Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Sepsis represents a major health issue, which claims over 270,000 lives each year in the United States alone, resulting in more than $23 billion in health care costs. While sepsis is caused by bacterial infections that are treated with intravenous (IV) antibiotics, the often very rapid progression into septic shock and ultimately organ failure is a consequence of an overreaction of the immune and coagulation system. The prognosis for sepsis remains poor, with mortality rates exceeding 30%, due to a lack of effective treatment options. Thus far, efforts to therapeutically block any single step in the inflammation or coagulation pathways have had little impact on patient survival. High-density lipoprotein (HDL) is a key component of circulating blood and plays essential roles in vascular endothelial cell (EC) health and balance of the immune system response. Clinical data demonstrate that HDL levels drop by 40-70% in septic patients, which is associated with poor survival prognosis. We and others have shown that infusions of synthetic HDL (sHDL) result in improved survival in mouse models of sepsis. Prophylactic administration of a first generation sHDL product in humans subsequently challenged with an endotoxin infusion was shown to suppress inflammation, inhibit hypotension and markedly decrease the severity of clinical symptoms. These preclinical and clinical studies indicate that replenishing circulating HDL in sepsis patients may provide an effective therapy approach, and HDL itself may serve as a predictive marker for patient outcomes. Previous sHDL candidates have been tested clinically in sepsis relevant settings, but development was discontinued due to safety concerns related to product impurities. Newer and safer versions of sHDL have been developed which have been shown to be safe in humans. We have since developed SPS-701, with further optimized composition to maximize anti- inflammatory properties and utility for sepsis. The objective of this grant is therefore to perform the initial preclinical studies and develop the regulatory strategy for filing an Investigational New Drug (IND) application to advance SPS-701 towards clinical evaluation for the treatment of sepsis.
Public Health Relevance Statement: TSRL and its collaborators at The University of Michigan are developing a novel therapeutic for the treatment of sepsis. The proposed research will establish the preclinical proof-of-concept that effective treatment of patients with systemic blood infections can be achieved with this novel drug candidate, SPS-701, without rendering significant treatment limiting toxic effects.
Project Terms: Animals; Anti-Inflammatory Agents; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Antibiotics; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Bacterial Infections; bacteria infection; bacterial disease; Blood; Blood Reticuloendothelial System; Cardiovascular Diseases; cardiovascular disorder; Cardiovascular system; Cardiovascular; Cardiovascular Body System; Cardiovascular Organ System; Heart Vascular; circulatory system; Cecum; Clinical Chemistry; Clinical Protocols; Clinical Research; Clinical Study; Communicable Diseases; Infectious Disease Pathway; Infectious Diseases; Infectious Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Endotoxins; Equilibrium; balance; balance function; Feedback; Patient Care; Patient Care Delivery; Grant; Health; Human; Modern Man; Hypotension; Low Blood Pressure; Vascular Hypotensive Disorder; Industrialization; Industry; Inflammation; Interleukin-6; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; HPGF; Hepatocyte-Stimulating Factor; Hybridoma Growth Factor; IFN-beta 2; IFNB2; IL-6; IL6 Protein; MGI-2; Myeloid Differentiation-Inducing Protein; Plasmacytoma Growth Factor; interferon beta 2; Laboratories; Ligation; Closure by Ligation; High Density Lipoproteins; HDL; HDL Lipoproteins; Heavy Lipoproteins; High density lipoprotein; alpha-Lipoproteins; Methods; Methodology; Michigan; mortality; Mus; Mice; Mice Mammals; Murine; Pathology; Patients; Peptides; Choline Chloride Dihydrogen Phosphate; Choline Phosphate; Choline Phosphate Chloride; Phosphocholine; Phosphorylcholine Chloride; Phosphorylcholine; Play; Production; Common Rat Strains; Rat; Rats Mammals; Rattus; Research; Rodentia; Rodents Mammals; Rodent; social role; Role; Safety; Septic Shock; Testing; thrombotic disease; thrombotic disorder; Thrombosis; Toxicology; United States; Universities; Veterans; cytokine; Generations; Apolipoprotein A-I; Apo A-1; Apo A-I; Apo A1; Apo AI; ApoA-1; ApoA-I; Apolipoprotein A-1; Apolipoprotein A1; Apolipoprotein AI; Health Care Costs; Health Costs; Healthcare Costs; Custom; Investigational New Drug Application; analytical method; Organ; improved; Clinical; Phase; Ensure; Evaluation; Technology Transfer; Toxicokinetics; Immunological response; host response; immune system response; immunoresponse; Immune response; Therapeutic; Contracting Opportunities; Contracts; Inflammatory; septic; Intravenous; Immunes; Immune; Severities; Complex; prophylactic; System; meetings; Infusion; Infusion procedures; particle; Toxicities; Toxic effect; sterile; Sterility; Prevention; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; (TNF)-a; Cachectin; Macrophage-Derived TNF; Monocyte-Derived TNF; TNF; TNF A; TNF Alpha; TNF-a; TNFA; TNFa; Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; TNF gene; Property; Organ failure; Drops; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; Vascular Endothelial Cell; Clotting; Coagulation; Coagulation Process; 3-10C; AMCF-I; CXCL8; GCP1; IL-8; IL8; K60; SCYB8; TSG-1; b-ENAP; IL8 gene; Dose; Symptoms; Clinical Data; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; Peptide Synthesis; Process; Text; Development; developmental; Pathway interactions; pathway; pre-clinical; preclinical; preclinical study; pre-clinical study; Sepsis; blood infection; bloodstream infection; manufacturing process; scale up; multidisciplinary; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; mouse model; murine model; effective therapy; effective treatment; product development; drug candidate; predictive marker; predictive biomarkers; predictive molecular biomarker; response biomarker; response markers; prognostic of survival; prognostic of overall survival; survival prognosis; clinical translation; clinical development; preclinical development; pre-clinical development; septic patients; sepsis patients; pharmacokinetics and pharmacodynamics; PK/PD; efficacy outcomes; Prognosis
