候选药物。此外，KL 4表面活性剂的广泛临床前和临床安全性/有效性经验（>1000例治疗患者）及其潜在的 FDA在2012年初批准用于预防新生儿RDS，这将促进该药物作为MCM的监管批准。 外源性表面活性剂治疗放射性肺病尚未进行评估。我们的目的是评估KL 4表面活性剂作为一种新的方法，以减轻放射性肺炎的特点C57 BL/6小鼠模型。Discovery Labs将与宾夕法尼亚大学的Christofidou-Solomidou博士合作，他在该领域发表了大量文章，并曾与Segal博士（PI）合作并发表了关于KL 4表面活性剂减轻C57 BL/6小鼠模型急性肺损伤的文章。我们假设，当在高剂量辐射后24小时将KL 4表面活性剂递送至肺时，将减轻放射性肺病。具体目的是在C57 BL/6胸部放射小鼠模型中测试在放射后24小时开始递送2周的KL 4表面活性剂是否可以减少：1）急性放射性肺炎（蛋白渗漏、中性粒细胞/巨噬细胞迁移、细胞因子产生）; 2）延迟的亚急性炎症反应和改变的肺结构/纤维化（包括组织病理学、羟脯氨酸含量和氧化应激指标）。这些概念验证实验应确定是否应进一步评估KL 4表面活性剂（单独或与其他缓解剂一起），这可由SBIR第II阶段资助机制支持。长期目标是获得FDA批准KL 4表面活性剂作为放射性肺病的MCM，并将其纳入用于治疗辐射暴露的国家战略储备，这是Bioshield项目的一个重要目标。 公共卫生关系： 暴露于电离辐射和吸入来自核反应堆事故或蓄意恐怖主义行动的放射性粒子是一个特别的健康问题，因为急性肺损伤或延迟，往往致命的肺部疤痕可能发生在暴露的个人和无保护的救援人员。Discovery Laboratories，Inc.，一家生物技术公司正提议测试其专有的合成KL 4表面活性剂技术，作为治疗辐射引起的肺损伤的医学对策（MCM）。KL 4表面活性剂的肺保护和抗炎特性使其成为理想的广谱、多用途MCM候选物。拟议的概念验证动物实验应确定是否应进一步评估KL 4表面活性剂，并最终批准将其作为MCM列入国家战略储备，用于治疗辐射暴露，这是生物防护项目的一个重要目标。