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

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 可能并发严重肺炎(包括流感和新冠肺炎)的炎症性肺部状况， 创伤、败血症、癌症和许多其他病症。ARDS的死亡率分别为27%、32%和45%。 分别为中度疾病和重度疾病。患有急性呼吸窘迫综合征的新冠肺炎患者的存活率约为 25%。目前还没有针对ARDS的有效药物治疗方法。这突显出迫切需要有效的 ARDS的治疗。该项目的长期目标是开发一种有效且耐受性良好的ARDS 治疗的目的是降低ARDS患者的死亡率和改善预后。 ARDS患者肺部放大的、快速的急性炎症反应与细胞因子风暴有关。 急性呼吸窘迫综合征患者炎症放大因子--髓系细胞触发受体-1表达上调 还有新冠肺炎。在动物中，TREM-1阻断可减少细胞因子风暴，保护肺免受损伤。这个 这项研究的假说得到了最近的动物数据的支持，即TREM-1受体阻滞剂可以改善ARDS。 目前的TREM-1抑制剂都试图阻断TREM-1与其仍不确定的配体的结合(S)。至 在临床开发中将失败风险降至最低，我们开发出了一流的配体非依赖井- 耐受的Trem-1抑制肽GF9，可制成SignaBlok的长半衰期巨噬细胞- 特定的脂肽复合体(LPC)，以改善其半衰期，并针对炎症区域。 早些时候，我们发现GF9序列既可以作为游离肽，也可以作为LPC结合三官能团的一部分 多肽GA31(GA31-LPC)抑制炎性细胞因子的释放，保护感染性休克和 逆转小鼠肺纤维化。这项研究的目的是测试它是否抑制细胞因子风暴和缓解ARDS 在动物模型中。考虑到GF9和GA31-LPC的利弊，我们建议测试这两种导线。 本项目的具体目标是：1)制备和表征体外GF9和GA31-LPC注射剂， 2)在ARDS动物模型上进行GF9和GA31-LPC的对比检测。我们将综合和 GF9和GA31-LPC在体外对巨噬细胞摄取的稳定性、速率和效率 以及它们对内毒素刺激细胞释放细胞因子的抑制作用。我们将测试两种剂量的 ARDS动物的配方。配体依赖的TREM-1抑制剂LR12将进行比较研究。我们 将分析肺部炎症和肺损伤。将进行全面的HISTO/IHC研究。 预计这项第一阶段研究将确定一种新的、一流的、耐受性良好的制剂作为 为开发安全有效的治疗ARDS的方法提供了强大的平台。它的预期 SignaBlok的GF9疗法在动物身上的良好耐受性和TREM-1的安全性支持了安全性。 阻断方法在健康、脓毒症和新冠肺炎受试者中的应用。如果成功，第一阶段将在 第二阶段通过毒理学、ADME、药理学和CMC研究，提交IND并在人体上进行评估。

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.