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:
- 金额:$ 50万
- 依托单位:
- 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:
- 关键词:3-DimensionalAccelerationAdvanced DevelopmentAffectAgingAmericanAmyotrophic Lateral SclerosisAnimal ModelAstrocytesBiological AssayBiological MarkersBrainCell LineCell modelCellsCellular AssayClinical TrialsCoculture TechniquesCognitiveCustomCytoplasmDataDevelopmentDiagnosticDiseaseDisease ProgressionDisease modelEngineeringEnvironmentEvaluationFinancial HardshipFrontotemporal DementiaFutureGenesGeneticGoalsHealthHumanImpairmentIn VitroKnock-outMedicalMicrogliaModelingMorbidity - disease rateMutateMutationNeuronsOrganoidsOutcomePGRN genePathologicPathologyPatientsPharmacologic SubstancePhasePhenotypePhosphorylationPrognostic MarkerQuality of lifeRNA SplicingReportingReproducibilitySmall Business Innovation Research GrantTestingTherapeuticTranslatingTreatment EfficacyValidationVariantWorkamyotrophic lateral sclerosis therapybiomarker validationcell typecohortfrontotemporal lobar dementia amyotrophic lateral sclerosisgenetic variantimprovedin vitro Modelin vivoinduced pluripotent stem cellinnovationnew therapeutic targetnovelnovel markernovel therapeuticspatient stratificationpersonalized medicinepreclinical studyprognostic toolprognostic valueprogramsprotein TDP-43rapid testscreeningspecific biomarkersstathminstressortherapeutic candidatethree-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.
摘要
Synapticure正在开发一种新型的患者衍生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)。Synapticure的成熟脑类器官(mbOrgs)由来自患者的关键神经细胞组成,
诱导多能干细胞(iPSC),并定制组装到人脑共培养物中,
概括了在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,16,000名美国人受到ALS的影响,而多达30,000人患有FTD,
认知和身体损伤都很严重目前,ALS的有效诊断和治疗
和FTD缺乏,新的治疗方法对人类的转化很差,尽管在治疗方面显示出很大的希望。
体外和体内临床前研究。迫切需要这两种疾病的精确模型,以推动
开发新的生物标志物、诊断/预后工具和治疗方法。Synapticure的创新产品
平台通过提供高度可重复的方法来创建3D mbOrg,从而满足了这一需求,
反映与ALS和FTD相关的疾病状态,包括在现有研究中未观察到的匹配病理学特征
模型该平台使用类似工程的方法,生成细胞组件,
它们分别分化,然后组装成满足特定疾病模型需求的类器官。
Synapticure具有从成熟的人星形胶质细胞(iA)和同质的皮质样胶质细胞形成mbOrgs的能力。
神经元(iN)以确定的数量和比例,提供了一个3D环境与成熟的星形胶质细胞类似,
在健康的人类大脑和概括ALS的关键特征,如与衰老有关的疾病病理学,
之前在体外报道过。Synapticure和我们的合作者最近成功地将iPSC衍生的
将小胶质细胞植入mbOrgs,添加小胶质细胞是这个项目的优先事项。Synapticure的3D模型
通过测定TDP-43蛋白质病进行验证,TDP-43蛋白质病导致约97%的ALS和约45%的FTD患病
例这包括TDP-43定位和磷酸化的评估,以及
stathmin-2(STMN 2),最近表征的TDP-43蛋白质病的生物标志物。Synapticure的第一阶段证明
概念项目的目的是推进2D到3D筛选管道,以识别这些额外的化合物
通过以下特定目的拯救特定表型:1)建立并验证2D筛选,
TDP-43蛋白质病和补救,以及2)通过使用3D成像系统在3D中确认治疗候选物的功效。
mbOrgs评价治疗候选物拯救非应激的TDP-43蛋白质病的能力
诱导。成功完成该项目后,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,确认筛选能力
因此,我们需要在广泛的遗传背景下开发新的化合物,作为ALS/FTD个性化治疗的第一步。
项目成果
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