Novel patient-derived 3D platform for detecting TDP-43 proteinopathy and associated biomarkers for ALS/FTD

摘要 肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD）是两种最昂贵和最昂贵的疾病。 毁灭性的神经退行性疾病据估计，16，000名美国人受到ALS的影响，而高达1000人。 30，000人患有FTD，尽管这些数字可能被低估了。近几十年的研究表明， FTD与ALS具有显著的临床、病理和遗传重叠，现在认为两者 在同一疾病谱上。高达50%的ALS患者经历认知障碍，高达15%的患者经历认知障碍。 出现FTD症状。ALS/FTD及其引起的发病率和损伤伴随着显著的 医疗、社会和经济负担。ALS患者每年的总成本估计为70，000美元 患者和每年120，000美元的FTD患者。目前，有效的诊断和治疗这些 疾病缺乏，新的疗法对人类的转化很差，尽管在治疗方面显示出巨大的希望。 现有的体外和动物模型。新疗法开发和测试的一个主要挑战是 缺乏准确反映潜在病理生理学的模型。像所有神经退行性疾病一样， ALS和FTD的动物模型受到大多数动物寿命短的阻碍，这可能不允许 适当的疾病进展。人类和动物的基因组、发育和生理差异 大脑是另外的复杂因素。需要这些疾病的精确模型来推进 开发新的生物标志物、诊断和治疗。为了满足这一需求，SynaptiCure 开发一种新的患者衍生3D平台，用于TDP-43的高保真建模和筛选 ALS和FTD的蛋白质病和相关生物标志物。SynaptiCure的创新mAssemloids 该平台将提供一种新的，系统的方法来创建3D成熟的大脑类器官， 与ALS和FTD相关的疾病状态，包括在任何其他现有的 模型在之前的工作中，SynaptiCure能够从分化的人类星形胶质细胞中形成mAssemloids， 皮质样神经元的数量和比例。mAssemloids提供了一个3D环境，其中包含 成熟的星形胶质细胞与健康人脑中的星形胶质细胞非常相似，并重现了ALS的关键特征。 例如以前从未在体外报道过的衰老相关疾病病理学。对于这个直接到第二阶段的项目， SynaptiCure建议使用mAssembloid平台为几种不同的亚型开发模型系统 ALS和FTD。本项目的具体目标如下：1）生成并验证mAssemloids用于遗传 FTD、ALS和FTD/ALS模型; 2）生成并验证C9 ORF 72相关ALS/FTD的mAssemloids; 和3）生成并验证散发性ALS/FTD的mAssemloids。预计这项工作将使 开发上级模型和生物标志物，为研发、患者 分层，以及新的诊断，预后和治疗方法的发展。

Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two of the costliest and most devastating neurodegenerative diseases. An estimated 16,000 Americans are affected by ALS, while up to 30,000 suffer from FTD, although these are likely to be underestimates. Research in recent decades has shown that FTD has significant clinical, pathological, and genetic overlap with ALS, and the two are now considered to be on the same disease spectrum. Up to 50% of ALS patients experience cognitive impairment, and up to 15% develop FTD symptoms. ALS/FTD and the morbidity and impairments they cause are accompanied by significant medical, societal, and financial burdens. Total per patient costs are estimated at $70,000 annually for ALS patients and $120,000 annually for FTD patients. Currently, effective diagnostics and treatments for these diseases are lacking, and newer therapies have translated poorly to humans, despite showing great promise in existing in vitro and animal models. A major challenge in the development and testing of new therapies is the lack of models that accurately reflect the underlying pathophysiology. Like all neurodegenerative diseases, animal models for ALS and FTD are hindered by the short lifespans of most animals, which may not allow for adequate disease progression. Differences in the genomes, development, and physiology of human and animal brains are additional complicating factors. Accurate models of these diseases are needed to advance the development of novel biomarkers, diagnostics, and therapeutics. To address this need, SynaptiCure is developing a novel patient-derived 3D platform for high-fidelity modeling and screening of TDP-43 proteinopathy and associated biomarkers for ALS and FTD. SynaptiCure’s innovative mAssembloids platform will provide a new, systematic approach for creating 3D mature brain organoids that more closely reflect disease states relevant to ALS and FTD, including matched extracellular features not seen in any other existing models. In prior work, SynaptiCure was able to form mAssembloids from differentiated human astrocytes and cortical-like neurons in defined numbers and ratios. mAssembloids provide a 3D environment that contains mature astrocytes very similar to those in the healthy human brain, as well as recapitulating key features of ALS such as aging-related disease pathology never before reported in vitro. For this Direct to Phase II project, SynaptiCure proposes to use the mAssembloid platform to develop model systems for several different subtypes of ALS and FTD. Specific Aims of this project are as follows: 1) Generate and validate mAssembloids for genetic models of FTD, ALS, and FTD/ALS; 2) Generate and validate mAssembloids for C9ORF72-associated ALS/FTD; and 3) Generate and validate mAssembloids for sporadic ALS/FTD. It is anticipated that this work will enable the development of superior models and biomarkers that will pave the way for improvements in R&D, patient stratification, and the development of new diagnostic, prognostic, and therapeutic approaches.