Neural Circuits, Kinetics and Energetics HTS of Human iPSC-Neurons, -Microglia, and -Astrocytes: AI-Enabled Platform for Target ID, and Drug Discovery and Toxicity (e.g., Cancer Chemo & HIV ARTs)
人类 iPSC 神经元、小胶质细胞和星形胶质细胞的神经回路、动力学和能量 HTS:用于目标 ID、药物发现和毒性(例如癌症化疗)的 AI 平台
基本信息
- 批准号:10707866
- 负责人:
- 金额:$ 56.57万
- 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:2023-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAffectAftercareAlgorithmsAlzheimer&aposs DiseaseAnimal TestingAnimalsAntineoplastic AgentsApolipoprotein EArrhythmiaArtificial IntelligenceAstrocytesBRAIN initiativeBiological AssayBipolar DisorderBrainCalciumCancer SurvivorCanis familiarisCarcinogensCardiac MyocytesCardiovascular systemCell SurvivalCell membraneCellsChemotherapy-induced peripheral neuropathyClassificationClinicalClinical TrialsCoculture TechniquesComplexCytosolDLG4 geneDataDevelopmentDiseaseDoseDose LimitingDrug PrescriptionsDrug toxicityEffectivenessEndoplasmic ReticulumFDA approvedFailureFeeling suicidalGenotypeGoalsHIVHIV antiretroviralHIV-associated neurocognitive disorderHeadacheHepaticHourHumanImageImage CytometryImpaired cognitionImpairmentIn VitroIncubatedInduced pluripotent stem cell derived neuronsInstitutionIon ChannelKineticsLabelLeadMalignant NeoplasmsMarketingMeasuresMembraneMicrogliaMitochondriaModelingMusMutationNervous SystemNeurodegenerative DisordersNeurogliaNeurologicNeuronsPatientsPatternPerformancePersonsPharmaceutical PreparationsPharmacologic SubstancePhasePhenotypePoisonPreclinical TestingPreparationPublishingQuality ControlReportingRoboticsSafetySalesScienceSedation procedureSeizuresSensitivity and SpecificitySmall Business Innovation Research GrantSynapsesSynapsinsSystemTestingTherapeuticThinkingTissue ModelToxic effectToxinTrainingTreatment-related toxicityUnited States National Institutes of HealthValidationVariantVirus Diseasesabuse liabilityanti-cancerantiretroviral therapyapolipoprotein E-3cancer therapycancer-related cognitive impairmentclinical effectclinical predictorscompound 30costdosagedrug developmentdrug discoveryendoplasmic reticulum stressexperiencehigh throughput screeninghuman adult stem cellimprovedin vivoinduced pluripotent stem celllead seriesmanufacturing scale-upmultiplex assayneural circuitneuronal circuitryneurotoxicneurotoxicitynovelpostsynapticpre-clinicalpre-clinical researchpreclinical developmentpredicting responsepresynapticprogramsresponseretinal toxicitysafety studyscreeningscreening servicesside effectstem cellstherapeutic candidatetoxicantvoltage
项目摘要
Neurotoxicity is among the most common reasons for failure of drugs during clinical trials, illustrating that current
preclinical test models, which feature whole animals or animal cells are extremely poor at predicting human
neurotoxicity. Additionally, many currently FDA-approved therapeutics, such as anti-cancer chemotherapeutics,
are neurotoxic, which limits their therapeutic dosage and often results in impaired cognition during and after
treatment. FDA “black box” warnings, describing neurological side-effects, are common and currently prescribed
therapeutics for AIDs may contribute to HIV-Associated Neurocognitive Disorder (HAND). Accordingly, Vala
Sciences Inc., proposes a Fast-Track SBIR project to develop an assay system utilizing neurons, astrocytes,
and microglia, derived from human induced pluripotent stem cells (hiPSC-neurons/astrocytes/microglia) to test
candidate therapeutics for neurotoxicity. The cells will be cultured in 384-well dishes to enable high throughput
multiplexed assay of compound effects on neuronal activity (via Kinetic Image Cytometry [KIC] –
acquisition/analysis of videos of cells labeled with calcium and voltage indicators), and synapses, mitochondria,
endoplasmic reticulum, and cell viability. Since the assay will feature human cells, it will likely be more predictive
of human neurotoxicity vs. animal test systems currently used in preclinical research. Phase I activities will
develop the multiplexed system, to enable testing of compounds for toxic effects on mechanisms of action (MOA)
including alteration of plasma membrane ion channels, ER function and integrity, mitochondrial function, and
neuronal circuitry (correlated activity of neurons within a culture well). A total of 30 compounds with known MOA
and effects of humans, will be tested in Phase I, these data will be used to train artificial intelligence (AI) clustering
algorithms to recognize the MoAs, particularly for low doses of the test agents. The compounds will also be
tested on hiPSC-neurons/astrocytes/microglia representing APOE-3/4 and APOE-4/4 genotypes, as the
APOE-4 is associated increased neurotoxicity. In Phase II a total of 350 probes/drugs (of which 275 are known
to have clinical effects, and 75 will be expected to have no effect) will be screened, with the results used to
further train the AI and improve the overall clinical predictivity. Additional versions of the assay will be developed
featuring mutations/genotypes relevant to Alzheimer’s Disease and Bipolar Disease. In addition to recognition
of neurotoxicity, the assay system also will increase our understanding of neuronal circuits, which is responsive
to the BRAIN Initiative program. The neurotoxicity assay will be marketed to pharmaceutical companies
developing therapeutics across a broad spectrum of diseases/afflictions, including chemotherapeutics and
potential therapeutics for neurodegenerative diseases.
