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

项目摘要 人类群体中的遗传易感性与不可预测的药代动力学(PK)和 药效学(PD)，导致治疗效果丧失或增加药物不良反应的风险 (ADRS)。FDA估计，ADR是美国第四大致死原因，相关的治疗费用 每年的ADR超过1360亿美元。药物性肝损伤导致儿童发病率和死亡率增加 患者，并且仍然是市场上药物损耗的主要原因。由于存在物种间的差异， 对于外来生物的反应，必须开发新的方法来捕捉人类遗传变异以应对 此外，它还有助于保护对药物暴露有不同反应的敏感人群。 此SBIR Fast-Track专注于生成芯片上肝脏的平台，以评估临床相关的 外源化合物筛选中的基因变异。一旦成功开发、验证和 商业化后，芯片上的肝脏平台将成为化学毒性筛选的重要新工具， 提供了一种更具预测性的体外工具，用于在临床前阶段评估肝毒性，从而防止 不安全的候选药物不能进入临床试验。本申请中提出的方法利用 一种现有的、特征良好的芯片上肝脏模型，即肝腺泡微生理学系统(LAMP)。灯具 是通过连续的细胞分层和随后的组织自组织生成的3D分层组织模型。 设想的先进灯包括一组具有已知基因变异的肝细胞 临床意义，可以比较它们对外源物质的毒性反应。化验结果 集成到BioSystics Analytics PlatformTM中，以将体外结果与临床数据进行关联和分析 并在单个基于网络的平台中对灯数据进行计算建模。 第一阶段的设计是为了建立LAPS模型用于肝脏毒理学研究的人体变异性的可行性。 我们将利用Nortis的第二代ParVivoTM器官芯片平台，该平台支持768同步 每个标准细胞孵化器的高含量分析，以及先前建立的LAMP培养方案。 I/AIM 1期的设计目的是建立证据，证明从原代肝细胞产生的LAMP具有遗传性 不同的基因多态表现出临床上相关的对参比药物暴露反应的差异。阶段 II将开发基因多元化肝毒学筛查平台的核心小组。第二阶段/目标1将 确定细胞来源，为未来的人体肝脏毒性筛选平台。在第二阶段/目标2中，我们将 开发具有遗传多态的灯具核心面板，并通过关联验证面板 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 人体肝脏模型中代表具有以下特征的个体的亚群的候选和其他外源生物 一种特定的基因变种。

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.