Enhanced bioscavenger for medical countermeasures against organophosphorus agents
用于针对有机磷制剂的医疗对策的增强型生物清除剂
基本信息
- 批准号:8524618
- 负责人:
- 金额:$ 28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-11 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcetylcholinesteraseAnimal ModelBindingBiocompatibleBiological AssayBiological AvailabilityBiological PreservationButyrylcholinesteraseCessation of lifeCholinesterasesClinicalDataDevelopmentDosage FormsDoseDrug Delivery SystemsDrug FormulationsDrug KineticsEncapsulatedEnzymesEquilibriumGelGovernmentHumanHuman ResourcesHyaluronic AcidHyaluronidaseImmobilizationIn VitroInjectableInjection of therapeutic agentIntoxicationInvestigational New Drug ApplicationKineticsLifeMasksMedicalMissionMusNeuronsParticle SizePersonsPesticidesPharmacologic SubstancePharmacology and ToxicologyPhasePhysiologicalPlasmaPolysaccharidesPreparationPropertyProphylactic treatmentProteinsPublic HealthReadinessRecombinantsRelative (related person)RiskSecurityStagingStimulusSubstrate SpecificitySynapsesTechnologyTestingTherapeuticTimeTransgenic AnimalsTransgenic Plantsbasebioscavengerblood productcrosslinkeffective therapyenzyme activityglycosylationimmunogenicimprovedin vivoinnovationinterestnerve agentnew technologynoveloperationpractical applicationpre-clinicalpreventprogramspublic health relevancesuccesstool
项目摘要
DESCRIPTION (provided by applicant): Counteracting the threat of intoxication by organophosphorus nerve agents (OP's) is an important mission for homeland security as well as for treating workers exposed to pesticides. OP's act on acetylcholinesterase to prevent synaptic inactivation, thereby leading to immobilization and death on sustained application. Currently, the most promising strategy to counter OP intoxication is to scavenge the agents using recombinant butyrylcholinesterase (rBChE), the major cholinesterase in human which has low substrate specificity and thus offers broad spectrum protection by binding OP's prior to their damaging neurons. Natural BChE levels are too low to afford protection however, and exogenous enzymes are required. PEGylated rBChE offers improved bioavailability and protection relative to recombinant enzymes, however the lifetime is still insufficiently long for effective prophylaxis
and the bioavailability is still low, requiring larger doses for an effective therapy. Luna propose an alternative strategy to enhance and extend the efficacy of recombinant BChE in vivo based on a novel, proven protein formulation technology. Recombinant BChE is encapsulated in polysaccharide microgel preparations to provide sustained release of enzymes with much enhanced bioavailability and pharmacokinetics. Success of the program will provide a valuable medical countermeasure tool for enhanced OP prophylaxis or sustained treatment of OP intoxication. The final product could be an important addition to the Strategic National Stockpile.
This proposed technology enhances the nation's preparedness against OP warfare agents and thus is of great interest to the public health.
描述(由申请人提供):对抗有机磷神经毒剂(OP's)中毒的威胁是国土安全以及治疗接触农药的工人的重要使命。OP作用于乙酰胆碱酯酶以防止突触失活,从而在持续应用时导致固定和死亡。目前,对抗OP中毒最有希望的策略是使用重组丁酰胆碱酯酶(rBChE)来抑制药物,rBChE是人体中主要的胆碱酯酶,其具有低底物特异性,因此通过在其损伤神经元之前结合OP而提供广谱保护。然而,天然BChE水平太低而不能提供保护,并且需要外源酶。相对于重组酶,PEG化的rBChE提供了改善的生物利用度和保护,但是对于有效的预防,其寿命仍然不够长
并且生物利用度仍然很低,需要更大的剂量才能有效治疗。Luna提出了一种替代策略,以增强和延长重组BChE在体内的功效,该策略基于一种新的、经过验证的蛋白质制剂技术。重组BChE被封装在多糖微凝胶制剂中,以提供酶的持续释放,从而大大提高生物利用度和药代动力学。该计划的成功将为加强OP预防或持续治疗OP中毒提供有价值的医疗对策工具。最终产品可能是国家战略储备的重要补充。
这项拟议中的技术提高了国家对OP战剂的准备,因此对公众健康具有重大意义。
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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Zhiguo Zhou其他文献
Zhiguo Zhou的其他文献
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