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

基本信息

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
项目类别：
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

项目摘要

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) 及其更严重的形式急性呼吸窘迫综合征 (ARDS) 会危及生命。超过 200,000 人患有未经 FDA 批准的药物治疗的威胁性疾病。美国每年都会发生急性肺损伤 (ALI)/急性呼吸窘迫综合征 (ARDS)，他们主要是 ICU 患者，他们的肺部会遭受继发性器官损伤。外伤、输血、烧伤、感染、败血症、失血性休克、吸入烟雾或吸氧所致 ALI/ARDS 暴露的死亡率高达 40%，并且长期发病率很高。 ALI/ARDS 发病机制的特点是中性粒细胞炎症和中性粒细胞胞外释放 Neutrolis 的创始团队对 NET 引起的生物学和病理学有深入的了解。 NET 是与有毒蛋白质复合的高分子量染色质丝的晶格。 NET 积聚在肺泡腔和肺毛细血管中，阻碍血液氧合。开发了 NET 治疗靶向的主要候选药物。在这项研究计划中，Neutrolis 将生成有关其先导药物的非临床特性和配方的信息具体来说，这些目标的主要成果是： Neutrolis 将评估静脉注射和吸入方法，以确定最有效的给药途径。治疗 ALI 的药物输送，并描述其 (1) 有效剂量、(2) 药理学 (PK/PD) 和 (3)毒理学特性。总之，Neutrolis 处于有利地位，可以将其治疗 ALI 的专有开发领先优势带入市场。鉴于 NET 在急性和慢性炎症性疾病中大量存在，Neutrolis 旨在最终解决多种炎症性疾病，为数百万苦难者带来希望和缓解全世界的患者。