Novel TREM-1 targeting therapies for sepsis

Project Summary Abstract Sepsis kills more thanAmericans annuallyNo approved drugs are available and overdrug candidates failed late stage clinical trialswhich highlights the urgent need for novel approachesThe longterm goal of this project is to develop a new mechanism basedefficient and low toxicity sepsis therapyTriggering receptor expressed on myeloid cellsTREMan inflammation amplifieris overexpressed in patients with sepsisIn mice with lipopolysaccharideLPSinduced endotoxic shockblockade of TREMinhibits inflammation and protects animals from deathHowevercurrent TREMinhibitors block binding of the unknown ligand to TREMwhich highly increases the risk of their failure in clinical developmentSignaBlok developed a first in class ligand independent TREMinhibitory peptide GFGFis welltolerated and can be formulated into SignaBlokandapos s lipopeptide complexesLPCthat contain two modified peptides of human apolipoproteinapoA I PEand PAand intracellularly deliver GFto macrophages probably due to apo A I epitopes for binding to scavenger receptorsSRSR APEand PAand SRBIPASR BI is also expressed on hepatocytes and provides hepatic clearance of GFLPC affecting their half lifeIn Phase Iwe will test the hypothesis that combination and exposure of these epitopes in GFLPC can be optimized to provide fast and efficient GFdelivery to macrophages by long half life GFLPCThis is anticipated to provide a prompteffective and long lasting protection against sepsisPhase I specific aims are tooptimize GFLPC composition for fast and efficient delivery of GFto macrophages in vitroandtest GFLPC comparatively in mouse models of polymicrobial and LPSinduced sepsisWe will generateoptimize and select the most promising GFLPC formulations based upon their stabilityGFcontentand rate and efficiency of murine and human macrophage uptake in vitro as well as upon their inhibitory effect on cytokine release by LPS stimulated cellsWe will determine in vivo pharmacokineticsbioavailabilityand biodistribution of these formulationsselect the optimal GFLPC formulation and test two doses of it in mice with sepsis induced by cecal ligation and punctureCLPor LPSThe use of two animal models will address the known differences in their patterns of cytokines and pharmacomodulationWe will determine both systemic inflammationby measuring serum and tissue cytokinesand animal survivalComprehensive histology will be performed to analyze organ protection and or potential non specific toxicity for organs tissuesGFbiodistribution will be analyzed using LC MSIt is anticipated that the Phase I study will identify novelfirst in classlow toxic TREMinhibitors that will provide a powerful platform for development of effective and safe sepsis therapiesthereby improving sepsis treatment and increasing patient survivalIf successfulPhase I will be followed in Phase II by toxicologyADMEpharmacology and CMC studiesfiling an IND and subsequent evaluation in humans Project Narrative More thancases of sepsis occur annually in the USandtoof these patients dieDespite the use of potent antibiotics and advanced resuscitative equipment costing $billion a yearseptic shock remains the leading cause of death in intensive care unitsThe proposed research is anticipated to result in the development of novel mechanism based anti sepsis therapeutics that could substantially improve sepsis treatment and increase survival of patients