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

• 批准号: 10707866
• 负责人: Jeffrey H. Price
• 金额: $ 56.57万
• 依托单位: VALA SCIENCES, INC.
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10707866
• 关键词: Action Potentials; Affect; Aftercare; Algorithms; Alzheimer' s Disease; Animal Testing; Animals; Antineoplastic Agents; Apolipoprotein E; Arrhythmia; Artificial Intelligence; Astrocytes; BRAIN initiative; Biological Assay; Bipolar Disorder; Brain; Calcium; Cancer Survivor; Canis familiaris; Carcinogens; Cardiac Myocytes; Cardiovascular system; Cell Survival; Cell membrane; Cells; Chemotherapy-induced peripheral neuropathy; Classification; Clinical; Clinical Trials; Coculture Techniques; Complex; Cytosol; DLG4 gene; Data; Development; Disease; Dose; Dose Limiting; Drug Prescriptions; Drug toxicity; Effectiveness; Endoplasmic Reticulum; FDA approved; Failure; Feeling suicidal; Genotype; Goals; HIV; HIV antiretroviral; HIV-associated neurocognitive disorder; Headache; Hepatic; Hour; Human; Image; Image Cytometry; Impaired cognition; Impairment; In Vitro; Incubated; Induced pluripotent stem cell derived neurons; Institution; Ion Channel; Kinetics; Label; Lead; Malignant Neoplasms; Marketing; Measures; Membrane; Microglia; Mitochondria; Modeling; Mus; Mutation; Nervous System; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Patients; Pattern; Performance; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Poison; Preclinical Testing; Preparation; Publishing; Quality Control; Reporting; Robotics; Safety; Sales; Science; Sedation procedure; Seizures; Sensitivity and Specificity; Small Business Innovation Research Grant; Synapses; Synapsins; System; Testing; Therapeutic; Thinking; Tissue Model; Toxic effect; Toxin; Training; Treatment-related toxicity; United States National Institutes of Health; Validation; Variant; Virus Diseases; abuse liability; anti-cancer; antiretroviral therapy; apolipoprotein E-3; cancer therapy; cancer-related cognitive impairment; clinical effect; clinical predictors; compound 30; cost; dosage; drug development; drug discovery; endoplasmic reticulum stress; experience; high throughput screening; human adult stem cell; improved; in vivo; induced pluripotent stem cell; lead series; manufacturing scale-up; multiplex assay; neural circuit; neuronal circuitry; neurotoxic; neurotoxicity; novel; postsynaptic; pre-clinical; pre-clinical research; preclinical development; predicting response; presynaptic; programs; response; retinal toxicity; safety study; screening; screening services; side effect; stem cells; therapeutic candidate; toxicant; voltage

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，这说明目前 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方面极差 此外，许多目前 FDA 批准的治疗药物，例如抗癌化疗药物， 具有神经毒性，这限制了它们的治疗剂量，并且经常导致治疗期间和治疗后认知受损 FDA 描述神经系统副作用的“黑匣子”警告很常见，目前也是处方药。 Vala 认为，艾滋病治疗可能会导致 HIV 相关神经认知障碍 (HAND)。 Sciences Inc. 提出了一个 Fast-Track SBIR 项目，开发利用神经元、星形胶质细胞、 和小胶质细胞，源自人类诱导多能干细胞（hiPSC-神经元/星形胶质细胞/小胶质细胞）进行测试 神经毒性的候选疗法将在 384 孔培养皿中培养细胞，以实现高通量。 复合物对神经活动影响的多重测定（通过动态图像细胞术 [KIC] – 采集/分析用钙和电压指示剂标记的细胞的视频，以及突触、线粒体、 由于该检测以人类细胞为特征，因此可能更具预测性。 人类神经毒性与目前临床前研究中使用的动物测试系统的比较。 开发多重系统，以测试化合物对作用机制 (MOA) 的毒性作用 包括质膜离子通道、内质网功能和完整性、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）总共 30 种具有已知 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 MoAs 的算法，特别是对于低剂量的测试药物，这些化合物也将被识别。 在代表 APOE-3/4 和 APOE-4/4 基因型的 hiPSC 神经元/星形胶质细胞/小胶质细胞上进行测试， APOE-4 与增加的神经毒性有关。在 II 期中，共有 350 种探针/药物（其中 275 种是已知的）。 有临床效果，预计有75个没有效果）将进行筛选，结果用于 进一步训练人工智能并提高整体临床预测能力 将开发更多版本的检测方法。 除了识别之外，还具有与阿尔茨海默病和双相情感障碍相关的突变/基因型。 除了神经毒性之外，该检测系统还将增加我们对神经元回路的理解，神经元回路具有反应性 该神经毒性检测将向制药公司销售。 开发针对广泛疾病/痛苦的治疗方法，包括化疗和 神经退行性疾病的潜在治疗方法。