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
基本信息
- 批准号:9204427
- 负责人:
- 金额:$ 11.25万
- 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:2016-01-08 至 2018-07-31
- 项目状态:已结题
- 来源:
- 关键词:ADME StudyAdjuvantAdjuvant TherapyAdultAge-YearsAmericanAnimal ModelAnimalsApoptosisApoptoticBindingBiologicalBiological AssayBloodBlood flowBrainCardiac OutputCause of DeathCellsCessation of lifeChromatographyCircular DichroismClinical TrialsCreatinineDiscipline of obstetricsDoseDrug KineticsElectroconvulsive TherapyEndotoxinsEpidermal Growth FactorEscherichia coliExcretory functionFutureGoalsHalf-LifeHeartHemorrhageHemorrhagic ShockHepaticHigh Pressure Liquid ChromatographyHistologicHospitalsHourHumanHuman MilkIndividualInflammatoryInjectableInjection of therapeutic agentInjuryInterleukin-1Interleukin-1 betaInterleukin-6IntravenousKidneyLabelLactated Ringer&aposs SolutionLarge IntestineLethal Dose 50Liquid substanceLiverLungLysineMass Spectrum AnalysisMaximum Tolerated DoseMedicalMonitorMuscleNeutrophil InfiltrationOrganPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPharmacotherapyPhaseProductionProteinsRattusRecombinantsResuscitationSafetySalineSerumSkinSmall Business Innovation Research GrantSmall IntestinesSpleenStomachStroke VolumeSurgical complicationSurvival RateTNF geneTdT-Mediated dUTP Nick End Labeling AssayTestingTherapeuticTimeTissuesToxic effectTraumaTraumatic injuryUnited StatesUrineWestern Blottingattenuationbasecytokinedrug developmentefficacy studygastrointestinalhemodynamicsimprovedmilk fat globulemortalitynovelnovel therapeuticspreclinical studypressurepublic health relevancestandard of caresuccessurinaryvasoactive agentvector
项目摘要
DESCRIPTION (provided by applicant): The primary objective of this project is to further demonstrate the feasibility of developing recombinant human milk fat globule epidermal growth factor-factor 8 (rhMFG-E8) as a novel and effective adjuvant therapy for the resuscitation of patients with hemorrhagic shock. Hemorrhagic shock is a major cause of mortality worldwide. In the United States, traumatic injury is the main cause of death in individuals younger than 44 years of age, and hemorrhagic shock accounts for one third of trauma-related deaths. Even when treated with the standard of care and in a hospital setting, 10% of patients with hemorrhagic shock die within hours. Therefore, there is an unmet and critical need for a novel and effective adjuvant therapy capable of improving the success rate of the existing volume and vasoactive agents for hemorrhage resuscitation. MFG-E8 is a protein that promotes the clearance of apoptotic/dying cells and inhibits the production of pro-inflammatory cytokines. In preliminary studies, we treated hemorrhaged animals with rhMFG-E8 and observed significant decreases in circulating pro-inflammatory cytokines, neutrophil infiltration to the lungs, and apoptosis. Treatment with rhMFG-E8 also nearly doubled the survival rate from 43% to 83%. Therefore, we hypothesize that rhMFG-E8 can be further developed as a new and effective adjuvant therapy for hemorrhagic shock. To advance the drug development, we will produce a new non His-tagged rhMFG-E8 and analyze its biological activity, homogeneity, and folding status. We will then determine the dose-dependent effects of rhMFG-E8 on reducing organ injury, hemodynamic instability, pro-inflammatory cytokines, and histological damage caused by hemorrhagic shock. Its therapeutic window to improve survival after hemorrhagic shock will be investigated. Finally, we will determine its safety pharmacology and pharmacokinetic profile in healthy and hemorrhaged animals. Our future steps (SBIR Phase II and beyond) will include completing preclinical studies, such as ADME studies and efficacy studies in a non-rodent species, as well as comparing with the standard of care. We will then file an investigative 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 adjuvant drug for the resuscitation of patients with hemorrhagic shock.
描述(申请人提供):本项目的主要目标是进一步证明开发重组人乳脂球表皮生长因子8(rhMFG-E8)作为失血性休克患者复苏的一种新的有效辅助疗法的可行性。失血性休克是世界范围内死亡的主要原因。在美国,创伤性损伤是44岁以下人群的主要死亡原因,失血性休克占创伤相关死亡的三分之一。即使在标准的护理和医院环境下进行治疗,10%的失血性休克患者也会在数小时内死亡。因此,迫切需要一种新的、有效的辅助治疗方法,以提高现有的容量和血管活性药物用于出血复苏的成功率。MFG-E8是一种促进凋亡/死亡细胞清除并抑制促炎细胞因子产生的蛋白质。在初步研究中,我们用rhMFG-E8治疗出血动物,观察到循环中的促炎细胞因子、中性粒细胞对肺的渗透和细胞凋亡显著减少。用rhMFG-E8治疗的存活率也几乎翻了一番,从43%增加到83%。因此,我们推测,rhMFG-E8可以进一步发展成为一种新的、有效的失血性休克辅助治疗方法。为了推进药物的开发,我们将生产一种新的非组氨酸标记的重组人MFG-E8,并对其生物学活性、均一性和折叠状态进行分析。然后,我们将确定rhMFG-E8在减少失血性休克引起的器官损伤、血流动力学不稳定、促炎细胞因子和组织学损害方面的剂量依赖效应。其提高失血性休克后存活率的治疗窗口将被调查。最后,我们将确定其在健康和出血动物身上的安全药理和药代动力学。我们未来的步骤(SBIR第二阶段及以后)将包括完成临床前研究,如ADME研究和对非啮齿动物物种的疗效研究,以及与护理标准进行比较。然后,我们将向FDA提交调查性新药(IND)申请,以启动临床试验。我们的最终目标是将rhMFG-E8作为一种安全有效的辅助药物用于失血性休克患者的复苏。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Weng-Lang Yang其他文献
Weng-Lang Yang的其他文献
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A Novel Recombinant Protein as an Effective Therapy for Acute Kidney Injury
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9314562 - 财政年份:2016
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A Novel Recombinant Protein as an Effective Therapy for Acute Kidney Injury
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9346602 - 财政年份:2014
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A Novel Recombinant Protein for Mitigating Total Body Radiation Injury
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8781840 - 财政年份:2014
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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
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$ 11.25万 - 项目类别:
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- 批准号:
8865549 - 财政年份:2014
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Preclinical Testing of Human Ghrelin and Growth Hormone for Sepsis in the Elderly
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9199963 - 财政年份:2014
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