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活动（包括“脏弹”爆炸）造成的电离辐射是一个严重的后果 公共卫生问题。肺部特别容易受到外部来源的电离辐射损伤或吸入放射性沉降物的放射性粒子。放射性肺炎可表现为急性放射性肺炎（ARS）和/或急性辐射暴露的延迟效应（DEARE），导致进行性、通常致命的肺纤维化。由于不可能事先发出暴露警告，因此需要在暴露后数小时、数天甚至数月内采取医疗对策（MCM）来减轻大规模伤亡情况下的放射性肺炎。我们使用成熟的靶向胸部辐射小鼠模型 (C57BL/6) 进行的 I 期 SBIR 研究的原理验证方法数据提供了强有力的证据，支持 KL4 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 KL4 表面活性剂，持续两周。在接受 KL4 表面活性剂处理的小鼠中，在照射后 2 周和 4 周时观察到肺功能得到保留并减少炎症（即 ARS 减轻），重要的是，在照射后 4.5 个月时亚急性炎症和肺纤维化 (DEARE) 减少。 Discovery Laboratories, Inc. 是一家生物技术公司（小型企业），继续评估 KL4 表面活性剂（lucinactant）作为一种广谱、多用途的 MCM，对抗针对肺部的化学、生物、放射性和核威胁剂。鉴于 KL4 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的能力及其稳健性（对发炎肺部中存在的血浆蛋白和氧化剂的失活具有抵抗力），该药物是治疗放射性肺炎的理想 MCM 测试候选者。此外，KL4表面活性剂广泛的临床前和临床安全性/有效性经验（超过1000名接受治疗的患者），以及FDA最近批准用于预防新生儿RDS，应有助于监管部门批准该药物作为MCM。外源性表面活性剂从未被评估用于治疗放射性肺炎；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 期中使用的更具临床相关性的方案，对 KL4 表面活性剂作为放射性肺炎缓解剂进行深入评估。与大学的 Melpo Christofidou-Solomidou 博士合作，利用相同的 C57BL/6 胸部照射小鼠模型。与宾夕法尼亚州第一阶段一样，我们现在将在气雾剂配方中提供 KL4 表面活性剂，此外还评估可能与临床相关的三种不同治疗方案：（a）“早期”治疗； (b) “早”加“晚”； (c) 仅“晚期”治疗。目标 1 评估（a）中递送的雾化 KL4 表面活性剂是否可以预防 ARS；目标2，如(b)和(c)中那样递送KL4表面活性剂是否可以减轻DEARE。长期目标是获得 FDA 批准 KL4 表面活性剂作为放射性肺炎的 MCM。