A microphysiologic multicellular organ-on-chip to inform clinical trials in FTD/ALS
为 FTD/ALS 临床试验提供信息的微生理多细胞器官芯片
基本信息
- 批准号:10651873
- 负责人:
- 金额:$ 70.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalALS patientsAgeAgingAgonistAmyotrophic Lateral SclerosisAntisense OligonucleotidesAreaAstrocytesAutologousAutopsyBehavioralBiological AssayBiological MarkersBiological ModelsBlood - brain barrier anatomyBlood VesselsBrainC9ALSC9FTDC9ORF72Cause of DeathCell DeathCell LineCell modelCellsCessation of lifeClinicalClinical DataClinical PathologyClinical TrialsClinical Trials DesignClustered Regularly Interspaced Short Palindromic RepeatsDegenerative DisorderDementiaDevicesDiagnosisDiseaseEtiologyEventFrontotemporal DementiaFrontotemporal Lobar DegenerationsGene MutationGenesGeneticGoalsHumanImageIn VitroIndustry CollaborationIntervention TrialLanguageLiquid substanceMeasuresMemoryMicrogliaMitochondriaModelingMonitorMotor NeuronsMutationNerve DegenerationNeurodegenerative DisordersNeurogliaNeuronsNuclear RNAOrganPathogenesisPathologicPathologyPathway interactionsPatientsPhenotypePhysiologicalProsencephalonRIPK1 geneReproducibilityRespiratory FailureSpinalSyndromeSystemTDP-43 aggregationTemporal LobeTherapeuticTherapeutic AgentsTherapeutic TrialsTissuesToxic effectTreatment EfficacyValidationVariantVertebral columnbiomarker identificationbiomarker validationbrain endothelial cellc9FTD/ALScell cortexcell typeclinical developmentclinical predictorscohortdisease phenotypeearly phase clinical trialefficacy testingfrontal lobefrontotemporal lobar dementia amyotrophic lateral sclerosishuman tissueinduced pluripotent stem cellinhibitormicrophysiology systemmotor neuron degenerationmultiple omicsnovelorgan on a chippatient responsepatient stratificationpreclinical efficacypredictive markerprotein aggregationrepositoryresponseresponse biomarkersafety testingsmall moleculetechnology platformtherapeutic candidatetherapeutic evaluationtraffickingtranscriptome sequencingtranscriptomicsvirtualvirtual clinical trial
项目摘要
Project Summary/Abstract
Frontotemporal dementia (FTD) is a common dementia syndrome in patients under age 65, while
amyotrophic lateral sclerosis (ALS) is a progressive degeneration of motor neurons causing death
from respiratory failure within 3-5 years. FTD and ALS represent a spectrum of
neurodegeneration, with significant overlap clinically, pathologically, and genetically. Aggregates
of TDP-43 are the defining pathology of FTD (FTLD-TDP variant) and ALS, and the most common
genetic cause of both FTD and ALS are repeat expansions in the C9orf72 gene. C9orf72 is
expressed in multiple cell types in the brain including in microglia and neurons, and there is strong
evidence that interaction between different cell types are necessary for pathogenesis of FTD/ALS.
We will develop a microphysiologic system (MPS) using human induced pluripotent stem cell
(iPSC) derived cortical neurons, astrocytes and microglia on a 3D platform that includes a blood
brain barrier (BBB) component to model C9-FTD/ALS forebrain on a chip. Our goal in this project
is to develop a highly reproducible and translatable in vitro human cell-based model of FTD/ALS
to discover and validate translatable biomarkers for preclinical efficacy testing, and to assist in
patient stratification for clinical trial design. We propose to i) develop and validate robustness of
a 3D forebrain MPS incorporating cortical neurons and astrocytes, microglia and brain
microvascular endothelial cells (BMECs) derived from human iPSCs; ii) utilize FTD and ALS
patient derived forebrain MPS's to identify disease biomarkers in C9orf72 related FTD/ALS; iii)
cross validate biomarkers identified using clinical data and pathology from C9-FTD/ALS patients
used to seed the chips, and iv) assess and stratify responses of C9-FTD/ALS fMPS models to
five different therapeutics entering early phase clinical trials ranging from antisense
oligonucleotides to small molecule modulators of mitochondrial function, endocytic trafficking and
cell death pathways.
