A Novel Therapy for Septic Shock

感染性休克的新疗法

• 批准号: 7404793
• 负责人: RONGQIAN WU
• 金额: $ 42.95万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7404793
• 关键词: Acute; Animal Model; Animals; Apoptosis; Apoptotic; Attenuated; Biological; Blood; Blood gas; Body Weight; Bolus Infusion; Cardiac; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cecum; Cells; 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; Modeling; Monitor; Mus; Necrosis; Numbers; Operative Surgical Procedures; Organ failure; Patients; Phagocytosis; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Plasma; Play; Precipitation; Preparation; Procedures; Production; Property; Proteins; Puncture procedure; Radioactive; Rate; Rattus; Recombinants; Research; Rodent Model; Role; Sepsis; Septic Shock; Serum; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Survival Rate; Sus scrofa; System; Testing; Therapeutic Agents; Time; Tissue Sample; Tissues; Toxic effect; Trauma; United States Food and Drug Administration; apoptosis in lymphocytes; cytokine; day; hemodynamics; immunogenicity; implantation; improved; knockout animal; milk fat globule; mortality; novel; novel therapeutics; pre-clinical; preclinical study; research study; response; 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）：本SBIR I期/II期快速通道提案旨在为脓毒症和脓毒性休克患者开发一种新疗法。感染性休克是非心脏重症监护病房的主要死亡原因。尽管在创伤患者的管理方面取得了进展，但脓毒症和脓毒性休克的发病率显著增加。每年有超过750，000名患者发生脓毒症和脓毒性休克，仅在美国的总死亡率为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，成功开发一种新型有效的抗菌治疗方法不仅对医疗保健产生积极影响，而且还将产生重大的商业效益。虽然细胞凋亡在脓毒症的病理生物学中起着重要的作用，但凋亡细胞的清除在很大程度上被忽视了。最近的证据表明，调理蛋白乳脂肪球表皮生长因子-因子VIII（MFG-E8）参与凋亡细胞的清除。我们已经发现MFG-E8的下调是脓毒症中凋亡细胞清除减少的原因。早期施用含有大鼠MFG-E8的外泌体或重组鼠MFG-E8（rmMFG-E8）增加凋亡细胞的吞噬作用，减少促炎细胞因子，并改善败血性休克啮齿动物模型中的存活率。然而，阻碍MFG-E8作为脓毒症患者治疗剂的一个障碍是动物蛋白在人体中的潜在免疫原性。为了克服这一点，我们已经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，即使在脓毒症发作后的后期，rhMFG-E8的给药也能改善心血管功能，减轻组织损伤和炎症，并降低死亡率。该SBIR快速通道项目的主要目标是完成rhMFG-E8作为降低感染性休克死亡率的新型治疗药物的临床前开发。在I期阶段，我们将1）扩大rhMFG-E8的生产规模; 2）进一步证实rhMFG-E8在感染性休克啮齿动物模型中的有益作用。这些容易实现的里程碑应该提供有用的可行性信息，使我们能够进行拟议的第二阶段实验。在II期阶段，我们将3）确定rhMFG-E8对啮齿动物败血性休克模型中细胞凋亡、心血管反应、组织损伤、炎症和存活的剂量-反应效应和时间-过程（延迟给药）; 4）评估rhMFG-E8在正常和败血性动物中的毒性和药代动力学特性; 5）确定rhMFG-E8在猪败血性休克模型中的疗效。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提交IND申请，以启动临床试验，从而获得rhMFG-E8作为脓毒症和脓毒性休克患者安全有效的治疗方法的商业利用。