Development of Synthetic High-Density Lipoproteins for Treatment of Sepsis

用于治疗脓毒症的合成高密度脂蛋白的开发

• 批准号: 10569516
• 负责人: Elke Lipka
• 金额: $ 64.38万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10569516
• 关键词: Animals; Anti-Inflammatory Agents; Antibiotics; Apolipoprotein A-I; Bacterial Infections; Blood; Cardiovascular Diseases; Cardiovascular system; Clinical; Clinical Chemistry; Clinical Data; Clinical Protocols; Clinical Research; Coagulation Process; Communicable Diseases; Complex; Contracts; Custom; Development; Dose; Drops; Endotoxins; Ensure; Equilibrium; Evaluation; Feedback; Generations; Grant; Health; Health Care Costs; High Density Lipoproteins; Human; Hypotension; IL8 gene; Immune response; Industrialization; Industry; Inflammation; Inflammatory; Infusion procedures; Interleukin-6; Intravenous; Investigational Drugs; Investigational New Drug Application; Laboratories; Ligation; Maximum Tolerated Dose; Methodology; Methods; Michigan; Mus; Organ; Organ failure; Pathology; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Peptide Synthesis; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphorylcholine; Play; Prevention; Process; Production; Prognosis; Property; Rattus; Recommendation; Research; Rodent; Role; Safety; Sepsis; Septic Shock; Severities; Sterility; Symptoms; System; TNF gene; Technology Transfer; Testing; Text; Therapeutic; Thrombosis; Toxic effect; Toxicokinetics; Toxicology; United States; Universities; Vascular Endothelial Cell; Veterans; analytical method; clinical development; clinical translation; cytokine; drug candidate; effective therapy; efficacy outcomes; immunoreaction; improved; manufacture; manufacturing organization; manufacturing process; meetings; mortality; mouse model; multidisciplinary; novel therapeutics; particle; peptide I; pharmacokinetics and pharmacodynamics; pre-Investigational New Drug meeting; pre-clinical; preclinical development; preclinical study; predictive marker; product development; prognostic of survival; prophylactic; research clinical testing; response biomarker; scale up; septic; septic patients

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.

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