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包括“脏弹”爆炸在内的蓄意恐怖行动的电离辐射是重要的