Discovery of apoE4 modulators for Alzheimer’s disease therapy

发现用于治疗阿尔茨海默病的 apoE4 调节剂

基本信息

批准号：
10502511
负责人：
THOMAS D Y CHUNG
金额：
$ 46.79万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10502511
关键词：
3-Dimensional Abeta synthesis Actins Affect Age-Years Alleles Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Animals Apolipoprotein E Astrocytes Benchmarking Biochemical Biological Biological Assay Blood - brain barrier anatomy Brain CD69 antigen Catalogs Cell model Cells Cerebrum Chemicals Chemistry Cognitive deficits Collaborations Complement Critical Pathways Dementia Detection Disease Down-Regulation Drug Kinetics Evaluation Future Genes Genotype Human Late Onset Alzheimer Disease Lead Life Luciferases Measures Modeling Monitor Morphologic artifacts Neurofibrillary Tangles Neurons Organoids Pathogenicity Pathologic Penetrance Penetration Performance Pharmaceutical Preparations Phenotype Positioning Attribute Property Protein Fragment Proteins Reporter Risk Rodent Model Senile Plaques Signal Transduction Synaptic plasticity Tauopathies Therapeutic Effect Toxic effect Treatment Efficacy abeta accumulation amyloid pathology analog apolipoprotein E-4 base cheminformatics cytotoxic cytotoxicity dementia risk drug candidate drug discovery genetic risk factor high throughput screening improved in vivo induced pluripotent stem cell inhibitor neuronal survival novel novel therapeutic intervention novel therapeutics pre-clinical programs response scaffold scale up small molecule small molecule libraries tau Proteins tau phosphorylation therapeutic target

3-Dimensional Abeta synthesis Actins Affect Age-Years Alleles Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Animals Apolipoprotein E Astrocytes Benchmarking Biochemical Biological Biological Assay Blood - brain barrier anatomy Brain CD69 antigen Catalogs Cell model Cells Cerebrum Chemicals Chemistry Cognitive deficits Collaborations Complement Critical Pathways Dementia Detection Disease Down-Regulation Drug Kinetics Evaluation Future Genes Genotype Human Late Onset Alzheimer Disease Lead Life Luciferases Measures Modeling Monitor Morphologic artifacts Neurofibrillary Tangles Neurons Organoids Pathogenicity Pathologic Penetrance Penetration Performance Pharmaceutical Preparations Phenotype Positioning Attribute Property Protein Fragment Proteins Reporter Risk Rodent Model Senile Plaques Signal Transduction Synaptic plasticity Tauopathies Therapeutic Effect Toxic effect Treatment Efficacy abeta accumulation amyloid pathology analog apolipoprotein E-4 base cheminformatics cytotoxic cytotoxicity dementia risk drug candidate drug discovery genetic risk factor high throughput screening improved in vivo induced pluripotent stem cell inhibitor neuronal survival novel novel therapeutic intervention novel therapeutics pre-clinical programs response scaffold scale up small molecule small molecule libraries tau Proteins tau phosphorylation therapeutic target

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项目摘要

PROJECT SUMMARY Alzheimer's disease (AD) is the most common form of dementia accompanied by detrimental cognitive deficits and pathological accumulation of amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles. The majority of AD cases occur late in life, and it usually develops after 65 years of age. The strongest genetic risk factor for late-onset AD (LOAD) is apolipoprotein E (APOE) genotype, with the ε4 allele increasing AD risk and the ε2 allele being protective compared with the common ε3 allele. Increasing evidence indicates that down- regulation of apoE4 protein level and/or inhibition of apoE4 aggregation not only alleviate amyloid pathology but also protect against tau-mediated neurodegeneration. In our preliminary studies, we have developed an apoE4 reporter assay with a split luciferase protein-fragment complementation, enabling us to not only monitor apoE4 protein level but also measure apoE4 self-oligomerization/aggregation by luciferase bioluminescent signals in a high-throughput screening format. Under the support of the Mayo-SBP (Sanford Burnham Prebys) Drug Discovery Collaboration Program, we performed a pilot screen of ~17,000 small molecule compounds with satisfactory performance, and discovered a novel apoE4 modulator that down-regulates apoE4 protein level and inhibits tau phosphorylation in induced pluripotent stem cells (iPSCs)-derived cerebral organoids from AD patient carrying APOE4, demonstrating that our HTS assay is robust and capable of identifying novel apoE4 modulators. Herein, we proposed a collaborative effort to identify apoE4 modulators that down-regulate apoE4 protein level and/or suppress apoE4 aggregation for AD therapy. Aim 1 will complete the apoE4 reporter high-throughput screen on a large chemical library to identify potent and specific apoE4 modulators for suppressing apoE4 level and/or aggregation. Aim 2 will examine the potency, modes of actin (MOA), and therapeutic effects of apoE4 modulators using biochemical and cell-based assays and human iPSC-derived cellular models. Aim 3 will perform SAR-by-catalog and limited chemistry on lead compounds to improve their potency and efficacy and determine the therapeutic efficacy of the most promising candidate compounds in 3-D cerebral organoid models such that our findings may have relevance in a humanized setting. Moreover, the “drug-like” and pharmacokinetics properties and brain penetration will be characterized and benchmarked to position them for future in vivo preclinical animal studies. The identified apoE4 modulators will be promising drug leads in novel therapeutic strategies for AD.

项目摘要阿尔茨海默氏病（AD）是有害认知实现的最常见痴呆症形式淀粉样蛋白β（Aβ）斑块和含TAU神经原纤维缠结的缺乏和病理积累。大多数AD病例发生在生活后期，通常在65岁以后发展。强烈的遗传风险晚发（负载）的因子是载脂蛋白E（APOE）基因型，ε4等位基因增加了AD风险，并且与常见的ε3等位基因相比，受保护的ε2等位基因。越来越多的证据表明 - 调节APOE4蛋白水平和/或抑制APOE4聚集不仅减轻淀粉样蛋白病理学，而且减轻还可以防止tau介导的神经变性。在我们的初步研究中，我们开发了一个APOE4 记者分析荧光素酶蛋白质碎片完成的测定，使我们不仅可以监视APOE4 蛋白质水平，但还测量了荧光素酶生物发光信号的APOE4自我聚集/聚集高通量筛选格式。在Mayo-SBP（Sanford Burnham Prebys）药物的支持下发现协作计划，我们执行了一个约17,000个小分子化合物的试验屏幕令人满意的性能，并发现了一种新型的APOE4调节剂，该调制器下调了APOE4蛋白水平和抑制来自AD患者的诱导多能干细胞（IPSC）衍生的大脑器官的tau磷酸化携带APOE4，证明我们的HTS分析是强大的，并且能够识别新型的APOE4调节剂。在此，我们提出了一项协作努力，以识别下调APOE4蛋白水平的APOE4调节剂和/或抑制APOE4聚合进行广告疗法。 AIM 1将完成APOE4记者高通量大型化学库上的屏幕以识别抑制APOE4级的潜在和特定的APOE4调节器和/或聚合。 AIM 2将检查APOE4的效力，肌动蛋白模式（MOA）和治疗作用使用生化和基于细胞的测定以及人IPSC衍生的细胞模型的调节剂。目标3意志在铅化合物上进行肉食核糖和有限的化学反应，以提高其效力和效率，并且确定3D大脑器官模型中最有前途的候选化合物的治疗效率使我们的发现可能在人性化的环境中具有相关性。此外，“类似药物”和药代动力学特性和大脑渗透将被表征和基准测试以定位未来的体内临床前动物研究。已确定的APOE4调节剂将在新颖 AD的治疗策略。