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

用于检测 TDP-43 蛋白病和 ALS/FTD 相关生物标志物的新型患者衍生 3D 平台

基本信息

批准号：
10571879
负责人：
Erik M Ullian
金额：
$ 100.37万
依托单位：
SYNAPTICURE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571879
关键词：
3-Dimensional ALS patients Address Advanced Development Affect Age Aging American Amyotrophic Lateral Sclerosis Animal Model Animals Astrocytes Biological Assay Biological Markers Biological Models Brain C9ORF72 Cell Line Cell Lineage Cell model Cells Cellular Assay Clinical Clinical Trials Coculture Techniques Cognitive Complex Consumption Custom Cytoplasm Data Development Diagnostic Disease Disease Progression Disease model Embryo Engineering Environment Evaluation Financial Hardship Frontotemporal Dementia Functional disorder Genes Genetic Genetic Models Genome Human Impaired cognition Impairment In Vitro Knock-out Longevity Medical Microglia Modeling Morbidity - disease rate Mutate Mutation Neurodegenerative Disorders Neurons Organoids Outcome Pathologic Pathology Patient Care Patients Pharmacologic Substance Phase Phosphorylation Physiology Prognostic Marker RNA Splicing Reporting Reproducibility Research Small Business Innovation Research Grant Specific qualifier value Standardization Symptoms System TBK1 gene Testing Therapeutic Time Translating Variant Work aged aging brain astrocyte progenitor brain cell cell type cohort cost estimate detection platform experience extracellular frontotemporal lobar dementia amyotrophic lateral sclerosis genetic manipulation genetic variant improved in vitro Model induced pluripotent stem cell innovation knock-down nerve stem cell new therapeutic target novel novel diagnostics novel marker novel strategies novel therapeutics patient stratification prognostic prognostic tool prognostic value programs protein TDP-43 rapid test research and development screening specific biomarkers sporadic amyotrophic lateral sclerosis stathmin success three dimensional structure tool

项目摘要

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.

抽象的肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 是最昂贵且最常见的两种疾病据估计，有 16,000 名美国人受到 ALS 的影响，而多达近几十年来的研究表明，有 30,000 人患有 FTD，但这一数字可能被低估了。 FTD 与 ALS 具有显着的临床、病理和遗传重叠，现在认为两者高达 50% 的 ALS 患者患有相同的疾病谱，高达 15% 的患者患有认知障碍。出现 FTD 症状，并且它们引起的发病率和损害伴随着显着的后果。每名 ALS 患者每年的医疗、社会和经济负担估计为 70,000 美元。目前，针对这些患者的有效诊断和治疗每年为 FTD 患者提供 120,000 美元。疾病缺乏，尽管新的疗法在人类身上显示出巨大的希望，但对人类的转化效果不佳现有的体外和动物模型是开发和测试新疗法的主要挑战。与所有神经退行性疾病一样，缺乏准确反映潜在病理生理学的模型。 ALS 和 FTD 的动物模型受到大多数动物寿命短的阻碍，这可能不允许人类和动物的基因组、发育和生理学的差异。大脑是这些疾病的额外复杂因素，需要准确的模型来推进。为了满足这一需求，SynaptiCure 开发了新型生物标志物、诊断方法和治疗方法。开发一种新型的源自患者的 3D 平台，用于 TDP-43 的高保真建模和筛选 SynaptiCure 的创新 mAssembloids 的蛋白质病和相关生物标志物。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，更密切地反映与 ALS 和 FTD 相关的疾病状态，包括任何其他现有疾病中未见的匹配细胞外特征在之前的工作中，SynaptiCure 能够从分化的人类星形胶质细胞中形成 mAsembloids。具有确定数量和比例的皮质样神经元提供了一个包含以下内容的 3D 环境。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，并且概括了 ALS 的关键特征例如以前从未在体外报道过的与衰老相关的疾病病理学。 SynaptiCure 建议使用 mAssembroid 平台开发多种不同亚型的模型系统 ALS 和 FTD 的具体目标如下： 1) 生成并验证用于遗传的 mAsembloids。 FTD、ALS 和 FTD/ALS 模型；2) 生成并验证 C9ORF72 相关 ALS/FTD 的 mAsembloid； 3) 生成并验证偶发性 ALS/FTD 的 mAsembloids 预计这项工作将使开发卓越的模型和生物标志物，将为研发、患者的改进铺平道路分层以及新的诊断、预后和治疗方法的开发。