A Novel Therapy for Septic Shock

感染性休克的新疗法

• 批准号: 8133737
• 负责人: Xiaoling Qiang
• 金额: $ 57.11万
• 依托单位: THERASOURCE, LLC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-23 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133737
• 关键词: Acute; Acute myocardial infarction; Animal Model; Animals; Apoptosis; Apoptotic; Attenuated; Biological; Blood gas; Blood specimen; Body Weight; Bolus Infusion; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cecum; Cells; Cessation of life; Chromatography; Clinical Trials; Coagulation Process; Creatinine; Data; Development; Dose; Down-Regulation; Drug Kinetics; Endotoxins; Enzymes; Epidermal Growth Factor; Escherichia coli; Evaluation; Factor VIII; Family suidae; Goals; Healthcare; Human; Incidence; Inflammation; Inflammatory Response; Injection of therapeutic agent; Injury; Intensive Care Units; Label; Lethal Dose 50; Ligation; Liver; Marketing; Maximum Tolerated Dose; Measurement; Measures; Medical; Modeling; Monitor; Mus; Necrosis; Organ failure; Patients; Phagocytosis; Pharmaceutical Preparations; Phase; Plasma; Play; Precipitation; Preparation; Procedures; Production; Property; Proteins; Puncture procedure; Radioactive; Rattus; Recombinants; Reporting; Research; Rodent Model; Role; Sepsis; Septic Shock; Serum; Small Business Innovation Research Grant; Survival Rate; System; Testing; Therapeutic Agents; Time; Tissue Sample; Tissues; Toxic effect; Trauma; United States; apoptosis in lymphocytes; cost; cytokine; effective therapy; hemodynamics; immunogenicity; implantation; improved; knockout animal; milk fat globule; mortality; novel; novel therapeutics; operation; phase 2 study; pre-clinical; preclinical study; public health relevance; research study; response; response to injury; scale up; septic

DESCRIPTION (provided by applicant): This SBIR Phase I/Phase II Fast-Track proposal is intended to develop a novel therapy for patients with sepsis and septic shock. Septic shock is the leading cause of death in non-cardiac intensive care units. Despite advances in the management of trauma victims, the incidence of sepsis and septic shock has increased significantly. More than 750,000 patients develop sepsis and septic shock each year with an overall mortality rate of 28.6% in the US alone. The global market potential for sepsis treatment is estimated at over $30 billion annually. Thus, successful development of a novel and effective anti-sepsis therapy will not only have a positive impact on health care, but will also have significant commercial benefits. Although apoptosis plays an important role in the pathobiology of sepsis, the clearance of apoptotic cells has largely been ignored. Recent evidence shows that the opsonizing protein milk fat globule epidermal growth factor-factor VIII (MFG-E8) is involved in apoptotic cell clearance. We have discovered that downregulation of MFG-E8 is responsible for the reduced apoptotic cell clearance in sepsis. Early administration of rat MFG-E8-containing exosomes or recombinant murine MFG-E8 (rmMFG- E8) increases phagocytosis of apoptotic cells, reduces proinflammatory cytokines, and improves survival in a rodent model of septic shock. However, one obstacle hampering the development of MFG-E8 as a therapeutic agent for septic patients is the potential immunogenicity of animal proteins in humans. To overcome this, we have successfully expressed recombinant human MFG-E8 (rhMFG-E8). Our data strongly suggest that rhMFG-E8 is as effective as animal MFG-E8. We therefore hypothesize that administration of rhMFG-E8, even late after the onset of sepsis, improves cardiovascular function, attenuates tissue injury and inflammation, and reduces mortality. The primary goal of this SBIR Fast-Track project is targeted toward completing the preclinical development of rhMFG-E8 as a novel therapeutic agent in reducing mortality in septic shock. In the Phase I Segment, we will 1) scale up the production of rhMFG- E8; and 2) further confirm the beneficial effect of rhMFG-E8 in a rodent model of septic shock. These readily achievable milestones should provide useful feasibility information that will allow us to conduct the proposed Phase II experiments. In the Phase II Segment, we will 3) determine the dose-response effect and time-course (delayed administration) of rhMFG-E8 on apoptosis, cardiovascular responses, tissue injury, inflammation, and survival in a rodent model of septic shock; 4) assess the toxicity and pharmacokinetic properties of rhMFG-E8 in normal and septic animals; and 5) determine the efficacy of rhMFG-E8 in a swine model of septic shock. These proposed studies should provide useful preclinical information that will allow us to file an IND application to the FDA for initiating clinical trials in order to obtain commercial utilization of rhMFG-E8 as a safe and effective therapy for patients with sepsis and septic shock.

