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，它是您的应用程序的新摘要信息。此部分不得超过30行文本。 败血症是一个主要的健康问题，仅在美国每年就有超过27万人丧生，导致超过230亿美元的医疗费用。而败血症是由静脉注射治疗的细菌感染引起的 (4)抗生素，通常非常迅速地发展为感染性休克，最终导致器官衰竭，这是免疫和凝血系统过度反应的结果。由于缺乏有效的治疗选择，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个步骤的努力对患者的存活率几乎没有影响。高密度脂蛋白(高密度脂蛋白)是血液循环中的关键成分，对血管内皮细胞(EC)的健康和免疫系统反应的平衡起着至关重要的作用。临床资料表明，脓毒症患者的高密度脂蛋白水平下降40-70%，这与预后不良有关。我们和其他人已经证明，输注合成高密度脂蛋白(SHDL)可以改善脓毒症小鼠模型的存活率。在人类中预防性使用第一代高密度脂蛋白产品，随后接受内毒素输注，被证明可以抑制炎症，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，在脓毒症患者中补充循环中的高密度脂蛋白可能提供一种有效的治疗方法，而高密度脂蛋白本身可以作为患者预后的预测标志。 以前的sHDL候选药物已经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，开发工作停止了。更新、更安全的sHDL已经被开发出来，已经被证明对人类是安全的。自那以后，我们开发了SPS-701，进一步优化了成分，以最大限度地提高抗炎性能和对脓毒症的效用。因此，这笔赠款的目标是进行初步的临床前研究，并制定监管战略，以提交研究性新药(IND)申请，以推动SPS-701对脓毒症治疗的临床评估。