Project Grant R41HL164154

TARGETING THE P SELECTIN PATHWAY TO IMPROVE ARDS SURVIVAL - ABSTRACT ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) IS A CRITICAL ILLNESS WITH 30- 40% MORTALITY AND CURRENTLY THERE ARE NO FDA-APPROVED THERAPIES. QUELL PHARMA AND AQUALUNG THERAPEUTICS HAVE DEVELOPED A RECOMBINANT SOLUBLE, CELL-FREE FORM OF RECOMBINANT HUMAN P-SELECTIN GLYCOPROTEIN LIGAND-1 (PSGL-1) DESIGNATED TANDEM P-SELECTIN GLYCOPROTEIN LIGAND-1 IMMUNOGLOBULIN (TSGL-IG), WHICH IS A POTENT PAN-SELECTIN ANTAGONIST WITH GREAT POTENTIAL AS A NOVEL ARDS THERAPY. TSGL-IG WORKS BY INHIBITING THE ADHESION OF POLYMORPHONUCLEAR (PMN) LEUKOCYTES ON ACTIVATED ENDOTHELIAL CELLS (ECS), A KEY DRIVER IN THE DEVELOPMENT AND PROGRESSION OF ARDS AND SYSTEMIC VASCULAR INFLAMMATION IN OTHER ORGANS. PMN LEUKOCYTE "TRAFFICKING" ACROSS ACTIVATED ECS IS ASSOCIATED WITH THE UPREGULATION OF CELL ADHESION MOLECULES SUCH AS P-SELECTIN. SELECTINS INITIATE THE PMN TRAFFICKING PROCESS BY BINDING TO LIGANDS THAT STICK OUTWARDS FROM SURFACE OF OPPOSING CELLS, A PROCESS DESCRIBED AS THE "MOLECULAR VELCRO" OF THE IMMUNE SYSTEM. PSGL-1, THE MOST IMPORTANT SELECTIN LIGAND, HAS THE CAPACITY TO BIND ALL THREE SELECTIN TYPES, P-SELECTIN, L-SELECTIN, AND E-SELECTIN. OUR GROUP WAS THE FIRST TO IDENTIFY VARIANTS IN THE SELECTIN P LIGAND GENE (SELPLG), TO BE ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO ARDS AMONG AFRICAN-AMERICANS. SELECTIN ANTAGONISTS HAVE SHOWN GREAT PROMISE IN ISCHEMIA REPERFUSION MODELS OF LIVER TRANSPLANTATION, SICKLE CELL MODELS AND PRECLINICAL MODELS OF ARDS. OUR PRELIMINARY DATA INDICATES THAT TSGL-IG IS A PROMISING THERAPEUTIC OPTION FOR ARDS, HOWEVER, THE OPTIMAL DOSE AND THERAPEUTIC WINDOW HAS NOT BEEN DETERMINED IN PRECLINICAL MODELS OF ARDS. THE SPECIFIC AIMS (SAS) OF THIS STTR WILL DETERMINE OPTIMAL DOSE AND THERAPEUTIC WINDOW FOR TSGL-IG IN C57BL6 MURINE MICE (SA #1) AND SPRAGUE DAWLEY RATS (SA #2) SUBJECTED TO A COMBINED LPS/VILI-INDUCED LUNG INJURY MODEL. THREE DOSES OF TSGL-IG (0.1 MG/KG, 0.5 MG/KG, AND 1MG/KG, IV) WILL BE INJECTED CONCURRENTLY WITH LPS TO DETERMINE OPTIMAL EFFICACIOUS DOSE. NEXT, TSGL-IG WILL BE INJECTED AT 0, 1, 3, AND 6 HOURS POST LPS INJECTION BUT PRIOR TO VILI EXPOSURE TO DETERMINE THE THERAPEUTIC WINDOW. READOUTS INCLUDE BRONCHOALVEOLAR LAVAGE (BAL) FLUID CELL COUNTS, BAL PROTEIN, PLASMA CYTOKINES, AND HISTOLOGICALLY QUANTIFIED LUNG INJURY SCORE. FINALLY, SA #3 STUDIES WILL VALIDATE THESE RESULTS IN A CLINICALLY-RELEVANT PORCINE MODEL OF ARDS. PHASE II PLANNING. SUCCESSFUL COMPLETION OF PHASE I SAS WILL ALLOW US TO PROCEED TO PHASE II, WHERE WE WILL ASSESS PHARMACOKINETIC (PK), PHARMACODYNAMIC (PD), AND SAFETY (TOXICOLOGY) PROFILES OF TSGL-IG AS WELL AS THE DEVELOPMENT OF A CHEMISTRY, MANUFACTURING, AND CONTROL (CMC) CONTRACTED INFRASTRUCTURE TO SUPPORT CLINICAL DEVELOPMENT. SUCCESSFUL COMPLETION OF THE PHASE II SAS WILL POSITION US TO APPLY AND RECEIVE IND APPROVAL FROM THE FDA, AND TO VALIDATE TSGL-IG AS A THERAPEUTIC APPROACH IN HEALTHY VOLUNTEERS (PHASE I TRIAL) AND IN SUBJECTS WITH ARDS (PHASE II TRIAL).