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:
    9202013
  • 负责人:
  • 金额:
    $ 22.25万
  • 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.
项目简介:该项目的主要目标是论证 重组人乳脂球表皮生长因子8的研制 低肾缺血所致急性肾损伤的有效治疗 灌流。Aki是延长住院时间和增加死亡率的主要原因。缺血性AKI常见 与体外循环心脏手术相关的肾血流量减少, 尤其是冠状动脉搭桥术和瓣膜置换术。尽管是频繁的,缩短生命的, 和昂贵的并发症,目前还没有FDA批准的药物临床可用于治疗缺血性AKI。 MFG-E8是一种促进促炎症死亡细胞清除的蛋白质,并减少 破坏组织的中性粒细胞大量涌入受伤部位。在初步研究中,我们使用了重组 小鼠MFG-E8对严重肾缺血再灌注性急性肾损伤的治疗作用。通过以下方式治疗 重组小鼠MFG-E8显著减轻肾功能障碍,降低促炎水平 细胞因子,减少中性粒细胞对肾脏的侵袭。因此,我们假设重组人MFG-E8可以是 作为治疗缺血性AKI的一种新的有效的生物药物。事实上,政府 His标记的重组人MFG-E8可使AKI缺血鼠的10天存活率从47%提高到68%。自.以来 His标记的蛋白质不适合在人类身上使用,我们已经开始生产一种可用药的、类似人类的蛋白质 糖基化hMFG-E8在中国仓鼠卵巢(CHO)细胞中的表达 系统。在本项目中,我们将表达、纯化和鉴定CHO表达的重组人MFG-E8。接下来,我们将 检测CHO表达的重组人巨噬细胞集落刺激因子E8‘S减轻肾损伤和提高存活率的作用 缺血型AKI及其在健康和AKI动物中的药代动力学(PK)谱。我们的未来步骤(SBIR 第二阶段及以后)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,并提交研究新药(IND)申请 与FDA合作启动临床试验。我们的最终目标是将重组人MFG-E8作为一种 安全有效的生物药物治疗缺血性AKI。

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:
    $ 22.25万
  • 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:
    9314562
  • 财政年份:
    2016
  • 资助金额:
    $ 22.25万
  • 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:
    $ 22.25万
  • 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:
    $ 22.25万
  • 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:
    $ 22.25万
  • 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:
    $ 22.25万
  • 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:
    $ 22.25万
  • 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:
    $ 22.25万
  • 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:
    $ 22.25万
  • 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:
    $ 22.25万
  • 项目类别:
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