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.

抽象的突触正在开发一个新型的患者衍生的3D平台，用于高保真建模和筛查TDP- 43蛋白质病和相关生物标志物用于肌萎缩性侧索硬化症（ALS）和额颞痴呆（FTD）。突触的成熟脑器官（Mborgs）由源自患者的关键神经元细胞组成诱导多能干细胞（IPSC），并定制为人脑共培养，允许它们为了概括几种在任何现有的体外模型中尚未全面看到的ALS/FTD疾病特征。保守地，有16,000名美国人受ALS的影响，而多达30,000人患有FTD，发病率认知和身体障碍很大。目前，ALS的有效诊断和治疗和FTD缺乏，新的疗法转化为人类，目的地表现出巨大的希望体外和体内临床前研究。两种疾病的准确模型都至关重要开发新型生物标志物，诊断/预后工具和治疗。突触的创新Mborg 平台通过提供高度可重复的方法来创建3D Mborgs，以准确地解决这一需求反映与ALS和FTD相关的疾病状态，包括现有的匹配病理特征型号。该平台使用类似工程的方法，在该方法中生成细胞组件，然后分别分化，然后组装成满足特定疾病模型需求的器官。突触具有从成熟的人类星形胶质细胞（IA）和类似皮质样的成熟人类星形胶质细胞（IA）形成Mborgs的能力神经元（in）的定义数量和比率，提供了一个3D环境，具有与之相似的成熟星形胶质细胞在健康的人脑中，并概括了ALS的关键特征，例如与衰老有关的疾病病理在报告体外。突触和我们的合作者最近成功地合并了IPSC衍生的小胶质细胞进入Mborgs，并添加小胶质细胞是该程序的优先事项。突触的3D型号已经通过测定TDP-43蛋白质疗法验证，该蛋白质疗法在〜97％的ALS中有助于疾病，而〜45％的FTD有助于疾病案例。这包括评估TDP-43定位和磷酸化，以及错误的分解 Stathmin-2（STMN2），最近表征的TDP-43蛋白质病的生物标志物。突触的第一阶段证明概念项目的旨在推进2到3D筛选管道，以识别此类其他化合物通过以下特定目的挽救特定表型：1）建立和验证2D屏幕显示 TDP-43蛋白质病和救援，以及2）使用3D证实3D治疗候选物的效率 Mborgs评估治疗候选者营救TDP-43蛋白质病的能力，而不是压力诱导。成功完成该项目后，在将来的II阶段应用程序中，突触将寻找将平台扩展到患者衍生的细胞并包括其他相关的单元格，请确认筛选的能力与广泛的遗传背景相对的化合物是迈向ALS/FTD个性化治疗的第一步。