tPA and NGF therapy for stroke
tPA 和 NGF 治疗中风
基本信息
- 批准号:10251710
- 负责人:
- 金额:$ 35.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-20 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdultAdverse effectsAlteplaseAlzheimer&aposs disease modelAnimal ModelAnimalsApoptosisAttenuatedBindingBiodistributionBlindedBlood - brain barrier anatomyBrainBypassCell DensityCell LineCellsChemicalsCleaved cellClinicalClinical TrialsClone CellsComplicationCorpus striatum structureDataDisabled PersonsEdemaEnzymesEscherichia coliExhibitsEyedropsFDA approvedFemaleGlaucomaGoalsGrowthGuidelinesHourHumanInfarctionInjuryIntracranial HemorrhagesIntranasal AdministrationInvestigational New Drug ApplicationIschemic StrokeLifeMediatingMemory impairmentModelingModificationMusNerve DegenerationNerve Growth FactorsNervous System PhysiologyNeuraxisNeurodegenerative DisordersNeurologic DeficitNeurological outcomeNeuronsNeurotrophic Tyrosine Kinase Receptor Type 1OutcomePatientsPeptide Signal SequencesPeripheralPharmaceutical PreparationsPhasePrincipal InvestigatorProcessProductionProteinsRandomizedRattusReceptor SignalingRecommendationRecoveryRetinal Ganglion CellsRiskSafetySerumSignal TransductionStrokeSuspensionsSymptomsSynaptic plasticitySystemTechnologyTherapeuticTimeToxic effectTraumatic Brain InjuryTrypsinValidationVariantWorkagedanalogangiogenesisaquaporin 4basal forebrainbrain tissueclinically relevantcomorbiditycost effectivedisabilityexpression vectorimprovedinnovationischemic injurymalemutantneurogenesisneuron apoptosisneurovascularpost strokepost stroke depressionpre-clinicalpreclinical studypreservationpreventprogramspromoterstroke modelstroke outcomestroke patientstroke recoverystroke therapythromboembolic stroke
项目摘要
Principal Investigator/Program Director (Last, First, Middle: Soon Seog Jeong
Abstract
Due to its narrow time-window of administration (up to 4.5 hours post symptoms) and 6-7 fold increased risk
of intracranial hemorrhage, merely 3-5% of acute ischemic stroke patients receive recombinant tissue
plasminogen activator (tPA), the only FDA-approved drug for this indication. NGF prevents neuronal apoptosis
in primary cultured neurons and reduces neuronal degeneration in animal models of neurodegenerative
diseases. In the central nervous system, NGF is produced throughout adult life and primarily targets basal
forebrain and striatal neurons. It has been shown that intranasal (IN) NGF bypassed the blood-brain barrier and
distributed in the whole brain without peripheral adverse effects. IN administration of wildtype NGF significantly
reduced infarct volume and improved neurological outcomes by protecting neurons from ischemic injury,
promoting angiogenesis, and enhancing striatal neurogenesis with at least a 24h treatment window after stroke
onset.
We have optimized a human NGF variant and developed a cost-effective protein production system for
making the variant. This proprietary variant selectively activates the NGF TrkA receptor with enhanced activity
to promote neuron survival and function. In a randomized and blinded study in rats, IN treatment with the variant
for 3 weeks 6h after thrombo-embolic stroke (outside the therapeutic treatment time window for rt-PA) robustly
improved short- and long-term neurological deficit score as assessed 28 days after stroke. In this study, we will
follow the STAIR recommendations and RIGOR guidelines to conduct a Phase I preclinical study to validate the
the combination treatment with tPA in a rat model of stroke using both male and female animals. The long-term
goal is to develop the dug candidate as acute or sub-acute therapy, alone or in combination with tPA, to safely
reduce disability for millions of stroke patients.
Specific Aim. Determine whether combining tPA with the proprietary NGF variant more effectively improves
long-term outcomes compared to vehicle and tPA in a rat model of thrombo-embolic stroke when administered
at 6h after occlusion.
主要研究者/项目负责人(最后,第一,中间:Soon Seog Jeong
摘要
由于其给药时间窗较窄(症状后最多4.5小时),风险增加6-7倍
在颅内出血中,只有3-5%的急性缺血性卒中患者接受重组组织
纤溶酶原激活剂(tPA)是FDA批准的唯一用于该适应症的药物。神经生长因子预防神经元凋亡
在原代培养的神经元中,
疾病在中枢神经系统中,NGF在整个成人生活中产生,并且主要针对基底神经系统。
前脑和纹状体神经元。已经表明,鼻内(IN)NGF绕过血脑屏障,
分布于全脑,无外周副作用。IN施用野生型NGF显著地
通过保护神经元免受缺血性损伤减少梗死体积和改善神经学结果,
促进血管生成,并在卒中后至少24小时的治疗窗内增强纹状体神经发生
发病
我们已经优化了人NGF变体,并开发了一种具有成本效益的蛋白质生产系统,
制作变体。这种专利变体选择性激活NGF TrkA受体,活性增强
来促进神经元的存活和功能在一项大鼠随机盲法研究中,
血栓栓塞性卒中后6小时(rt-PA治疗时间窗外)持续3周,
卒中后28天评估的短期和长期神经功能缺损评分改善。在这项研究中,我们将
遵循STAIR建议和RIGOR指南进行I期临床前研究,以验证
在使用雄性和雌性动物的中风大鼠模型中使用tPA的组合治疗。长期
我们的目标是开发dug候选药物作为急性或亚急性治疗,单独或与tPA联合,
减少数百万中风患者的残疾。
具体目标。确定将tPA与专有的NGF变体组合是否更有效地改善
在血栓栓塞性卒中大鼠模型中,与溶媒和tPA相比,
缺血6 h。
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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Soon Seog Jeong其他文献
Soon Seog Jeong的其他文献
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{{ truncateString('Soon Seog Jeong', 18)}}的其他基金
Optimization of TIL Cell Manufacturing for Cancer Treatment
用于癌症治疗的 TIL 细胞制造优化
- 批准号:
10696746 - 财政年份:2023
- 资助金额:
$ 35.95万 - 项目类别:
Optimizing NGF for Topical Treatment of Glaucoma
优化 NGF 局部治疗青光眼
- 批准号:
10757536 - 财政年份:2017
- 资助金额:
$ 35.95万 - 项目类别:
Optimizing NGF for Topical Treatment of Glaucoma
优化 NGF 局部治疗青光眼
- 批准号:
9341566 - 财政年份:2017
- 资助金额:
$ 35.95万 - 项目类别:
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