Targeting Neutrophil Extracellular Traps for Acute Lung Injury

靶向中性粒细胞胞外陷阱治疗急性肺损伤

• 批准号: 9908309
• 负责人: Tobias Fuchs
• 金额: $ 20.95万
• 依托单位: NEUTROLIS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908309
• 关键词: Acute; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Aerosols; Alveolar; Animal Model; Antibodies; Applications Grants; Biological Assay; Biology; Biotechnology; Blood; Blood capillaries; Burn injury; Chromatin; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Complex; Cyclic GMP; Deposition; Development; Development Plans; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug Screening; Evaluation; Event; Feedback; Filament; Formulation; Future; Generations; Goals; Hematology; Hemorrhagic Shock; Homeostasis; Hypoxemia; Infection; Inflammation; Inflammatory; Inhalation; Inhalation Therapy; Injury; Intravenous; Investigational Drugs; Irrigation; Lead; Life; Liquid substance; Lung; Lung Compliance; Massachusetts; Maximum Tolerated Dose; Measures; Medical; Methods; Mission; Modeling; Molecular Weight; Morbidity - disease rate; Mus; Nebulizer; Organ; Outcome; Oxygen; Pathogenesis; Pathogenicity; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Phase; Pneumonia; Positioning Attribute; Process; Property; Proteins; Reperfusion Injury; Reporting; Research Proposals; Respiratory physiology; Rodent; Route; Safety; Sepsis; Serum; Small Business Innovation Research Grant; System; Testing; Therapeutic; Therapeutic Index; Time; Toxic effect; Toxicology; Transfusion; Trauma; United States Food and Drug Administration; Urine; Wild Type Mouse; analytical tool; base; chronic inflammatory disease; clinical development; clinical investigation; combinatorial; extracellular; in vivo; lead candidate; liquid formulation; lung injury; meetings; microbial; mortality; mouse model; neutrophil; organ injury; pre-clinical; preclinical efficacy; prevent; smoke inhalation; therapeutic target; therapy development; treatment strategy

ABSTRACT Acute lung injury (ALI), and its more severe form, acute respiratory distress syndrome (ARDS), are life- threatening conditions with no FDA-approved pharmacologic therapy. More than 200,000 people suffer from ALI/ARDS annually in the US. They are primarily ICU patients who suffer secondary organ injury to the lungs as a result of trauma, transfusion, burns, infection, sepsis, hemorrhagic shock, smoke inhalation, or oxygen exposure. ALI/ARDS has demonstrated mortality rates as high as 40% as well as significant long-term morbidity. ALI/ARDS pathogenesis is characterized by neutrophilic inflammation and the release of Neutrophil Extracellular Traps (NETs). Neutrolis’ founding team has deep understanding of the biology and pathology caused by NETs. NETs are lattices of high-molecular weight chromatin filaments complexed with toxic proteins. In ALI/ARDS, NETs accumulate in alveolar cavities and capillaries of the lung and prevent blood oxygenation. Neutrolis has developed a lead candidate for therapeutic targeting of NETs. In this research proposal, Neutrolis will generate information on non-clinical properties and formulation of its lead that are required for the pre-IND meeting with the FDA. Specifically, the key outcomes of these aims are to determine the most effective route of administration. Neutrolis will assess an intravenous and inhalational method of drug delivery for treatment of ALI, and characterize their (1) efficacy dose, (2) pharmacological (PK/PD), and (3) toxicological properties. In summary, Neutrolis is well positioned to bring its proprietary developmental lead for treating ALI into the clinic. Given that NETs are abundant in acute and chronic inflammatory diseases, Neutrolis aims to ultimately address the multiplicity of inflammatory conditions, offering hope and relief to millions of suffering patients worldwide.

抽象的 急性肺损伤（ALI）及其更严重的急性呼吸窘迫综合征（ARDS）是生命 威胁性疾病，没有FDA批准的药学疗法。超过20万人遭受 每年在美国的Ali/Ards。他们是主要的ICU患者，他们因肺而遭受继发器官损伤 创伤，输血，烧伤，感染，败血症，出血性休克，烟雾吸入或氧气的结果 接触。 ALI/ARDS的死亡率高达40％，长期发病率高。 ALI/ARDS发病机理的特征是嗜中性粒细胞注射和嗜中性粒细胞外的释放 陷阱（网）。中立人的创始团队对网络引起的生物学和病理学有深刻的了解。 网是与有毒蛋白复合的高分子染色质丝的晶格。在Ali/ards中， 网中积聚在肺部的肺泡和毛细血管中，并防止血液氧合。中心有 开发了网络治疗靶向的主要候选者。 在这项研究建议中，中性粒子将产生有关非临床特性的信息并制定其铅的信息 与FDA预先开会的会议所必需的。具体而言，这些目标的主要结果是 确定最有效的管理途径。中性物将评估一种静脉和意外方法 用于治疗ALI的药物递送，并表征其（1）效率剂量，（2）药物（PK/PD）和 （3）毒理学特性。 总而言之，中性粒子良好，可以将其专有的发育领先优势用于治疗Ali 诊所。鉴于网中的急性和慢性炎症性疾病丰富，中性疾病的目的是 最终解决了多种炎症状况，为数百万苦难提供了希望和救济 全球患者。