Development of a Neutrophil Degranulation Inhibitor to Treat ARDS

开发治疗 ARDS 的中性粒细胞脱颗粒抑制剂

基本信息

批准号：
10697442
负责人：
Kenneth R MCLEISH
金额：
$ 30.64万
依托单位：
DEGRANIN THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10697442
关键词：
Accounting Acute Lung Injury Acute Respiratory Distress Syndrome Admission activity Animal Model Animal Organ Animals Anti-Bacterial Agents Attenuated Bacteria Binding Biodistribution Biological Blood COVID-19 COVID-19 pandemic Cells Characteristics Clinical Clinical Trials Complication Critical Illness Cytoplasmic Granules Data Development Discipline of Nursing Disease Endotoxins Event Exocytosis Exocytosis Inhibition Extravasation Failure Family suidae Foundations Healthcare Systems Histopathologic Grade Host Defense Human Immune Immunohistochemistry In Vitro Inflammatory Influenza A Virus, H1N1 Subtype Inhalation Injury Innovative Therapy Intensive Care Units Laboratories Legal patent Life Limulus Lung Lung infections Maintenance Mass Spectrum Analysis Measures Modeling Molecular Target Mus Neutrophil Activation Neutrophil Infiltration Organ Oryctolagus cuniculus Outcome Pathogenesis Patients Peptides Permeability Phagocytes Phagocytosis Phagosomes Pharmaceutical Preparations Pharmacologic Substance Pharmacological Treatment Pharmacotherapy Phase Physicians Physiological Plasma Play Positron-Emission Tomography Production Proteins Protocols documentation Pulmonology Quality Control Radiolabeled Reactive Oxygen Species Recombinant Proteins Reproducibility Respiratory Failure Respiratory physiology Rodent Model Role SARS-CoV-2 infection SNAP receptor SNAP23 gene Scientist Sheep Small Business Innovation Research Grant Supportive care Syndrome Technology Therapeutic Therapeutic Effect Time Toxic Neutrophil Toxic effect Transmembrane Transport Treatment Cost Treatment Efficacy Validation Vascular Endothelial Cell Virus Work alveolar epithelium aptamer cecal ligation puncture cell injury clinically relevant commercialization cost drug candidate experimental study extracellular immunogenicity improved in vivo influenzavirus inhibitor innovation lung injury manufacturing capabilities manufacturing quality manufacturing run mortality mouse model neutrophil novel therapeutic intervention pharmacokinetics and pharmacodynamics pharmacologic phase 2 study pneumonia model preclinical study prevent recruit screening sepsis induced ARDS side effect therapeutic candidate therapeutic target

