KL4 Surfactant to Mitigate Radiation-Induced Lung Injury

描述(申请人提供)：暴露于核反应堆事故的电离辐射或蓄意的恐怖行为，包括引爆“脏弹”是一种重要的 公共卫生问题。肺部特别容易受到外部来源的电离辐射伤害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(ARS)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。由于不太可能事先发出暴露警告，因此需要在暴露后数小时、数天甚至数月采取医学对策(MCM)，以减轻在大规模伤亡情况下可以给予的辐射-肺病。我们使用成熟的靶向胸部放射小鼠模型(C57BL/6)进行的第一阶段SBIR研究的数据提供了强有力的证据，支持KL4表面活性物质(一种专利的多肽合成表面活性物质)在缓解ARS和DEARE方面的有效性。在这些实验中，KL4表面活性物质从照射后24小时开始，每天两次鼻腔给药，持续2周。KL4表面活性物质治疗的小鼠在照射后2周和4周观察到肺功能的保存和炎症的减轻(即ARS的缓解)，重要的是，在照射后4.5个月亚急性炎症和肺纤维化(DeARE)减少。发现实验室公司是一家生物技术公司(小型企业)，它继续评估KL4表面活性物质(Lucinactive)是一种广谱、多用途的MCM，可对抗针对肺部的化学、生物、辐射和核威胁物质。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(治疗了1000名患者)，以及最近FDA批准用于预防新生儿RDS，应该有助于监管部门批准该药物作为MCM。从未对外源性表面活性物质治疗放射性肺病进行过评估，因此我们的方法是新颖的。这项SBIR第二阶段提案的具体目标是使用比第一阶段使用的更临床相关的方案来深入评估KL4表面活性物质作为放射性肺炎的缓释剂，并与大学的Melpo Christofidou-Solomidou博士合作使用相同的C57BL/6胸部照射小鼠模型。与第一阶段一样，我们现在将在气雾剂配方中提供KL4表面活性剂，此外还将评估三种可能与临床相关的不同治疗方案：(A)“早期”治疗；(B)“早期”治疗；(B)“早期”加“晚期”；以及(C)“晚期”仅治疗。目的1评估(A)中提供的雾化KL4表面活性物质能否预防ARS；以及目标2评估(B)和(C)中提供的KL4表面活性物质是否可以缓解DeARE。长期目标是获得FDA批准KL4表面活性物质作为放射性肺病的MCM。

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.