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

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。

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.