A Novel Recombinant Protein as an Effective Therapy for Acute Kidney Injury

一种新型重组蛋白可有效治疗急性肾损伤

基本信息

  • 批准号:
    9314562
  • 负责人:
  • 金额:
    $ 11.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-07-15 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT DESCRIPTION: The primary objective of this project is to demonstrate the feasibility of developing recombinant human milk fat globule epidermal growth factor-factor 8 (rhMFG-E8) as a novel and effective therapeutic for patients with acute kidney injury (AKI) associated with ischemia due to low renal perfusion. AKI is a major cause of prolonged hospitalization and increased mortality. Ischemic AKI often results from decreased renal blood flow associated with cardiac surgery involving cardiopulmonary bypass, especially coronary artery bypass graft and valve replacement. Despite being a frequent, life-shortening, and costly complication, no FDA-approved drugs are currently clinically available to treat ischemic AKI. MFG-E8 is a protein that promotes the clearance of inflammation-promoting dying cells and decreases the influx of tissue-damaging neutrophils to the injured site. In the preliminary study, we used recombinant mouse MFG-E8 to treat mice with AKI induced by severe renal ischemia-reperfusion. Treatment with recombinant mouse MFG-E8 significantly attenuated renal dysfunction, decreased levels of proinflammatory cytokines, and reduced kidney infiltration by neutrophils. Therefore, we hypothesize that rhMFG-E8 can be developed as a new and effective biologic drug to treat patients with ischemic AKI. Indeed, administration of His-tagged rhMFG-E8 increased the 10-day survival of mice with ischemic AKI from 47% to 68%. Since His-tagged proteins are not suited for use in humans, we have started to produce a druggable, human-like glycosylated, His tag-free rhMFG-E8 using a mammalian Chinese hamster ovary (CHO) cell expression system. In this project we will express, purify, and characterize CHO-expressed rhMFG-E8. We will next determine CHO-expressed rhMFG-E8's efficacy to attenuate renal injury and improve survival after ischemic AKI, and its pharmacokinetic (PK) profile in healthy and AKI animals. Our future steps (SBIR Phase II and beyond) include completing preclinical and safety studies, establishing ADME and safety studies, determining efficacy in a second species, and filing an investigational new drug (IND) application with the FDA to initiate clinical trials. Our ultimate goal is to obtain commercial utilization of rhMFG-E8 as a safe and effective biologic drug to treat patients with ischemic AKI.
项目描述:本项目的主要目标是证明 开发重组人乳脂球表皮生长因子-因子8(rhMFG-E8)作为新的, 急性肾损伤(阿基)患者的有效治疗方法, 灌注。阿基是延长住院时间和增加死亡率的主要原因。缺血性阿基通常 这是由于与包括心肺分流术的心脏手术相关的肾血流量减少, 特别是冠状动脉旁路移植术和瓣膜置换术。尽管是一个频繁的,缩短寿命, 和昂贵的并发症,目前临床上没有FDA批准的药物可用于治疗缺血性阿基。 MFG-E8是一种蛋白质,其促进促炎性死亡细胞的清除并降低促炎性死亡细胞的凋亡。 组织损伤性中性粒细胞流入损伤部位。在初步研究中,我们使用重组 小鼠MFG-E8来治疗患有由严重肾缺血-再灌注诱导的阿基的小鼠。治疗 重组小鼠MFG-E8显著减轻肾功能不全,降低促炎水平, 细胞因子,并减少中性粒细胞的肾脏浸润。因此,我们假设rhMFG-E8可以被 作为一种新的有效的生物药物开发,用于治疗缺血性阿基患者。事实上,行政 His-标记的rhMFG-E8使缺血性阿基小鼠的10天存活率从47%增加到68%。以来 组氨酸标记的蛋白质不适合用于人类,我们已经开始生产一种可药用的,类似人类的蛋白质。 使用哺乳动物中国仓鼠卵巢(CHO)细胞表达的糖基化、无His标签的rhMFG-E8 系统在这个项目中,我们将表达,纯化和表征CHO表达的rhMFG-E8。我们接下来将 确定CHO表达的rhMFG-E8减轻肾损伤和改善术后存活率的功效。 缺血性阿基及其在健康和阿基动物中的药代动力学(PK)特征。我们的未来步骤(SBIR II期及以后)包括完成临床前和安全性研究,建立ADME和安全性 研究,确定在第二个物种中的疗效,并提交研究性新药(IND)申请 与食品药品监督管理局合作启动临床试验我们的最终目标是获得rhMFG-E8的商业利用, 治疗缺血性阿基患者的安全有效的生物药物。

项目成果

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Weng-Lang Yang其他文献

Weng-Lang Yang的其他文献

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{{ truncateString('Weng-Lang Yang', 18)}}的其他基金

rhMFG-E8 as an Effective Adjuvant Therapy for Hemorrhagic Shock
rhMFG-E8 作为失血性休克的有效辅助疗法
  • 批准号:
    9204427
  • 财政年份:
    2016
  • 资助金额:
    $ 11.28万
  • 项目类别:
A Novel Recombinant Protein as an Effective Therapy for Acute Kidney Injury
一种新型重组蛋白可有效治疗急性肾损伤
  • 批准号:
    9202013
  • 财政年份:
    2016
  • 资助金额:
    $ 11.28万
  • 项目类别:
Preclinical Testing of Human Ghrelin and Growth Hormone for Sepsis in the Elderly
人类生长素释放肽和生长激素治疗老年人脓毒症的临床前测试
  • 批准号:
    9346602
  • 财政年份:
    2014
  • 资助金额:
    $ 11.28万
  • 项目类别:
A Novel Recombinant Protein for Mitigating Total Body Radiation Injury
一种用于减轻全身辐射损伤的新型重组蛋白
  • 批准号:
    8781840
  • 财政年份:
    2014
  • 资助金额:
    $ 11.28万
  • 项目类别:
PRECLINICAL TESTING OF HUMAN GHRELIN AND GROWTH HORMONE FOR SEPSIS IN THE ELDLY
人类生长素释放肽和生长激素治疗老年脓毒症的临床前测试
  • 批准号:
    8714409
  • 财政年份:
    2014
  • 资助金额:
    $ 11.28万
  • 项目类别:
A Novel Recombinant Protein for Mitigating Total Body Radiation Injury
一种用于减轻全身辐射损伤的新型重组蛋白
  • 批准号:
    8865549
  • 财政年份:
    2014
  • 资助金额:
    $ 11.28万
  • 项目类别:
Preclinical Testing of Human Ghrelin and Growth Hormone for Sepsis in the Elderly
人类生长素释放肽和生长激素治疗老年人脓毒症的临床前测试
  • 批准号:
    9199963
  • 财政年份:
    2014
  • 资助金额:
    $ 11.28万
  • 项目类别:
Human Ghrelin As An Effective Mitigator of Acute Radiation Injury
人类生长素释放肽作为急性辐射损伤的有效缓解剂
  • 批准号:
    8198739
  • 财政年份:
    2011
  • 资助金额:
    $ 11.28万
  • 项目类别:
Human Ghrelin As An Effective Mitigator of Acute Radiation Injury
人类生长素释放肽作为急性辐射损伤的有效缓解剂
  • 批准号:
    8303441
  • 财政年份:
    2011
  • 资助金额:
    $ 11.28万
  • 项目类别:
Human Ghrelin as an Effective Mitigator of Acute Radiation Injury
人类生长素释放肽作为急性辐射损伤的有效缓解剂
  • 批准号:
    9141294
  • 财政年份:
    2011
  • 资助金额:
    $ 11.28万
  • 项目类别:
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