Project Grant R43AI174395

NOVEL PEPTIDE IMMUNOMODULATORS FOR TREATING SEPSIS - NOVEL PEPTIDE IMMUNOMODULATORS FOR TREATING SEPSIS SEPSIS IS A LIFE-THREATENING CLINICAL CONDITION WHICH RESULTS FROM A DYSREGULATION OF HOST IMMUNE RESPONSES TO INFECTION, WHICH LEADS TO MULTI-ORGAN FAILURE. SEPSIS OCCURS IN ~1.7 MILLION US ADULTS ANNUALLY RESULTING IN HOSPITALIZATION AND 270,000 DEATHS. OF THOSE THAT SURVIVE, NEARLY 50% OF SEPSIS PATIENTS ARE RE-HOSPITALIZED AND ONE IN SIX OF SURVIVORS DO NOT SURVIVE PAST ONE YEAR. SEPSIS IS CHARACTERIZED BY INCREASED BACTEREMIA RESULTING IN HYPER-SYSTEMIC INFLAMMATORY RESPONSES AND A FAILURE TO NORMALIZE IMMUNE HOMEOSTASIS RESULTING IN SEPTIC SHOCK5. TREATMENT CONSISTS OF ANTIBIOTICS TO TARGET BACTERIAL INFECTIONS AND SUPPORTIVE CARE FOR TARGETED ORGANS. HOWEVER, NO DRUGS ARE CURRENTLY AVAILABLE TO TARGET AND TREAT THE HYPER IMMUNE RESPONSE, INDICATING THAT THERE IS CRITICAL UNMET NEED FOR PROGRESSIVE SEPSIS THERAPIES. ORAI1 IS A PLASMA MEMBRANE CA2+ CHANNEL THAT REGULATES STORE OPERATED CA2+ ENTRY (SOCE), A FUNDAMENTAL PROCESS. ORAI1/SOCE IS PROXIMAL IN INFLAMMATORY SIGNALING AND REGULATES NF-B-MEDIATED TRANSCRIPTION AND SECRETION OF PRO- INFLAMMATORY RESPONSES. SHORT PALATE LUNG AND NASAL EPITHELIAL CLONE 1 (SPLUNC1) IS A SECRETED INNATE DEFENSE PROTEIN. WE FOUND THAT SPLUNC1'S C-TERMINAL A6 REGION IS A SPECIFIC INHIBITOR OF ORAI1. THUS, SPLUNC1/A6 NEGATIVELY REGULATES ORAI1 TO REDUCE SOCE AND INFLAMMATION. ELDEC THEREFORE PLANS TO INHIBIT ORAI1 USING A6 PEPTIDOMIMETICS TO INHIBIT INFLAMMATION DURING SEPSIS. ELDEC HAS SUCCESSFULLY DEVELOPED ELD607, A SPLUNC1 PEPTIDOMIMETIC THAT IS FULLY SIZE- OPTIMIZED, AND SIGNIFICANTLY MORE POTENT AND MORE PROTEOLYTICALLY STABLE THAN SPLUNC1 A6. WE HAVE FOUND THAT ELD607 SIGNIFICANTLY REDUCES ORAI1/SOCE AND SUBSEQUENT INFLAMMATORY RESPONSES ASSOCIATED WITH SEPSIS AND/OR BACTERIAL PNEUMONIA. OUR PRELIMINARY DATA DEMONSTRATE THAT ELD607 REDUCES SEPSIS CAUSED BY S. AUREUS AND P. AERUGINOSA IN MURINE PNEUMONIA MODELS. ADDITIONALLY, MICE TREATED WITH ELD607 HAD INCREASED SURVIVAL, SUGGESTING THAT ELD607 IS NOT IMMUNOSUPPRESSIVE. OUR DATA ALSO INDICATE THAT ELD607 REDUCED BLOOD NEUTROPHILIA AND IMPROVED WEIGHT IN AN LPS-INDUCED SEPSIS MODEL. THUS, OUR STUDIES DEMONSTRATE THAT ELD607 IS A NOVEL IMMUNOMODULATOR THAT IS EFFECTIVE AGAINST SEPSIS. WE ACKNOWLEDGE THE LIMITATIONS OF MURINE SEPSIS MODELS. THUS, TO BETTER TRANSLATE OUR FINDINGS, WE WILL EVALUATE ELD607 AS A TREATMENT FOR LPS-INDUCED SEPSIS IN HUMAN SEPSIS PATIENT IMMUNE CELLS AND IN NONHUMAN PRIMATES. WE WILL FIRST EVALUATE THE STABILITY OF ELD607 HUMAN SERUM FROM SEPSIS PATIENTS. WE WILL THEN EVALUATE ELD607'S EFFICACY IN HUMAN BLOOD NEUTROPHILS OF SEPSIS PATIENTS. WE WILL THEN VALIDATE ELD607'S EFFICACY IN NONHUMAN PRIMATES IN AN LPS-INDUCED SEPSIS IN ORDER TO STUDY THE IMPACT OF ELD607 ON REDUCING SEPSIS DISEASE PROGRESS.