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: 8912357
• 负责人: Robert Segal
• 金额: $ 99.2万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8912357
• 关键词: Acute; Aerosols; Alveolar; Animal Experiments; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Architecture; Biochemical; Biological; Biological Markers; Biological Preservation; Bioshield; Biotechnology; Blood; Breathing; Businesses; Capillary Permeability; Cells; Chemical Surfactants; Chemicals; Chest; Chronic; Clinical; Collaborations; Cytokine Activation; Data; Devices; Drug Approval; Drug Formulations; Early Intervention; Early treatment; Effectiveness; Evaluation; Exposure to; Fibrosis; Goals; Health; Hour; Human; Hydroxyproline; Hyperoxia; Immune; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Ionizing radiation; Laboratories; Lead; Lipid Peroxidation; Liquid substance; Lung; Medical; Membrane; Methods; Mus; Newborn Respiratory Distress Syndrome; Nuclear; Nuclear Reactor Accidents; Oxidants; Oxidative Stress; Pathway interactions; Patients; Pennsylvania; Peptides; Pharmaceutical Preparations; Phase; Phase II/III Trial; Plasma Proteins; Prevention; Property; Protein Analysis; Proteins; Public Health; Pulmonary Fibrosis; Pulmonary Inflammation; Pulmonary Surfactants; Radiation; Radiation Injuries; Radiation Pneumonitis; Radioactive; Resistance; Respiration; Respiratory physiology; Safety; Small Business Innovation Research Grant; Source; Structure of parenchyma of lung; Symptoms; Technology; Testing; Therapeutic; Tissues; Treatment Protocols; aerosolized; base; clinically relevant; cytokine; dirty bomb; experience; falls; irradiation; lung injury; mass casualty; mouse model; novel; particle; phase 1 study; pre-clinical; prevent; radiation effect; research study; surfactant; treatment duration; treatment strategy

DESCRIPTION (provided by applicant): Exposure to ionizing radiation from a nuclear reactor accident or deliberate terrorist actions including the detonation of "dirty bombs" is a significant public health 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 (ARS) and/or delayed effects of acute radiation exposure (DEARE) leading to progressive, often fatal pulmonary fibrosis. As prior warning of exposure is unlikely, medical countermeasures (MCMs) to mitigate radiation-pneumonopathy that can be given in mass-casualty situations many hours, days, and even months post-exposure are needed. Data from our proof-of-principle approach Phase I SBIR study using a well-established, targeted thoracic-radiation mouse model (C57BL/6), provided robust evidence supporting the effectiveness of KL4 surfactant (a proprietary, peptide-based synthetic surfactant) in mitigating both ARS and DEARE. In these experiments, KL4 surfactant was delivered intranasally twice daily for 2 weeks beginning 24 hrs post-irradiation. Preservation of lung function and reduced inflammation was observed in KL4 surfactant-treated mice at 2 and 4 wks post irradiation (i.e. mitigation of ARS), and importantly, reduction in subacute inflammation and pulmonary fibrosis (DEARE) at 4.5 months post exposure. Discovery Laboratories, Inc., a biotechnology company (small business concern) continues to evaluate 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 recent approval by the FDA for prevention of neonatal RDS should facilitate the regulatory approval of the drug as a MCM. Exogenous surfactants have never been evaluated for treating radiation pneumonopathy; thus our approach is novel. This SBIR Phase II proposal's Specific Aims are to conduct an in-depth evaluation of KL4 surfactant as a mitigator of radiation pneumonopathy using a more clinically-relevant scenario than that used in Phase I. Utilizing the same C57BL/6 thoracic irradiation mouse model in collaboration with Dr. Melpo Christofidou-Solomidou at the Univ. of Pennsylvania as in Phase I, we will now deliver KL4 surfactant in an aerosol formulation, in addition to evaluating three different treatment regimens that could be clinically relevant: (a) "early" treatment; (b) "early" plus "late"; and (c) "late" only treatment. Aim 1 evaluates whether aerosolized KL4 surfactant delivered as in (a) can prevent ARS; and Aim 2, whether delivery of KL4 surfactant as in (b) and (c) can mitigate DEARE. The long-term objective is to obtain FDA approval of KL4 surfactant as a MCM for radiation pneumonopathy.

描述（由申请人提供）：暴露于核反应堆事故或蓄意恐怖行动（包括引爆“脏弹”）产生的电离辐射是一种严重的 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或吸入来自放射性沉降物的放射性颗粒。放射性肺炎可以表现为急性放射性肺炎（ARS）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。由于不太可能事先发出辐射警告，因此需要在大规模伤亡情况下，在辐射后数小时、数天甚至数月内采取医学对策（MCM）来减轻辐射性肺病。来自我们的原理验证方法I期SBIR研究的数据使用了完善的靶向胸部放射小鼠模型（C57 BL/6），提供了有力的证据支持KL 4表面活性剂（一种专有的基于肽的合成表面活性剂）在缓解ARS和DEARE方面的有效性。在这些实验中，从照射后24小时开始，每天两次鼻内递送KL 4表面活性剂，持续2周。在照射后2周和4周，在KL 4表面活性剂处理的小鼠中观察到肺功能的保留和炎症的减少（即ARS的减轻），并且重要的是，在暴露后4.5个月亚急性炎症和肺纤维化（DEARE）的减少。Discovery Laboratories，Inc.，一家生物技术公司（小型企业）继续评估KL 4表面活性剂（Lucinactant）作为广谱、多用途MCM，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）以及FDA最近批准用于预防新生儿RDS应有助于监管机构批准该药物作为MCM。外源性表面活性剂治疗放射性肺病从未被评估，因此我们的方法是新颖的。该SBIR II期提案的具体目标是使用比I期更临床相关的场景对KL 4表面活性剂作为放射性肺病缓解剂进行深入评价。利用与I期相同的C57 BL/6胸部照射小鼠模型，与宾夕法尼亚大学的Melpo Christofidou-Solomidou博士合作，我们现在将以气雾剂制剂的形式递送KL 4表面活性剂，此外还评估了可能具有临床相关性的三种不同治疗方案：（a）“早期”治疗;（B）“早期”加“晚期”;和（c）仅“晚期”治疗。目的1评价如（a）中递送的雾化KL 4表面活性剂是否可以预防ARS;目的2评价如（B）和（c）中递送的KL 4表面活性剂是否可以减轻DEARE。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。