New mechanism-based TREM-1 therapy for acute respiratory distress syndrome

基于新机制的 TREM-1 疗法治疗急性呼吸窘迫综合征

• 批准号: 10678788
• 负责人: Alexander B Sigalov
• 金额: $ 27.27万
• 依托单位: SIGNABLOK, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10678788
• 关键词: Acute; Acute Respiratory Distress Syndrome; Affect; American; Amplifiers; Animal Model; Animals; Area; Arthritis; Beds; Binding; Bleomycin; Body Weight Changes; Bordetella pertussis; Bronchoalveolar Lavage Fluid; CCL2 gene; COVID-19; COVID-19 mortality; COVID-19 patient; COVID-19/ARDS; Cancer Patient; Cause of Death; Cells; Clinic; Comparative Study; Complex; Data; Development; Disease; Dose; Drug Targeting; Endotoxic Shock; Evaluation; Failure; Fibrosis; Formulation; France; Goals; Half-Life; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Influenza; Injectable; Intensive Care Units; Interleukin-1 beta; Interleukin-10; Interleukin-6; Intubation; Lead; Ligands; Liver diseases; Lung; Lung diseases; Macrophage; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Mus; Myeloid Cells; Patients; Peptides; Pertussis; Pharmacology; Pharmacotherapy; Phase; Phase II Clinical Trials; Plasma; Pneumonia; Population; Pulmonary Fibrosis; Pulmonary Inflammation; Research; Risk; Safety; Sepsis; Septic Shock; Serum; Survival Rate; TNF gene; Testing; Therapeutic; Toxicology; Trauma; animal data; clinical development; comparative; cytokine; cytokine release syndrome; effective therapy; high risk population; immunomodulatory therapies; improved; improved outcome; in vivo evaluation; inhibitor; innovation; keratinocyte; lung injury; mortality; novel; novel therapeutics; overexpression; phase 1 study; polymicrobial sepsis; prognostic; prototype; receptor; risk minimization; septic; severe COVID-19; uptake

Project Summary/Abstract Every year, 150,000 Americans are affected by Acute Respiratory Distress Syndrome (ARDS), an inflammatory lung condition that may complicate severe pneumonia (including influenza and COVID-19), trauma, sepsis, cancer, and many other conditions. The mortality of ARDS is 27%, 32%, and 45% for mild, moderate, and severe disease, respectively. The survival rate for COVID-19 patients with ARDS is about 25%. There is no proven drug treatment for ARDS per se. This highlights an urgent need for effective treatment of ARDS. The long-term goal of this project is to develop an effective and well-tolerable ARDS therapy aimed to reduce the mortality rate and improve outcomes in ARDS patients. Amplified, rapid acute inflammatory response in the lungs in ARDS is associated with cytokine storm. Triggering receptor expressed on myeloid cells1 (TREM-1), inflammation amplifier, is upregulated in ARDS and COVID-19. In animals, TREM-1 blockade reduces cytokine storm and protects against lung injury. The hypothesis of this study supported by recent animal data is that TREM-1 blockade ameliorates ARDS. Current TREM-1 inhibitors all attempt to block binding of TREM-1 to its still uncertain ligand(s). To minimize risk of failure in clinical development, we developed a first-in-class ligand-independent well- tolerated TREM-1 inhibitory peptide GF9 that can be formulated into SignaBlok's long half-life macrophage- specific lipopeptide complexes (LPC) to improve its half-life and targeting to the inflammation areas. Earlier, we showed that GF9 sequence either as a free peptide or as a part of LPC-bound trifunctional peptide GA31 (GA31-LPC) suppresses inflammatory cytokine release, protects against septic shock and reverses lung fibrosis in mice. This study aims to test if it suppresses cytokine storm and alleviates ARDS in an animal model. Considering the pros and cons of GF9 and GA31-LPC, we suggest to test both leads. Specific aims of this project are to: 1) generate and characterize in vitro GF9 and GA31-LPC injectables, and 2) test GF9 and GA31-LPC comparatively in an animal model of ARDS. We will synthesize and characterize GF9 and GA31-LPC for their stability, rate and efficiency of macrophage uptake in vitro as well as for their inhibitory effect on cytokine release by LPS-stimulated cells. We will test two doses of the formulations in ARDS animals. Ligand-dependent TREM-1 inhibitor LR12 will be studied comparatively. We will analyze lung inflammation and lung damage. Comprehensive Histo/IHC studies will be performed. It is anticipated that that this Phase I study will identify a novel, first-in-class, well-tolerable agent as a powerful platform for development of safe and effective therapy capable of treating ARDS. Its anticipated safety is supported by good tolerability of SignaBlok's GF9 therapy in animals and by safety of TREM-1- blocking approach in healthy, septic and COVID-19 subjects. If successful, Phase I will be followed in Phase II by toxicology, ADME, pharmacology and CMC studies, filing an IND and evaluation in humans.

项目摘要/摘要 每年，有15万美国人受到急性呼吸窘迫综合征（ARDS）的影响 炎症性肺部疾病可能会使严重的肺炎复杂化（包括流感和Covid-19）， 创伤，败血症，癌症和许多其他疾病。轻度的ARDS死亡率为27％，32％和45％ 中度和严重疾病。 CoVID-19患有ARDS患者的生存率大约 25％。 ARDS本身没有证实的药物治疗。这突出了迫切需要有效的 ARDS的处理。该项目的长期目标是开发一个有效且可遭受良好的ARDS 治疗旨在降低ARDS患者的死亡率和改善预后。 ARDS中肺部的扩增，快速的急性炎症反应与细胞因子风暴有关。 在ARDS中触发在髓样细胞1（Trem-1）的触发受体1（TREM-1），炎症放大器，在ARDS中上调 和Covid-19。在动物中，TREM-1阻断可减少细胞因子风暴并防止肺部损伤。这 最新动物数据支持的这项研究的假设是，TREM-1阻断可改善ARDS。 当前的TREM-1抑制剂都试图阻止TREM-1与其仍然不确定的配体的结合。到 最小化临床发育失败的风险，我们开发 可耐受的TREM-1抑制性肽GF9可以被配合到Signablok的长期半衰期巨噬细胞中 特定的脂肪肽复合物（LPC）以改善其半衰期并靶向炎症区域。 早些时候，我们表明GF9序列是自由肽或LPC结合的三功能的一部分 肽GA31（GA31-LPC）抑制炎症细胞因子释放，可预防败血性休克和 逆转小鼠的肺纤维化。这项研究旨在测试它是否抑制细胞因子风暴并减轻ARDS 在动物模型中。考虑到GF9和GA31-LPC的优缺点，我们建议测试这两个导线。 该项目的具体目的是：1）生成和表征体外GF9和GA31-LPC注射剂， 2）在ARDS动物模型中，测试GF9和GA31-LPC。我们将合成，并 特征GF9和GA31-LPC的体外巨噬细胞摄取的稳定性，速率和效率为 以及它们对LPS刺激细胞释放细胞因子释放的抑制作用。我们将测试两剂 ARDS动物中的配方。将相对研究配体依赖性TREM-1抑制剂LR12。我们 将分析肺部炎症和肺部损伤。将进行全面的历史/IHC研究。 可以预料的是，这一阶段的研究将确定一种新颖的，一流的，可忍受的药物作为一个 强大的平台开发能够治疗ARD的安全有效疗法。它的预期 Signablok在动物中的GF9疗法的良好耐受性以及TREM-1-的安全性得到了安全支持。 在健康，化粪池和199受试者中阻止方法。如果成功，我将遵循 II阶段由毒理学，ADME，药理学和CMC研究，对人类进行IND和评估。