项目摘要

Project Summary Acute respiratory distress syndrome (ARDS) is a critical problem in pulmonary medicine, accounting for 10% of intensive care unit (ICU) admissions and totaling over 200,000 patients/year in the U.S. Current treatment cost typically exceeds $70,000 per patient. Decades of clinical trials failed to identify effective pharmacologic therapy for ARDS, while mortality remains above 30%. Thus, there is a critical, unmet clinical need for successful pharmacologic strategies to treat ARDS. Neutrophils play an essential role in the lung injury leading to ARDS, including that due to COVID-19, through extracellular release of reactive oxygen species (ROS), granule constituents, and neutrophil extracellular traps (NETs). The scientific foundation underlying our innovative therapy is that inhibition of neutrophil degranulation also prevents release of ROS and NETs, making degranulation a therapeutic target. We generated a recombinant protein, degranin-23 (degranulation inhibitor of SNAP-23, DGN-23) containing a SNARE motif from SNAP-23 and a cell permeability peptide. DGN-23 rapidly enters human neutrophils in vitro and in vivo, inhibits degranulation by 50% to 80%, prevents priming of ROS release, and reduces NET formation. Importantly, in vitro studies show DGN-23 does not impair neutrophil phagocytosis, granule fusion with phagosomes, or bacterial killing within phagosomes, and in vivo studies show that DGN-23 administration at the initiation of lung injury inhibits acute lung injury in 3 rodent models, without obvious toxicity. Thus, in vitro and in vivo data provide strong support for our novel therapeutic strategy that inhibition of neutrophil exocytosis attenuates lung injury leading to ARDS. The next steps are development of manufacturing capability and quality control to move from a laboratory grade recombinant protein to a pharmaceutical grade drug and validation of therapeutic effect without toxicity under clinically relevant conditions. This transition will be accomplished by two Aims. Aim 1: Characterize production characteristics and off-target/side effects of DGN-23. This aim will determine purity, presence of bacterial contaminants, yield, reproducibility of potency, and stability in multiple production runs of DGN-23. Cell toxicity and off target effects on circulating immune cells will be determined. Organ and cell localization of DGN-23 will be determined in all major organs from animals undergoing experiments described in Aim 2. Aim 2: Determine therapeutic efficacy of DGN-23 under clinically relevant conditions. The ability of DGN-23 to prevent acute lung injury and improve mortality when administered at various times after the initiating injury will be determined in a mouse model of H1N1 influenza virus-induced acute lung injury. Improved survival and improved blood oxygenation will serve as outcomes to proceed with development. At the conclusion of this work, this Phase 1 project will have identified a drug candidate with an optimal combination of efficacy, yield, stability, and potency to advance to advanced pre-clinical studies in a Phase 2 project.

项目摘要急性呼吸窘迫综合征（ARDS）是肺医学中的关键问题美国目前的重症监护室（ICU）入院（ICU）的10％和总计超过200,000名患者治疗费用通常超过每位患者$ 70,000。数十年的临床试验无法确定有效 ARDS的药理学治疗，而死亡率仍高于30％。因此，有一个关键的未修复的临床需要成功治疗ARDS的药理策略。中性粒细胞在肺中起着至关重要的作用通过细胞外释放，导致ARD的损伤导致ARDS，包括由于Covid-19的损伤物种（ROS），颗粒成分和中性粒细胞外陷阱（网）。科学基础我们的创新疗法的基础是，抑制中性粒细胞脱粒也可防止ROS的释放和网，使脱粒成为治疗靶点。我们产生了重组蛋白，脱脂蛋白-23 （SNAP-23，DGN-23的脱粒抑制剂）包含SNAP-23和一个细胞的圈套图案渗透性肽。 DGN-23在体外和体内迅速进入人类嗜中性粒细胞 50％至80％，可防止ROS释放的启动，并减少净形成。重要的是，体外研究表明 DGN-23不会损害中性粒细胞吞噬作用，颗粒融合与吞噬体或在内部的细菌杀死吞噬体和体内研究表明，肺损伤开始时DGN-23抑制了急性 3种啮齿动物模型中的肺损伤，没有明显的毒性。因此，体外和体内数据为我们的新型治疗策略抑制嗜中性粒细胞增多症会减弱肺损伤导致ARDS。接下来的步骤是制造能力和质量控制以从实验室移动级重组蛋白针对药物级药物和治疗作用验证而无需毒性在临床相关条件下。这种过渡将通过两个目标来实现。目标1：特征 DGN-23的生产特性和靶向/副作用。这个目标将决定纯度，存在 DGN-23多生产运行中的细菌污染物，产量，效能的可重复性和稳定性。细胞毒性和关闭靶标对循环免疫细胞的影响将得到确定。器官和细胞定位 DGN-23将在AIM 2中描述的动物的所有主要器官中确定。 2：确定在临床相关条件下DGN-23的治疗功效。 DGN-23的能力为了防止急性肺损伤并改善了在启动损伤后的不同时间服用的死亡率将在H1N1流感病毒诱导的急性肺损伤的小鼠模型中确定。改善生存和改善的血液氧合将作为发展的结果。在此结束时工作，该第1阶段项目将确定具有最佳疗效，产量，收益率最佳组合的药物在第二阶段项目中，稳定性和效力可以晋升为高级临床前研究。