Mature brain organoid platform for therapeutic screening for ALS/FTD

用于 ALS/FTD 治疗筛选的成熟脑类器官平台

基本信息

批准号：
10759584
负责人：
Martina de Majo
金额：
$ 50万
依托单位：
SYNAPTICURE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10759584
关键词：
3-Dimensional Acceleration Advanced Development Affect Aging American Amyotrophic Lateral Sclerosis Animal Model Astrocytes Biological Assay Biological Markers Brain Cell Line Cell model Cells Cellular Assay Clinical Trials Coculture Techniques Cognitive Custom Cytoplasm Data Development Diagnostic Disease Disease Progression Disease model Engineering Environment Evaluation Financial Hardship Frontotemporal Dementia Future Genes Genetic Goals Health Human Impairment In Vitro Knock-out Medical Microglia Modeling Morbidity - disease rate Mutate Mutation Neurons Organoids Outcome PGRN gene Pathologic Pathology Patients Pharmacologic Substance Phase Phenotype Phosphorylation Prognostic Marker Quality of life RNA Splicing Reporting Reproducibility Small Business Innovation Research Grant Testing Therapeutic Translating Treatment Efficacy Validation Variant Work amyotrophic lateral sclerosis therapy biomarker validation cell type cohort frontotemporal lobar dementia amyotrophic lateral sclerosis genetic variant improved in vitro Model in vivo induced pluripotent stem cell innovation new therapeutic target novel novel marker novel therapeutics patient stratification personalized medicine preclinical study prognostic tool prognostic value programs protein TDP-43 rapid test screening specific biomarkers stathmin stressor therapeutic candidate three-dimensional modeling

项目摘要

Abstract Synapticure is developing a novel patient-derived 3D platform for high-fidelity modeling and screening of TDP- 43 proteinopathy and associated biomarkers for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Synapticure’s mature brain organoids (mbOrgs) are composed of key neural cells derived from patient- induced pluripotent stem cells (iPSCs) and are custom assembled into human brain co-cultures, allowing them to recapitulate several ALS/FTD disease features not seen comprehensively in any existing in vitro models. Conservatively, 16,000 Americans are affected by ALS, while up to 30,000 suffer from FTD, and the morbidity and cognitive and physical impairments are significant. Currently, effective diagnostics and treatments for ALS and FTD are lacking, and newer therapies have translated poorly to humans, despite showing great promise in in vitro and in vivo preclinical studies. Accurate models of both diseases are critically needed to advance the development of novel biomarkers, diagnostic/prognostic tools, and therapeutics. Synapticure’s innovative mbOrg platform answers this need by providing a highly reproducible approach for creating 3D mbOrgs that accurately reflect disease states relevant to ALS and FTD, including matched pathological features not seen in existing models. The platform uses an engineering-like approach, where cellular components are generated and differentiated separately and then assembled into organoids that meet the needs of a specific disease model. Synapticure has the ability to form mbOrgs from mature human astrocytes (iA) and homogeneous cortical-like neurons (iN) in defined numbers and ratios, providing a 3D environment with mature astrocytes similar to those in the healthy human brain and recapitulating key features of ALS such as aging-related disease pathology never before reported in vitro. Synapticure and our collaborators have recently successfully incorporated iPSC-derived microglia into mbOrgs, and adding microglia is a priority for this program. Synapticure’s 3D models have been validated by assaying TDP-43 proteinopathy, which contributes to disease in ~97% of ALS and ~45% of FTD cases. This includes evaluation of TDP-43 localization and phosphorylation, as well as the mis-splicing of stathmin-2 (STMN2), a recently characterized biomarker of TDP-43 proteinopathy. Synapticure’s Phase I proof of concept project seeks to advance a 2D to 3D screening pipeline for identifying such additional compounds that rescue specific phenotypes via the following Specific Aims:1) Establish and validate a 2D screen showing TDP-43 proteinopathy and rescue, and 2) Confirm efficacy of therapeutic candidates in 3D by using the 3D mbOrgs to evaluate the ability of the therapeutic candidates to rescue TDP-43 proteinopathy that is not stress induced. Following successful completion of this project, in a future Phase II application, Synapticure will look to expand the platform to patient-derived cells and include other relevant cell types, confirming the ability to screen compounds against a broad genetic background as a first step towards personalized treatment for ALS/FTD.

抽象的 Synapticure 正在开发一种新型的源自患者的 3D 平台，用于 TDP 的高保真建模和筛选肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆的 43 种蛋白质病和相关生物标志物（FTD）的成熟大脑类器官（mbOrgs）由来自患者的关键神经细胞组成。诱导多能干细胞 (iPSC) 并被定制组装到人脑共培养物中，使它们能够概括了任何现有体外模型中未全面观察到的几种 ALS/FTD 疾病特征。保守估计，有 16,000 名美国人受到 ALS 的影响，而多达 30,000 人患有 FTD，并且发病率目前，ALS 的诊断和治疗十分有效。和 FTD 缺乏，尽管新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迫切需要这两种疾病的体外和体内临床前研究。开发新型生物标志物、诊断/预后工具和 Synapticure 的创新 mbOrg。平台通过提供高度可重复的方法来满足这一需求，用于创建准确的 3D mbOrgs 反映与 ALS 和 FTD 相关的疾病状态，包括现有技术中未见的匹配病理特征该平台使用类似工程的方法，生成并分析细胞组件。分别分化，然后组装成满足特定疾病模型需求的类器官。 Synapticure 能够从成熟的人星形胶质细胞 (iA) 和同质皮质样细胞形成 mbOrgs 神经元 (iN) 具有确定的数量和比例，提供具有类似于成熟星形胶质细胞的 3D 环境在健康人脑中，并概括 ALS 的关键特征，例如与衰老相关的疾病病理学，从未 Synapticure 和我们的合作者最近成功整合了 iPSC 衍生的药物。将小胶质细胞添加到 mbOrgs 中，添加小胶质细胞是该项目的首要任务。通过检测 TDP-43 蛋白病进行验证，该蛋白病导致约 97% 的 ALS 和约 45% 的 FTD 患病这包括 TDP-43 定位和磷酸化以及错误剪接的评估。 stathmin-2 (STMN2)，一种最近鉴定的 TDP-43 蛋白病生物标志物，Synapticure 的 I 期证明。概念项目旨在推进 2D 到 3D 筛选流程，以识别此类其他化合物通过以下具体目标拯救特定表型：1) 建立并验证 2D 屏幕显示 TDP-43 蛋白病和救援，以及 2) 使用 3D 确认候选治疗药物的 3D 功效 mbOrgs 评估候选治疗药物拯救非应激性 TDP-43 蛋白病的能力该项目成功完成后，在未来的第二阶段应用中，Synapticure 将着眼于将平台扩展到患者来源的细胞并包括其他相关细胞类型，确认筛选的能力针对广泛遗传背景的化合物，作为 ALS/FTD 个性化治疗的第一步。