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

基本信息

批准号：
8493993
负责人：
Robert Segal
金额：
$ 30万
依托单位：
DISCOVERY LABORATORIES, INC.
依托单位国家：
美国
项目类别：
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/8493993
关键词：
8-Oxo-2&apos -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

项目摘要

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.

描述（由申请人提供）：暴露于核反应堆事故，核攻击或故意恐怖行动（包括爆炸“肮脏炸弹”）中的电离辐射的威胁是一个重大的公共治疗问题。肺特别容易受到外部来源电离辐射损伤的影响从放射性辐射中吸入放射性颗粒。辐射性肺炎可能会出现急性辐射肺炎和/或急性辐射暴露的延迟作用（Deare），导致进行性，通常是致命的肺纤维化。需要医学对策（MCM）来减轻辐射 - 肺病；理想的治疗方法是在暴露后许多小时内在大规模休闲情况下给予的治疗方法，因为不太可能警告。生物技术公司Discovery Laboratories，Inc。（小型企业关注）正在评估其基于肽的合成KL4表面活性剂（Lucinactant）作为广泛的，多用途的MCM，以抗化学，生物学，放射线，放射线和核威胁药物。鉴于KL4表面活性剂的肺部保护和免疫调节特性，能够作为气溶胶作为气溶胶自发呼吸受试者及其稳健性（在发炎的肺中抗活化和氧化剂的抗活化）是理想的MCM测试候选者来治疗放射线pneiation pneumonopathy。此外，KL4表面活性剂（> 1000名接受治疗的患者）的广泛临床前和临床安全/功效经验及其潜力 FDA在2012年初批准预防新生儿RDS，应促进该药物作为MCM的监管批准。尚未评估外源表面活性剂治疗辐射肺炎。我们的目标是评估KL4表面活性剂作为一种新型方法，以减轻良好特征的C57BL/6小鼠模型中的辐射性肺炎。 Discovery Labs将与Univ的Christofidou-Solomidou博士合作。宾夕法尼亚州（Pennsylvania）在该地区发表良好的宾夕法尼亚州，他曾与Segal博士（PI）（PI）合作并发表了KL4表面活性剂，以减轻C57BL/6鼠标模型中的急性肺损伤。我们假设KL4表面活性剂在高剂量辐射后24小时输送到肺部时会减轻辐射性肺炎。具体目的是在C57BL/6胸辐射小鼠模型中进行测试。辐射后24小时开始24小时递送2周的KL4表面活性剂可以减少：1）急性辐射肺炎（蛋白质泄漏，嗜中性粒细胞/巨噬细胞迁移，细胞因子的产生，细胞因子的产生）在21天暴露后第二天都观察到； 2）延迟的亚急性炎症反应和肺结构/纤维化的改变（包括组织病理学，羟基含量和氧化应激的指标），在暴露后第18周观察到。这些概念的证明实验应确定是否应进一步评估KL4表面活性剂（单独或与其他缓解剂），这可以由SBIR II期融资机制支持。长期目的是获得FDA的批准，将KL4表面活性剂作为辐射性肺炎的MCM，并将其包含在战略性的国家库存中，以治疗辐射暴露，这是Bioshield项目的重要目标。