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Patient iPSC derived neural synaptic screen for drug discovery

用于药物发现的患者 iPSC 衍生神经突触筛选

基本信息

批准号：
9141432
负责人：
Wei Zhang
金额：
$ 22.48万
依托单位：
JUVOBIO PHARMACEUTICALS, INC.
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：
2016-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9141432
关键词：
Address Affect Alzheimer&apos s Disease Animals Architecture Autistic Disorder Behavioral Biological Assay Cell Line Cell model Clinical Cognitive deficits Complex DISC1 gene Defect Development Disease Disease model Etiology Frameshift Mutation Funding Genetic Genetic Risk Glutamates Human Impaired cognition Industry Interneurons Licensing Marketing Medical Mental Depression Mental disorders Modeling Mus Mutant Strains Mice Mutation Neurons Parkinson Disease Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Population Property Prosencephalon Protocols documentation Public Health Reporting Rett Syndrome Rolipram Schizophrenia Stem cells Susceptibility Gene Symptoms Synapses Therapeutic Therapeutic Effect Translating Work base density disease phenotype drug discovery genetic risk factor induced pluripotent stem cell innovation microdeletion mouse model nerve stem cell novel partial response public health relevance relating to nervous system response social tool treatment effect

项目摘要

DESCRIPTION (provided by applicant): We propose to 1). Use a set of human schizophrenia (SCZ) disease models utilizing induced pluripotent stem cells (iPSCs) derived from SCZ patients to evaluate six advanced SCZ compounds from a pharma partner, to assess their potential to be further developed into SCZ therapeutics; and 2). Discover new compound leads for SCZ. We will use one of the models - a validated synaptic density screen in 384-well format, using forebrain glutamatergic neurons (FGNs) derived from iPSCs bearing a Disrupted in schizophrenia 1 (DISC1) frameshift mutation. We will characterize the hits in the additional SCZ iPSC models. SCZ affects around 1% of the world's population and is a major public health problem. About 30% of SCZ patients do not response to available medications. 30% only show partial response. The industry's hunt for better therapeutics have been thwarted by inadequacy of current drug discovery models. Patient-specific iPSC-derived neurons hold great promises as effective disease models for mechanism studies and drug discovery. Our team has generated and characterized SCZ iPSC lines from patients with different genetic risk factors and background. These cell lines, isogenic and normal controls will be utilized for this proposal. We have optimized differentiation protocols that produce highly pure populations of cortical neural progenitors (NPCs), GABAergic interneurons and FGNs (>99%, >80% and >90% respectively). The purity of differentiated populations allows us to confidently attribute assay readouts to intrinsic properties of the cellular models and experimental manipulations. The high-throughput synaptic screen is validated: 1). Correcting DISC1 mutation in patient iPSCs corrected the synaptic and other functional defects; 2). Introducing DISC1 mutation into normal iPSCs or mice recreated cellular deficits and created animal behavioral and cognitive deficits; 3). A mechanism relevant compound rescues deficits in both DISC1 FGNs and DISC1 mutant mice; 4). Nine other compounds mechanistically related to this compound was shown to rescue synaptic deficit in a separate targeted screen. Aim 1. Evaluate six advanced discovery/development SCZ compounds from a pharma partner for potential continued development for SCZ. We will differentiate 14 SCZ and control iPSC lines into NPCs and then onto FGNs and GABAergic neurons. Treat the neurons for 2-4 weeks with the six compounds at four concentrations. Assess treatment effects with synaptic screen and other morphological and functional assays. Aim 2. Conduct primary screen of 50,000 compounds with synaptic screen and confirmation screens with additional SCZ iPSC models. We will use synaptic density assay with one DISC1 line for primary screen. We will use its isogenic control and another DISC1 line (with different clinical presentation) for counter and confirmation screens, and further characterize with other SCZ lines to generate leads.

描述（由申请人提供）：我们建议1）。使用一组人类精神分裂症（SCZ）疾病模型，利用源自SCZ患者的诱导多能干细胞（iPSC）来评估来自制药合作伙伴的六种先进SCZ化合物，以评估它们进一步开发成SCZ治疗剂的潜力;以及2）。发现SCZ的新化合物引线。我们将使用其中一种模型-一种384孔格式的经验证的突触密度筛选，使用来自具有精神分裂症1（DISC 1）移码突变中断的iPSC的前脑神经元（FGN）。我们将在其他SCZ iPSC模型中描述命中率。 SCZ影响世界人口的1%左右，是一个主要的公共卫生问题。大约30%的SCZ患者对可用的药物没有反应。30%的患者仅部分缓解。该行业寻找更好的治疗方法的努力因当前药物发现模式的不足而受阻。患者特异性iPSC衍生的神经元作为机制研究和药物发现的有效疾病模型具有很大的前景。我们的团队已经从具有不同遗传风险因素和背景的患者中产生并表征了SCZ iPSC系。这些细胞系、同基因和正常对照将用于本提案。我们已经优化了分化方案，其产生高纯度的皮质神经祖细胞（NPC）、GABA能中间神经元和FGN群体（分别> 99%、>80%和>90%）。分化群体的纯度使我们能够自信地将测定读数归因于细胞模型和实验操作的内在特性。验证了高通量突触筛选：1）。纠正患者iPSC中的DISC 1突变纠正了突触和其他功能缺陷; 2）。将DISC 1突变引入正常iPSC或小鼠中，重新产生细胞缺陷，并产生动物行为和认知缺陷; 3）。机制相关化合物拯救DISC 1 FGN和DISC 1突变小鼠中的缺陷; 4）。在单独的靶向筛选中，与该化合物机械相关的其他九种化合物显示出挽救突触缺陷。目标1。评估来自制药合作伙伴的六种先进的发现/开发SCZ化合物，以确定SCZ的潜在持续开发。我们将14个SCZ和对照iPSC系分化为NPC，然后分化为FGN和GABA能神经元。用四种浓度的六种化合物处理神经元2-4周。通过突触筛选和其他形态学和功能测定评估治疗效果。目标2.使用突触筛选和确认筛选对50，000种化合物进行初步筛选，并使用额外的SCZ iPSC模型进行确认筛选。我们将用一个DISC 1细胞系进行突触密度测定进行初步筛选。我们将使用其同基因对照和另一种DISC 1细胞系（具有不同的临床表现）进行计数和确认筛选，并进一步用其他SCZ细胞系进行表征以产生线索。