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.

在此输入文本，它是应用程序的新摘要信息。此部分不得超过30行文本。 脓毒症是一个主要的健康问题，仅在美国每年就有超过270，000人死亡，导致超过230亿美元的医疗保健费用。虽然败血症是由细菌感染引起的， (IV)在使用抗生素的情况下，通常非常迅速地进展为败血性休克并最终器官衰竭是免疫和凝血系统过度反应的结果。由于缺乏有效的治疗方案，脓毒症的预后仍然很差，死亡率超过30%。到目前为止，在治疗上阻断炎症或凝血途径中的任何一步的努力对患者的生存几乎没有影响。高密度脂蛋白（HDL）是循环血液的关键成分，在血管内皮细胞（EC）健康和免疫系统反应平衡中起着重要作用。临床数据表明，脓毒症患者的HDL水平下降了40-70%，这与生存预后不良有关。我们和其他人已经表明，输注合成HDL（sHDL）可改善败血症小鼠模型的存活率。在随后用内毒素输注激发的人体中预防性施用第一代sHDL产品显示出抑制炎症、抑制低血压并显著降低临床症状的严重程度。这些临床前和临床研究表明，补充败血症患者的循环HDL可能提供有效的治疗方法，HDL本身可能作为患者结局的预测标志物。 之前的sHDL候选药物已在败血症相关环境中进行了临床测试，但由于与产品杂质相关的安全问题，开发被停止。已经开发出更新和更安全的sHDL版本，这些版本已被证明对人类安全。此后，我们开发了SPS-701，进一步优化了组成，以最大限度地提高抗炎特性和败血症的效用。因此，该资助的目的是进行初步的临床前研究，并制定监管策略，以提交研究性新药（IND）申请，从而将SPS-701推向脓毒症治疗的临床评估。