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A microphysiologic multicellular organ-on-chip to inform clinical trials in FTD/ALS

为 FTD/ALS 临床试验提供信息的微生理多细胞器官芯片

基本信息

批准号：
10204148
负责人：
CLIVE Niels SVENDSEN
金额：
$ 80.08万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204148
关键词：
3-Dimensional ALS patients Age Aging Agonist Amyotrophic Lateral Sclerosis Antisense Oligonucleotides Area Astrocytes Autologous Autopsy Behavioral Biological Assay Biological Markers Biological Models Blood - brain barrier anatomy Blood Vessels Brain C9ORF72 Cause of Death Cell Death Cell Line Cells Cessation of life Clinical Clinical Data Clinical Pathology Clinical Trials Clinical Trials Design Clustered Regularly Interspaced Short Palindromic Repeats Degenerative Disorder Dementia Devices Diagnosis Disease Etiology Event Frontotemporal Dementia Gene Mutation Genes Genetic Goals Human Image In Vitro Industry Collaboration Intervention Trial Language Liquid substance Measures Memory Microglia Mitochondria Modeling Monitor Motor Neurons Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Nuclear RNA Organ Pathogenesis Pathologic Pathology Pathway interactions Patients Phenotype Prosencephalon RIPK1 gene Reproducibility Respiratory Failure Seeds Spinal Syndrome System TDP-43 aggregation Technology Temporal Lobe Therapeutic Therapeutic Agents Therapeutic Intervention Tissues Toxic effect Treatment Efficacy Validation Variant base brain endothelial cell cell type clinical development clinical predictors cohort disease phenotype early phase clinical trial efficacy testing frontal lobe frontotemporal lobar dementia-amyotrophic lateral sclerosis human tissue induced pluripotent stem cell inhibitor/antagonist microphysiology system motor neuron degeneration multiple omics novel organ on a chip patient response patient stratification phenotypic biomarker preclinical efficacy predictive marker protein TDP-43 protein aggregation repository response response biomarker safety testing small molecule therapeutic candidate therapeutic evaluation trafficking transcriptome sequencing transcriptomics virtual virtual clinical trial

项目摘要

Project Summary/Abstract Frontotemporal dementia (FTD) is a common dementia syndrome in patients under age 65, while amyotrophic lateral sclerosis (ALS) is a progressive degeneration of motor neurons causing death from respiratory failure within 3-5 years. FTD and ALS represent a spectrum of neurodegeneration, with significant overlap clinically, pathologically, and genetically. Aggregates of TDP-43 are the defining pathology of FTD (FTLD-TDP variant) and ALS, and the most common genetic cause of both FTD and ALS are repeat expansions in the C9orf72 gene. C9orf72 is expressed in multiple cell types in the brain including in microglia and neurons, and there is strong evidence that interaction between different cell types are necessary for pathogenesis of FTD/ALS. We will develop a microphysiologic system (MPS) using human induced pluripotent stem cell (iPSC) derived cortical neurons, astrocytes and microglia on a 3D platform that includes a blood brain barrier (BBB) component to model C9-FTD/ALS forebrain on a chip. Our goal in this project is to develop a highly reproducible and translatable in vitro human cell-based model of FTD/ALS to discover and validate translatable biomarkers for preclinical efficacy testing, and to assist in patient stratification for clinical trial design. We propose to i) develop and validate robustness of a 3D forebrain MPS incorporating cortical neurons and astrocytes, microglia and brain microvascular endothelial cells (BMECs) derived from human iPSCs; ii) utilize FTD and ALS patient derived forebrain MPS's to identify disease biomarkers in C9orf72 related FTD/ALS; iii) cross validate biomarkers identified using clinical data and pathology from C9-FTD/ALS patients used to seed the chips, and iv) assess and stratify responses of C9-FTD/ALS fMPS models to five different therapeutics entering early phase clinical trials ranging from antisense oligonucleotides to small molecule modulators of mitochondrial function, endocytic trafficking and cell death pathways.

项目摘要/摘要额颞性痴呆(FTD)是65岁以下患者常见的痴呆综合征，而肌萎缩侧索硬化症(ALS)是一种运动神经元进行性变性，导致死亡在3-5年内死于呼吸衰竭。FTD和ALS代表了一系列神经退行性变，在临床、病理和遗传上有显著重叠。集合体 TDP-43是FTD(FTLD-TDP变体)和ALS的定义病理，也是最常见的 FTD和ALS的遗传原因均为C9orf72基因重复扩增。C9ORF72是在大脑中的多种细胞类型中表达，包括在小胶质细胞和神经元中，并且有很强的有证据表明，不同细胞类型之间的相互作用在FTD/ALS的发病机制中是必要的。我们将开发一种使用人类诱导的多能干细胞的微生理系统(MPS) (IPSC)在包括血液的3D平台上获得皮质神经元、星形胶质细胞和小胶质细胞脑屏障(BBB)组件，在芯片上模拟C9-FTD/ALS前脑。我们在这个项目中的目标目的是建立一种重复性好、可翻译的FTD/ALS体外人体细胞模型发现和验证用于临床前疗效测试的可翻译生物标志物，并协助临床试验设计中的患者分层。我们建议i)开发和验证以下各项的健壮性结合皮质神经元和星形胶质细胞、小胶质细胞和脑的3D前脑MPS 人IPSCs来源的微血管内皮细胞(BMECs)；II)利用FTD和ALS 患者前脑MPS用于识别C9orf72相关FTD/ALS的疾病生物标记物；III) 交叉验证C9-FTD/ALS患者的临床和病理识别的生物标志物用于播种芯片，以及iv)评估和分层C9-FTD/ALS fMPS模型对从反义到反义的五种不同疗法进入早期临床试验从寡核苷酸到线粒体功能的小分子调节剂，内吞转运和细胞死亡途径。