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

项目总结/摘要 额颞叶痴呆（FTD）是65岁以下患者常见的痴呆综合征， 肌萎缩侧索硬化症（ALS）是一种导致死亡的运动神经元进行性变性 3-5年内呼吸衰竭。FTD和ALS代表了 神经变性，在临床上、病理学上和遗传学上具有显著重叠。聚集体 是FTD（FTLD-TDP变异体）和ALS的定义性病理学， FTD和ALS的遗传原因均为C9 orf 72基因的重复扩增。C9 orf 72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， 证据表明不同细胞类型之间的相互作用是FTD/ALS发病机制所必需的。 我们将利用人类诱导性多能干细胞建立一个微生理系统 在包括血液的3D平台上的iPSC（iPSC）衍生的皮质神经元、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。我们这个项目的目标 是开发一种高度可重现和可转化的FTD/ALS体外人细胞模型 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 用于临床试验设计的患者分层。我们建议i）开发和验证 3D前脑MPS，包括皮质神经元和星形胶质细胞、小胶质细胞和脑 源自人iPSC的微血管内皮细胞（BMEC）; ii）利用FTD和ALS 患者来源的前脑MPS，以鉴定C9 orf 72相关FTD/ALS中的疾病生物标志物; iii） 交叉验证使用C9-FTD/ALS患者的临床数据和病理学确定的生物标志物 用于接种芯片，和iv）评估和分层C9-FTD/ALS fMPS模型对 五种不同的治疗方法进入早期临床试验，从反义 寡核苷酸与线粒体功能、内吞运输和 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.