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

项目总结/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COVID-19）的炎性肺部疾病， 创伤、败血症、癌症和许多其他病症。急性呼吸窘迫综合征的死亡率分别为27%、32%和45%， 中度和重度疾病。COVID-19并发ARDS患者的存活率约为 百分之二十五目前还没有针对ARDS的有效药物治疗。这突出表明，迫切需要采取有效措施， 治疗ARDS。本计画的长期目标是发展一种有效且可耐受的急性呼吸窘迫综合征 治疗旨在降低ARDS患者的死亡率并改善预后。 急性呼吸窘迫综合征患者肺内急性炎症反应的增强与细胞因子风暴有关。 急性呼吸窘迫综合征患者髓样细胞触发受体1（TREM-1）表达上调 和新冠肺炎在动物中，TREM-1阻断可减少细胞因子风暴并防止肺损伤。的 由最近的动物数据支持的该研究的假设是TREM-1阻断剂改善了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。到 最大限度地降低临床开发失败的风险，我们开发了一流的配体非依赖性良好的- 耐受的TREM-1抑制肽GF 9，可配制成SignaBlok的长半衰期巨噬细胞- 特异性脂肽复合物（LPC），以改善其半衰期和靶向炎症区域。 早些时候，我们发现GF 9序列作为游离肽或作为LPC结合的三功能肽的一部分， 肽GA 31（GA 31-LPC）抑制炎性细胞因子释放，防止感染性休克， 逆转小鼠的肺纤维化。本研究的目的是测试它是否抑制细胞因子风暴和减轻ARDS 在动物模型中。考虑到GF 9和GA 31-LPC的优缺点，我们建议测试两种电极导线。 该项目的具体目标是：1）产生和表征体外GF 9和GA 31-LPC注射剂， 2）在ARDS动物模型中对比检测GF 9和GA 31-LPC。我们将合成， 表征GF 9和GA 31-LPC的体外巨噬细胞摄取的稳定性、速率和效率， 以及它们对LPS刺激的细胞释放细胞因子的抑制作用。我们将测试两剂 在ARDS动物中的制剂。将比较研究配体依赖性TREM-1抑制剂LR 12。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I期研究将确定一种新型的、一流的、耐受性良好的药物， 为开发能够治疗ARDS的安全有效疗法提供了强大的平台。其预期 SignaBlok的GF 9治疗在动物中的良好耐受性和TREM-1的安全性支持了安全性。 在健康、败血症和COVID-19受试者中采用阻断方法。如果成功，第一阶段将在 II期通过毒理学、ADME、药理学和CMC研究，提交IND和人体评价。

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.