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

项目总结/文摘

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.