A liver-on-chip platform to evaluate panels of clinically relevant gene variants for screening of xenobiotic compounds

用于评估临床相关基因变异组以筛选异生化合物的肝脏芯片平台

• 批准号: 10738215
• 负责人: Thomas Neumann
• 金额: $ 27.55万
• 依托单位: NORTIS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10738215
• 关键词: 3-Dimensional; ATP-Binding Cassette Transporters; Academia; Albumins; Apoptosis; Assessment tool; Automation; Bile fluid; Biological Assay; Biological Models; Biosensor; CYP2D6 gene; Cause of Death; Cell model; Cells; Chemical Exposure; Chemicals; Clinical; Clinical Data; Clinical Trials; Collection; Computer Models; Data; Data Analytics; Data Correlations; Development; Drug Exposure; Drug Industry; Drug toxicity; End Point Assay; Endothelial Cells; Ensure; Environmental Health; Exposure to; Fees; Fibrosis; Future; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Hepatocyte; Hepatotoxicity; Human; Human Genetics; In Vitro; Incubators; Individual; Kupffer Cells; Liver; Marketing; Measures; Methods; Microfluidics; Modeling; Monitor; Morbidity - disease rate; Organ Model; Output; Patient Selection; Patients; Performance; Pharmaceutical Preparations; Pharmacotherapy; Phase; Population; Predisposition; Protein Isoforms; Protocols documentation; Provider; Reproducibility; Research; Research Personnel; Risk; Safety; Services; Shipping; Small Business Innovation Research Grant; Source; System; Testing; Tissue Model; Tissues; Toxic effect; Toxicology; Treatment Cost; Treatment Efficacy; Universities; Urea; Validation; Variant; Work; Xenobiotics; adverse drug reaction; cell type; clinical toxicology; clinically relevant; clinically significant; commercialization; cytokine; data modeling; design; drug candidate; drug discovery; drug induced liver injury; drug testing; genetic variant; hepatic acinus structure; human model; induced pluripotent stem cell; microphysiology system; mortality; organ on a chip; pharmacokinetics and pharmacodynamics; pre-clinical; prevent; rare variant; research and development; response; risk prediction; safety assessment; screening; self organization; stellate cell; success; technology platform; tool; web platform

Project Summary Genetic predispositions in the human population are associated with unpredictable pharmacokinetic (PK) and pharmacodynamics (PD), which result in the loss of treatment efficacy or increase risks of adverse drug reactions (ADRs). The FDA estimates that ADRs are the 4th leading cause of death in the US, and treatment costs related to ADRs exceed $136 billion annually. Drug-induced liver injury leads to increased morbidity and mortality in patients and remains a major reason for drug attrition in the market. Since there are interspecies differences in response to xenobiotics, new methods must be developed to capture human genetic variability in response to chemical exposures and to help protect sensitive populations that respond differently to drug exposures. This SBIR Fast-Track is focused on generating a liver-on-chip platform to evaluate panels of clinically relevant gene variants for screening of xenobiotic compounds. Once successfully developed, validated, and commercialized, the liver-on-chip platform will serve as an important new tool in chemical toxicity screening, providing a more predictive in vitro tool for assessing hepatotoxicity during the preclinical stage that will prevent unsafe drug candidates from advancing into clinical trials. The approach proposed in this application leverages an existing, well characterized liver-on-chip model, the Liver Acinus Microphysiology System (LAMPS). LAMPS is a 3D layered tissue model generated through sequential cell layering and subsequent tissue self-organization. The envisioned advanced LAMPS includes a panel of hepatocytes with genetic variations that are known to have clinical significance and that can be compared regarding their toxicity response to xenobiotics. Assay outputs are integrated into the BioSystics Analytics PlatformTM to correlate and analyze in vitro results to clinical data and computationally model the LAMPS data in a single web-based platform. Phase I is designed to establish the feasibility of LAMPS to model human variability for liver toxicology studies. We will leverage the Nortis’ second-generation ParVivoTM organ-on-chip platform that supports 768 simultaneous high-content assays per standard cell incubator, as well as previously established LAMPS culture protocols. Phase I/AIM 1 is designed to establish evidence that LAMPS generated from primary liver cells with genetically diverse polymorphisms show clinically relevant differences in response to exposure to reference drugs. Phase II will develop the core panel of a genetically diversified liver toxicology screening platform. Phase II/AIM 1 will determine the source of cells for the future human liver toxicity screening platform. In Phase II/AIM 2 we will develop the core panel of LAMPS with genetic polymorphisms and validate the panel through correlation with clinical data. Once commercialized, the envisioned platform will give researchers the opportunity to test drug candidates and other xenobiotics in human liver models representing sub-populations of individuals who possess a specific gene variant.

项目摘要 人群中的遗传易感性与不可预测的药代动力学（PK）和 药效学（PD），导致治疗疗效丧失或药物不良反应风险增加 （发展成果评估）。FDA估计，ADR是美国第四大死亡原因，与治疗费用相关 美国存托凭证每年超过1360亿美元。药物性肝损伤导致糖尿病患者发病率和死亡率增加 患者，仍然是市场上药物流失的主要原因。由于物种间的差异， 因此，必须开发新的方法来捕捉人类遗传变异性，以应对外源性物质。 这是一个非常重要的问题，因为它有助于保护对化学品暴露有不同反应的敏感人群。 该SBIR快速通道专注于生成肝脏芯片平台，以评估临床相关的 用于筛选异生物质化合物的基因变体。一旦成功开发、验证， 商业化后，肝脏芯片平台将成为化学毒性筛选的重要新工具， 为临床前阶段评估肝毒性提供更具预测性的体外工具， 不安全的候选药物进入临床试验。本申请中提出的方法利用了 现有的、充分表征的肝芯片模型，肝腺泡微生理学系统（LAMPS）。灯 是通过连续细胞分层和随后的组织自组织生成的3D分层组织模型。 设想的先进LAMPS包括一组具有遗传变异的肝细胞，已知这些变异具有 临床意义，并且可以比较它们对外源性物质的毒性反应。测定输出 集成到BioSystics Analytics PlatformTM中，将体外结果与临床数据相关联并进行分析 并在单个基于网络的平台中对LAMPS数据进行计算建模。 I期旨在确定LAMPS用于肝脏毒理学研究的人体变异性建模的可行性。 我们将利用Nortis的第二代ParVivoTM器官芯片平台，支持768个同时 每个标准细胞培养箱的高含量测定，以及先前建立的LAMPS培养方案。 I期/AIM 1旨在建立LAMPS由原代肝细胞产生的证据， 不同的多态性显示了对暴露于参考药物的反应的临床相关差异。相 II将开发遗传多样性肝脏毒理学筛查平台的核心面板。第二阶段/AIM 1将 确定细胞来源，为未来人类肝毒性筛查平台奠定基础。在第二阶段/AIM 2中，我们将 开发具有遗传多态性的LAMPS核心面板，并通过与 临床数据。一旦商业化，设想的平台将为研究人员提供测试药物的机会。 候选物和其他外源性物质在人肝模型中的表达， 一种特殊的基因变体