描述（由申请人提供）：此SBIR I期/II期快速曲目提案旨在为败血症患者和败血性休克患者开发一种新的疗法。败血性休克是非心脏重症监护病房死亡的主要原因。尽管创伤受害者的管理进步，但败血症和败血性冲击的发生率显着增加。每年有超过750,000名患者出现败血症和败血性休克，仅在美国，总的死亡率为28.6％。脓毒症治疗的全球市场潜力估计每年超过300亿美元。因此，成功开发了一种新颖有效的抗盐疗法，不仅会对医疗保健产生积极影响，而且还将具有巨大的商业利益。尽管凋亡在败血症的病理生物学中起重要作用，但凋亡细胞的清除在很大程度上被忽略了。最近的证据表明，调向蛋白质牛奶脂肪球表皮生长因子因素VIII（MFG-E8）参与凋亡细胞清除率。我们已经发现，MFG-E8的下调是败血症中凋亡细胞清除率降低的原因。早期给予大鼠MFG-E8的外泌体或重组鼠MFG-E8（RMMFG-E8）会增加凋亡细胞的吞噬作用，减少促炎细胞因子，并提高屈服模型中的啮齿动物模型中的存活率。然而，一个阻碍MFG-E8作为化粪池患者的治疗剂的发展的障碍是人类动物蛋白的潜在免疫原性。为了克服这一点，我们成功地表达了重组人MFG-E8（RHMFG-E8）。我们的数据强烈表明RHMFG-E8与动物MFG-E8一样有效。因此，我们假设，即使在败血症发作后很晚，RHMFG-E8的给药也可以改善心血管功能，减轻组织损伤和炎症并降低死亡率。该SBIR快速轨道项目的主要目标是完成RHMFG-E8作为降低败血性休克死亡率的新型治疗剂的临床前开发。在第一阶段的细分市场中，我们将1）扩大rhmfg-e8的生产； 2）进一步证实了在败血性休克模型中RHMFG-E8的有益作用。这些易于实现的里程碑应提供有用的可行性信息，使我们能够进行拟议的II期实验。在II期段中，我们将3）确定RHMFG-E8的剂量反应效应和时间顺序（延迟施用）对败血性休克的啮齿动物模型中的凋亡，心血管损伤，组织损伤，炎症和存活； 4）评估正常动物和化粪池中RHMFG-E8的毒性和药代动力学特性； 5）确定RHMFG-E8在败血性休克模型中的功效。这些拟议的研究应提供有用的临床前信息，使我们能够向FDA提出IND应用，以启动临床试验，以便为败血症患者和败血性休克患者提供对RHMFG-E8的商业利用。

项目成果

Recombinant human milk fat globule-EGF factor VIII (rhMFG-E8) as a therapy for sepsis after acute exposure to alcohol.

重组人乳脂肪球 - EGF 因子 VIII (rhMFG-E8) 作为急性酒精暴露后败血症的治疗方法。

• DOI: 10.1186/s10020-019-0118-x
• 发表时间: 2019
• 期刊: Molecular medicine (Cambridge, Mass.)
• 作者: Chaung,WayneW;Brenner,Max;Yen,Hao-Ting;Ochani,MahendarL;Jacob,Asha;Wang,Ping
• 通讯作者: Wang,Ping