神经毒性是临床试验期间药物失败的最常见原因之一,说明目前
以整个动物或动物细胞为特征的临床前测试模型在预测人类疾病方面非常差。
神经毒性此外,许多目前FDA批准的治疗剂,如抗癌化疗剂,
是神经毒性的,这限制了它们的治疗剂量,并且经常导致在治疗期间和之后的认知受损。
治疗FDA的“黑盒”警告,描述神经系统的副作用,是常见的,目前规定
艾滋病的治疗可能会导致艾滋病相关的神经认知障碍(HAND)。因此,Vala
科学公司,提出了一个快速跟踪SBIR项目,以开发利用神经元,星形胶质细胞,
和小胶质细胞,来源于人诱导多能干细胞(hiPSC-神经元/星形胶质细胞/小胶质细胞),以测试
神经毒性的候选治疗剂。细胞将在384孔培养皿中培养,以实现高通量
化合物对神经元活性影响的多重测定(通过动力学图像细胞计数[KIC] -
用钙和电压指示剂标记的细胞的视频的采集/分析),以及突触,线粒体,
内质网和细胞活力。由于该检测将以人类细胞为特征,
人类神经毒性与目前临床前研究中使用的动物试验系统。第一阶段活动将
开发多路复用系统,以测试化合物对作用机制的毒性作用(MOA)
包括质膜离子通道、ER功能和完整性、线粒体功能的改变,以及
神经元回路(培养孔内神经元的相关活动)。共有30种已知MOA的化合物
和人类的影响,将在第一阶段进行测试,这些数据将用于训练人工智能(AI)聚类
识别MoA的算法,特别是对于低剂量的测试试剂。这些化合物也将是
对代表APOE-3/4和APOE-4/4基因型的hiPSC神经元/星形胶质细胞/小胶质细胞进行测试,因为
APOE β-4与神经毒性增加相关。在第二阶段,总共有350种探针/药物(其中275种已知
有临床效果,75人预计没有效果)将被筛选,结果用于
进一步训练AI并提高整体临床预测能力。将开发其他版本的检测试剂盒
其特征在于与阿尔茨海默病和双相情感障碍相关的突变/基因型。除了承认
神经毒性,分析系统也将增加我们对神经元回路的理解,这是响应
大脑倡议计划。神经毒性检测将向制药公司销售
开发广泛的疾病/痛苦的治疗方法,包括化疗和
神经退行性疾病的潜在治疗剂。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jeffrey H. Price其他文献
Comparison of phase-contrast and fluorescence digital autofocus for scanning microscopy.
扫描显微镜相差和荧光数字自动对焦的比较。
- DOI:
10.1002/cyto.990160402 - 发表时间:
1994 - 期刊:
- 影响因子:0
- 作者:
Jeffrey H. Price;D. Gough - 通讯作者:
D. Gough
Jeffrey H. Price的其他文献
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{{ truncateString('Jeffrey H. Price', 18)}}的其他基金
Combined Cardiomyopathy, e.g., of Cancer Chemotherapeutics, and Proarrhythmia for Cardiotoxicity Clinical Trials-in-a-Dish (CTiD) with iPSC-Derived Cardiomyocytes
联合心肌病,例如癌症化疗药物和致心律失常,使用 iPSC 来源的心肌细胞进行心脏毒性临床试验 (CTiD)
- 批准号:
10438273 - 财政年份:2021
- 资助金额:
$ 56.57万 - 项目类别:
Combined Cardiomyopathy, e.g., of Cancer Chemotherapeutics, and Proarrhythmia for Cardiotoxicity Clinical Trials-in-a-Dish (CTiD) with iPSC-Derived Cardiomyocytes
联合心肌病,例如癌症化疗药物和致心律失常,使用 iPSC 来源的心肌细胞进行心脏毒性临床试验 (CTiD)
- 批准号:
10268102 - 财政年份:2021
- 资助金额:
$ 56.57万 - 项目类别:
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