项目总结/摘要
额颞叶痴呆(FTD)是65岁以下患者常见的痴呆综合征,
肌萎缩侧索硬化症(ALS)是一种导致死亡的运动神经元进行性变性
3-5年内呼吸衰竭。FTD和ALS代表了
神经变性,在临床上、病理学上和遗传学上具有显著重叠。聚集体
是FTD(FTLD-TDP变异体)和ALS的定义性病理学,
FTD和ALS的遗传原因均为C9 orf 72基因的重复扩增。C9 orf 72是
在大脑中的多种细胞类型中表达,包括在小胶质细胞和神经元中,
证据表明不同细胞类型之间的相互作用是FTD/ALS发病机制所必需的。
我们将利用人类诱导性多能干细胞建立一个微生理系统
在包括血液的3D平台上的iPSC(iPSC)衍生的皮质神经元、星形胶质细胞和小胶质细胞
脑屏障(BBB)组件在芯片上模拟C9-FTD/ALS前脑。我们这个项目的目标
是开发一种高度可重现和可转化的FTD/ALS体外人细胞模型
发现和验证用于临床前疗效测试的可翻译生物标志物,并协助
用于临床试验设计的患者分层。我们建议i)开发和验证
3D前脑MPS,包括皮质神经元和星形胶质细胞、小胶质细胞和脑
源自人iPSC的微血管内皮细胞(BMEC); ii)利用FTD和ALS
患者来源的前脑MPS,以鉴定C9 orf 72相关FTD/ALS中的疾病生物标志物; iii)
交叉验证使用C9-FTD/ALS患者的临床数据和病理学确定的生物标志物
用于接种芯片,和iv)评估和分层C9-FTD/ALS fMPS模型对
五种不同的治疗方法进入早期临床试验,从反义
寡核苷酸与线粒体功能、内吞运输和
细胞死亡途径
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Organ-Chips Enhance the Maturation of Human iPSC-Derived Dopamine Neurons.
- DOI:10.3390/ijms241814227
- 发表时间:2023-09-18
- 期刊:
- 影响因子:5.6
- 作者:Otero MG;Bell S;Laperle AH;Lawless G;Myers Z;Castro MA;Villalba JM;Svendsen CN
- 通讯作者:Svendsen CN
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CLIVE Niels SVENDSEN其他文献
CLIVE Niels SVENDSEN的其他文献
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{{ truncateString('CLIVE Niels SVENDSEN', 18)}}的其他基金
A Lung-chip microphysiological system to model SARS-CoV-2 infection and test novel therapeutics
用于模拟 SARS-CoV-2 感染并测试新疗法的肺芯片微生理系统
- 批准号:
10179816 - 财政年份:2020
- 资助金额:
$ 70.82万 - 项目类别:
A microphysiologic multicellular organ-on-chip to inform clinical trials in FTD/ALS
为 FTD/ALS 临床试验提供信息的微生理多细胞器官芯片
- 批准号:
10204148 - 财政年份:2020
- 资助金额:
$ 70.82万 - 项目类别:
A microphysiologic multicellular organ-on-chip to inform clinical trials in FTD/ALS
为 FTD/ALS 临床试验提供信息的微生理多细胞器官芯片
- 批准号:
10515787 - 财政年份:2020
- 资助金额:
$ 70.82万 - 项目类别:
A microphysiologic multicellular organ-on-chip to inform clinical trials in FTD/ALS
为 FTD/ALS 临床试验提供信息的微生理多细胞器官芯片
- 批准号:
10038289 - 财政年份:2020
- 资助金额:
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Development of a Microphysiological Organ-on-Chip System to Model Amyotrophic
开发用于模拟肌萎缩症的微生理器官芯片系统
- 批准号:
10438517 - 财政年份:2017
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$ 70.82万 - 项目类别:
Development of a Microphysiological Organ-on-Chip System to Model Amyotrophic
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10015354 - 财政年份:2017
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