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.

抽象的肌萎缩性侧索硬化症（ALS）和额颞痴呆（FTD）是最昂贵，最昂贵的两个毁灭性神经退行性疾病。估计有16,000名美国人受ALS的影响，而 30,000人患有FTD，尽管这些可能被低估了。近几十年来的研究表明该FTD具有与ALS的显着临床，病理和遗传重叠，现在两者被认为是处于同一疾病范围内。多达50％的ALS患者遭受认知障碍，高达15％发展FTD症状。 ALS/FTD以及它们引起的发病率和障碍是通过大量而实现的医疗，社会和金融伯伦斯。 ALS每年估计每年每年的总费用总计70,000美元 FTD患者每年的患者和120,000美元。目前，有效的诊断和治疗缺乏疾病，新的疗法转化为人类，目的地表现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的短寿命的阻碍，这可能不允许足够的疾病进展。人和动物的基因组，发展和生理学的差异大脑是其他复杂因素。需要这些疾病的准确模型来推进新型生物标志物，诊断和治疗的开发。为了满足这一需求，突触是开发一个新型的患者来源的3D平台，用于高保真建模和TDP-43的筛选 ALS和FTD的蛋白质病和相关的生物标志物。突触的创新大型大囊泡平台将为创建3D成熟的脑器官提供一种新的系统方法，以更紧密地反映与ALS和FTD相关的疾病状态，包括其他现有的其他任何现有的匹配的细胞外特征型号。在先前的工作中，突触能够从分化的人类星形细胞和具有定义数量和比率的皮质状神经元。大胚胎提供了一个3D环境成熟的星形胶质细胞与健康的人脑非常相似，并且概括了ALS的关键特征例如与衰老相关的疾病病理学从未在体外报道。对于直接到第二阶段项目，突触提案使用大囊平台为几种不同的亚型开发模型系统 ALS和FTD。该项目的具体目的如下：1）生成和验证通用的大容量 FTD，ALS和FTD/ALS的模型； 2）生成和验证与C9ORF72相关的ALS/FTD的大容量； 3）生成和验证零星ALS/FTD的大胚胎。预计这项工作将使开发高级模型和生物标志物，这些模型和生物标志物将为改善研发，患者铺平道路分层以及新的诊断，预后和治疗方法的发展。