KL4 Surfactant to Mitigate Radiation-Induced Lung Injury

描述(由申请人提供)： 核反应堆事故、核袭击或包括引爆“脏弹”在内的蓄意恐怖行动造成的电离辐射威胁是一个重大的公众健康问题。肺特别容易受到外部来源的电离辐射损伤或 吸入放射性沉降物中的放射性粒子。放射性肺病可表现为急性放射性肺炎和/或急性辐射暴露(DEARE)的延迟效应，导致进行性肺纤维化，通常是致命的。需要医疗对策(MCM)来减轻放射性肺病；理想的治疗是在大量人员伤亡的情况下在暴露后许多小时给予的治疗，因为事先警告是不可能的。发现实验室公司是一家生物技术公司(小型企业)，该公司正在评估其专利的基于多肽的合成KL4表面活性剂(Lucinactive)作为一种广谱、多用途的MCM，以对抗针对肺部的化学、生物、放射和核威胁物质。考虑到KL4表面活性物质的肺保护和免疫调节特性，能够作为气雾剂输送给自主呼吸的受试者，以及它的健壮性(抵抗炎症肺中存在的血浆蛋白和氧化剂的失活)，该药物是治疗放射性肺炎的理想MCM测试候选药物。此外，KL4表面活性物质广泛的临床前和临床安全性/有效性经验(&gt；1000名治疗患者)及其潜力 FDA在2012年初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。外源性表面活性物质尚未被评价用于治疗放射性肺炎。我们的目标是评价KL4表面活性物质作为一种新的方法在C57BL/6小鼠模型中减轻放射性肺炎的作用。探索实验室将与大学的Christofidou-Solomidou博士合作。他曾与西格尔博士(Pi)合作发表过KL4表面活性物质，以减轻C57BL/6小鼠模型中的急性肺损伤。我们假设，当KL4表面活性物质在大剂量辐射后24小时进入肺部时，将减轻放射性肺炎。具体目的是在C57BL/6胸部照射小鼠模型上测试KL4表面活性物质在照射后24小时开始持续2周是否可以减少：1)照射后第21天观察到的急性放射性肺炎(蛋白渗漏、中性粒细胞/巨噬细胞迁移、细胞因子产生)；2)照射后18周观察到的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KL4表面活性剂(单独或与其他缓蚀剂一起)，这可得到SBIR第二阶段供资机制的支持。长期目标是获得FDA批准KL4表面活性物质作为治疗放射性肺炎的MCM，并将其纳入治疗辐射暴露的国家战略储备，这是生物防护计划的一个重要目标。

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.