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.

在此处输入文本，该文本是您的应用程序的新摘要信息。此部分的文本长度不得超过 30 行。 脓毒症是一个重大的健康问题，仅在美国每年就有超过 270,000 人丧生，造成超过 230 亿美元的医疗费用。脓毒症是由细菌感染引起的，可通过静脉注射治疗 (IV) 抗生素，由于免疫和凝血系统过度反应，通常会非常迅速地进展为感染性休克并最终导致器官衰竭。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%。迄今为止，治疗性阻断炎症或凝血途径中任何单一步骤的努力对患者的生存影响甚微。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发挥重要作用。临床数据表明，脓毒症患者的 HDL 水平下降 40-70%，这与不良的生存预后相关。我们和其他人已经证明，输注合成 HDL (sHDL) 可以提高脓毒症小鼠模型的存活率。在随后接受内毒素输注的人类中预防性施用第一代 sHDL 产品被证明可以抑制炎症、抑制低血压并显着降低临床症状的严重程度。这些临床前和临床研究表明，补充脓毒症患者的循环 HDL 可能提供一种有效的治疗方法，并且 HDL 本身可以作为患者预后的预测标志物。 之前的 sHDL 候选药物已在脓毒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而停止了开发。更新、更安全的 sHDL 版本已经开发出来，已被证明对人类是安全的。此后，我们开发了 SPS-701，其成分进一步优化，以最大限度地提高抗炎特性和对脓毒症的效用。因此，这笔拨款的目的是进行初步临床前研究，并制定提交研究性新药 (IND) 申请的监管策略，以推动 SPS-701 进行脓毒症治疗的临床评估。