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

基本信息

批准号：
10384700
负责人：
Elke Lipka
金额：
$ 98.85万
依托单位：
TSRL, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10384700
关键词：
Animals Anti-Inflammatory Agents Antibiotics Apolipoprotein A-I Bacterial Infections Blood Cardiovascular Diseases Cardiovascular system Cecum 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 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 Peptides Pharmaceutical Preparations Pharmacologic Substance Phase Phosphorylcholine Play Prevention Process Production Prognosis Property Rattus 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 improved manufacturing process meetings mortality mouse model multidisciplinary novel therapeutics particle pharmacokinetics and pharmacodynamics pre-clinical preclinical development preclinical study predictive marker product development prognostic of survival prophylactic research clinical testing response biomarker scale up septic septic patients

项目摘要

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，这是您应用程序的新摘要信息。本节必须不超过30行文本。败血症代表了一个重大的健康问题，仅在美国，每年就有超过270,000人的生命，导致超过230亿美元的医疗保健费用。败血症是由静脉注射治疗的细菌感染引起的（iv）抗生素，通常非常快速发展为败血性休克，最终器官衰竭是免疫和凝结系统过度反应的结果。由于缺乏有效的治疗选择，败血症的预后仍然很差，死亡率超过30％。到目前为止，在治疗上阻止炎症或凝结途径中任何单一步骤的努力对患者的生存影响很小。高密度脂蛋白（HDL）是循环血液的关键组成部分，在血管内皮细胞（EC）健康和免疫系统反应的平衡中起着至关重要的作用。临床数据表明，败血症患者的HDL水平下降了40-70％，这与存活不良有关。我们和其他人表明，合成HDL（SHDL）的输注可改善败血症小鼠模型的生存率。随后受到内毒素输注挑战的人类中第一代SHDL产物的预防性给药可抑制炎症，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，在败血症患者中补充循环的HDL可能会提供有效的治疗方法，而HDL本身可以作为患者结局的预测标志。以前的SHDL候选者已在败血症相关的环境中进行了临床测试，但是由于与产品杂质有关的安全问题，开发被停产。已经开发了新的，更安全的SHDL版本，这些版本在人类中已被证明是安全的。从那以后，我们开发了SPS-701，并具有进一步优化的组成，可最大程度地提高败血症的抗炎性特性和效用。因此，该赠款的目的是进行最初的临床前研究，并制定对提出研究新药（IND）申请的监管策略，以将SPS-701推向临床评估以促进败血症治疗。