A Novel Therapy for Septic Shock

描述(由申请人提供)：这项SBIR第一阶段/第二阶段快速通道建议旨在为脓毒症和感染性休克患者开发一种新的治疗方法。感染性休克是非心脏重症监护病房的主要死亡原因。尽管创伤伤员的治疗取得了进步，但败血症和感染性休克的发生率仍显著增加。每年有超过75万名患者发生败血症和感染性休克，仅在美国，总死亡率就达到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，成功开发一种新颖有效的抗感染疗法不仅将对医疗保健产生积极影响，而且还将具有显著的商业效益。尽管细胞凋亡在脓毒症的病理生物学中起着重要的作用，但细胞凋亡的清除在很大程度上被忽视了。最近的证据表明，调理蛋白乳脂球表皮生长因子VIII(MFG-E8)参与了细胞凋亡的清除。我们发现在脓毒症中MFG-E8的下调是导致细胞凋亡性清除减少的原因。早期给予含有MFG-E8的大鼠外切体或重组小鼠MFG-E8(rmMFG-E8)可增加对凋亡细胞的吞噬，减少促炎细胞因子，并提高败血症休克啮齿动物模型的存活率。然而，阻碍MFG-E8成为败血症患者治疗剂的一个障碍是动物蛋白对人类的潜在免疫原性。为了克服这个问题，我们成功地表达了重组人MFG-E8(rhMFG-E8)。我们的数据有力地表明，重组人MFG-E8与动物MFG-E8一样有效。因此，我们假设，即使在脓毒症发病晚些时候，给予重组人MFG-E8也能改善心血管功能，减轻组织损伤和炎症，并降低死亡率。这个SBIR快速通道项目的主要目标是完成rhMFG-E8作为一种降低感染性休克死亡率的新型治疗剂的临床前开发。在第一阶段，我们将1)扩大rhMFG-E8的生产；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。在第二阶段，我们将3)确定rhMFG-E8对感染性休克啮齿动物模型中细胞凋亡、心血管反应、组织损伤、炎症和存活的剂量-反应效应和时程(延迟给药)；4)评估rhMFG-E8在正常和脓毒症动物中的毒性和药代动力学特性；以及5)确定rhMFG-E8在猪感染性休克模型中的疗效。这些拟议的研究应该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，以便将rhMFG-E8作为一种安全有效的治疗败血症和感染性休克患者的药物进行商业应用。

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.