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-κB-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.
Public Health Relevance Statement: Public Health Narrative Due to a dysregulation of host immune responses after infection there is an increase inflammation in the blood leading to septicemia and ultimately organ damage. In this application, we propose to develop peptide-based therapies that can shift systemic inflammation balance to efficiently restore immune homeostasis as a treatment for sepsis.
Project Terms: new approaches; novel approaches; novel strategy; novel strategies; intervention efficacy; therapeutic efficacy; therapy efficacy; Treatment Efficacy; C-terminal; peptide mimetic; peptide mimic; peptidomimetics; murine model; mouse model; bio-markers; biologic marker; biomarker; Biological Markers; Formulation; clinical development; sepsis patients; septic patients; lead candidate; pneumonia models; pneumonia model; systemic inflammation; systemic inflammatory response; 21+ years old; Adult Human; adulthood; Adult; Animals; inhibitor; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Antibiotics; Antisepsis; Bacteremia; bacteraemia; bacterial sepsis; Bacterial Infections; bacteria infection; bacterial disease; Bacterial Pneumonia; bacteria pneumonia; Biological Availability; Bioavailability; Physiologic Availability; Biology; Blood; Blood Reticuloendothelial System; Capital; Cell membrane; Cytoplasmic Membrane; Plasma Membrane; plasmalemma; Cells; Cell Body; Clinical Trials; Cessation of life; Death; intravenous administration; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Equilibrium; balance; balance function; Escherichia coli; E coli; E. coli; Foundations; Homeostasis; Autoregulation; Physiological Homeostasis; Hospitalization; Hospital Admission; Human; Modern Man; Infection; Inflammation; intravenous injection; Lead; Pb element; heavy metal Pb; heavy metal lead; Lung; Lung Respiratory System; pulmonary; Multiple Organ Failure; MOF syndrome; Multiple Organ Dysfunction Syndrome; multiorgan failure; multiple organ system failure; Mus; Mice; Mice Mammals; Murine; neutrophil; Blood Neutrophil; Blood Polymorphonuclear Neutrophil; Marrow Neutrophil; Neutrophilic Granulocyte; Neutrophilic Leukocyte; Polymorphonuclear Cell; Polymorphonuclear Leukocytes; Polymorphonuclear Neutrophils; Peptides; Personal Satisfaction; well-being; wellbeing; Privatization; Proteins; Pseudomonas aeruginosa; P aeruginosa; P. aeruginosa; Pseudomonas pyocyanea; Public Health; Research; Safety; Septicemia; Blood Poisoning; septicaemia; septicemic; Septic Shock; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Staphylococcus aureus; S aureus; S. aureus; Staph aureus; Testing; Genetic Transcription; Gene Transcription; RNA Expression; Transcription; Translating; Universities; Weight; weights; Work; Leukocyte Elastase; Granulocyte Elastase; Lysosomal Elastase; Neutrophil Elastase; PMN Elastase; Polymorphonuclear Leukocyte Elastase; forest; Mediating; Neutrophilia; Organ; improved; Clinical; Phase; Survivors; Blood Serum; Serum; Failure; non-human primate; nonhuman primate; Disease Progression; Immunological response; host response; immune system response; immunoresponse; Immune response; Therapeutic; Inflammatory; Supportive care; Supportive Therapy; Intravenous; Life; programs; Immune; Immunes; Services; vervet; Nasal Epithelium; hospital readmission; hospital re-admission; re-admission; re-hospitalization; readmission; rehospitalization; novel; Palate; Modeling; Inflammatory Response; preventing; prevent; Causality; causation; disease causation; Etiology; Data; Doctor of Philosophy; Ph.D.; PhD; Glosso-Sterandryl; Eldec; Ero Test; Estratest; Malogen; Metandren; Neohombreol M; Orchisterone-M; Oreton methyl; Testomet; Testotonic B; Testovis; Testred; Pre-Clinical Model; Preclinical Models; Knock-out; Knockout; Process; Development; developmental; Immunomodulators; immune modulators; pre-clinical; preclinical; blood infection; bloodstream infection; Sepsis
