Evaluation of Alzheimers disease experimental small molecule therapeutics in the models of Amyotrophic lateral sclerosis
阿尔茨海默病实验性小分子疗法在肌萎缩侧索硬化症模型中的评价
基本信息
- 批准号:10259064
- 负责人:
- 金额:$ 45万
- 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:2021-06-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAgeAgonistAlanineAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyotrophic Lateral SclerosisAutopsyAxonBiologicalBiological AvailabilityBody WeightBrainBrain regionBrain-Derived Neurotrophic FactorCell SurvivalCessation of lifeChromosome 9ClinicalCodon NucleotidesCognitionDNA Sequence AlterationDNA-Binding ProteinsDataDendritesDevelopmentDisease modelDoseDrug ExposureElectromyographyEndoplasmic ReticulumEvaluationFeasibility StudiesFemaleG-Protein-Coupled ReceptorsGenesGlycineGrantHandHigh Pressure Liquid ChromatographyHistologyHourHumanLeadLettersLigandsLiteratureMaximum Tolerated DoseModelingMolecular ChaperonesMonitorMotor NeuronsMusMuscular AtrophyNerve DegenerationNeuraxisNeuritesNeurodegenerative DisordersNeuronsNeuroprotective AgentsNeurotransmittersOralParalysedPharmacotherapyPhasePhenotypePlasmaPlayPreparationProcessProgress ReportsProteinsReportingResearch DesignRoleRotarod Performance TestSmall Business Innovation Research GrantSpinalSpinal CordStrategic PlanningSystemThe Jackson LaboratoryTimeTimeLineTissue SampleToxicologyTransactTransgenic MiceWhole BloodWorkamyotrophic lateral sclerosis therapyefficacy evaluationefficacy outcomesefficacy studyexperimental groupexperimental studyfamilial amyotrophic lateral sclerosisfused in sarcomaimprovedinduced pluripotent stem celllead optimizationmalemouse modelmutantneuroprotectionnovelprogramsprotein TDP-43receptorresponsesample collectionscale upsciatic nervesexsigma-1 receptorsmall moleculesmall molecule therapeuticssuperoxide dismutase 1synaptogenesistherapy developmenttool
项目摘要
Abstract
The endoplasmic reticulum (ER) protein sigma-1 receptor represents a unique chaperone activity in the central
nervous system, and it exerts a potent influence on several neurotransmitter systems. S1R is distinct from
GPCRs and ionotropic receptors and is expressed in neurons in multiple brain regions in post-mortem human
brains. S1R plays a modulatory role in biological mechanisms associated with neurodegeneration. S1R ligands
activation is known to improve cognition, promote cell survival, and facilitate the release of the neuroprotectant
BDNF.
The broad objective is to evaluate selective sigma1 receptor (S1R) ligands toward commercial development for
the treatment of Amyotrophic Lateral Sclerosis (ALS). During feasibility studies under grant R41AG043243, we
identified EPGN644, a selective S1R small molecule ligand with CNS exposure with demonstrated efficacy in
mouse models of AD (Tg4510) upon oral dosing. Lead optimization efforts identified EPGN2544 and EPGN2665
as alternatives to EPGN644 with a superior overall profile and with the novel composition of matter claims.
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by progressive
muscle atrophy and paralysis due to the death of upper and lower Motor Neurons. The broad objective is to
evaluate selective sigma1 receptor ligands toward commercial development for the treatment of ALS. A recent
report indicated that PRE-084, a Sigma1R literature tool compound, demonstrated neuroprotection, neurite
elongation, and efficacy in a SOD1G93A mouse model of ALS. Taking together this literature precedence for the
benefit of S1R ligands in an ALS mouse model, and having a well-optimized S1R ligand (EPGN2665) in hand,
we propose to conduct efficacy studies in human induced pluripotent stem cells (iPSC) derived motor neurons,
and in two widely used mouse models of ALS (TDP-43 and SOD1G93A).
摘要
内质网(ER)蛋白σ-1受体代表了中枢神经系统中独特的伴侣活性。
神经系统,并对几种神经递质系统产生强有力的影响。S1 R不同于
GPCRs和离子型受体在死后人多个脑区神经元中的表达
大脑S1 R在与神经退行性变相关的生物学机制中起调节作用。S1 R配体
已知激活可改善认知、促进细胞存活并促进神经保护剂的释放
BDNF
广泛的目标是评估选择性σ 1受体(S1 R)配体的商业开发,
肌萎缩侧索硬化症(ALS)的治疗。在R41 AG 043243资助的可行性研究期间,我们
鉴定了EPGN 644,一种选择性S1 R小分子配体,暴露于CNS,
AD小鼠模型(Tg 4510)。领导优化工作确定了EPGN 2544和EPGN 2665
作为EPGN 644的替代物,具有上级的总体特征和所要求的新颖的物质组合物。
肌萎缩侧索硬化症(ALS)是一种以进行性脊髓损伤为特征的成人发病的神经退行性疾病。
由于上下运动神经元死亡而导致的肌肉萎缩和瘫痪。总体目标是
评估选择性σ 1受体配体用于ALS治疗的商业开发。最近的一
一份报告指出,PRE-084(一种Sigma 1 R文献工具化合物)表现出神经保护作用,
延伸和在ALS的SOD 1G 93 A小鼠模型中的功效。把这些文献的优先顺序放在一起,
S1 R配体在ALS小鼠模型中的益处,并且拥有充分优化的S1 R配体(EPGN 2665),
我们建议在人诱导多能干细胞(iPSC)衍生的运动神经元中进行功效研究,
以及在两种广泛使用的ALS小鼠模型(TDP-43和SOD 1G 93 A)中。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Satheesh B Ravula其他文献
Satheesh B Ravula的其他文献
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Druggable regulators of nitric oxide production as new Alzheimer's disease therap
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- 资助金额:
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