A microphysiological system with a synthetic hemoglobin, Blood Substitute, for mechanistic assessment of drug-induced liver injury

具有合成血红蛋白（血液替代品）的微生理系统，用于药物性肝损伤的机械评估

• 批准号: 10625293
• 负责人: Jelena Vukasinovic
• 金额: $ 7.89万
• 依托单位: LENA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625293
• 关键词: 3-Dimensional; Accounting; Acetaminophen; Active Biological Transport; Acute Liver Failure; Affect; Animals; Antioxidants; Bile Acids; Bile Acids and Salts; Biological; Biological Assay; Biological Markers; Biological Sciences; Biotechnology; Blood; Blood Substitutes; Cell Culture Techniques; Cell Death; Cell Membrane Proteins; Cell Respiration; Cell membrane; Cell model; Cell physiology; Cells; Cellular Stress; Cholestasis; Clinical; Complex; Consensus; Development; Drug Industry; Drug Screening; Drug usage; Electron Transport; Energy-Generating Resources; Engineering; Ensure; Enzymes; Erythrocytes; Etiology; Event; Foundations; Free Radicals; Galactose; Glucose; Glutathione; Goals; Heme Group; Hemochromatosis; Hemoglobin; HepG2; Hepatocyte; Hepatotoxicity; Homeostasis; Hospitalization; Human; Immune; In Vitro; Incidence; Industry; Infiltration; Injury; International; Iron; Lipid Peroxidation; Liver; Mediating; Membrane; Membrane Lipids; Methodology; Mitochondria; Modeling; N-acetyl-4-benzoquinoneimine; National Center for Advancing Translational Sciences; Organ; Organelles; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Oxidative Stress Induction; Oxygen; Parents; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Positioning Attribute; Prevention; Procedures; Production; Publications; Pump; Qualifying; Reactive Oxygen Species; Reperfusion Injury; Reporting; Respiration; Risk; Risk Reduction; Role; Running; Safety; Small Business Innovation Research Grant; Specificity; Standardization; Stress; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Toxic effect; Triage; adaptive immunity; adverse drug reaction; analog; bile salts; cell growth; cell injury; clinical decision-making; commercialization; cytokine; cytotoxicity; drug induced liver injury; drug metabolism; drug testing; drug withdrawal; extracellular vesicles; glutathione peroxidase; heme a; human model; in vitro Assay; in vitro testing; in vivo; inhibitor; injury prevention; innovation; insight; liver injury; liver ischemia; liver transplantation; microphysiology system; nitrosative stress; oxidation; peripheral blood; post-market; predictive test; response; success; temporal measurement

Drug induced liver injury (DILI) is a concern for patients, clinicians, the FDA, and the pharmaceutical industry as the leading cause of clinical drug attrition and post-marketing drug withdrawals. According to the FDA, DILI has been the most frequent cause of safety-related drug withdrawals for the past 50 years. As a potential solution to the problem, the IQ-MPS Affiliate to the International Consortium for Innovation and Quality in Pharmaceutical Development highlighted the need to qualify human liver microphysiological systems (MPS) for DILI context of use (CoU) with a set of pragmatic engineering and quality requirements for the MPS implementation into standard operating procedures. During an ongoing NCATS SBIR, Lena Biosciences (LB) developed and commercialized an SLAS-standardized, Perfused Organ Panel MPS that meets these prerequisites. The ultimate goal of this SBIR is to qualify the MPS with a revolutionary synthetic hemoglobin, Blood Substitute, for DILI CoU using the guidance of the FDA CDER and the IQ-MPS Affiliate. Our recent publication (Front. Mol. Biosci. 2020) shows that the MPS restores cellular oxidative metabolism in diverse, perfused, 3D liver models, significantly increasing cell respiration by mitochondrial electron transport chain, CYP450 oxidation required for metabolism of drugs, and OXPHOS ATP production required for holistic cell function, and all cell processes from active transport of molecules across the cell membrane to organelle function. An OXPHOS-competent model of cellular redox homeostasis will provide in vivo-like cell sensitivity to drugs and their reactive metabolites and free radicals, and drug-induced oxidative and nitrosative stress that leads to the loss of cellular antioxidant defense for comprehensive characterization of DILI threats, positioning the MPS to adequately meet biological qualification prerequisites for DILI CoU. While numerous factors contributing to DILI have been reported, to date there is no consensus on the rank of these factors for in vitro testing using primary human cells, and on the types of in vitro assays that are the most relevant for DILI prevention. Therefore, in this SBIR we will focus on testing those compounds that the drug industry found the most difficult to de-risk, examine the role of oxidative cell stress in the sequence of cellular events that lead to DILI, provide mechanism-informative insight into the DILI sequelae using a battery of assays to isolate the trigger(s) and identify causalities, and resolve temporal and log-fold change in biomarkers, including the FDA-designated biomarkers for clinical exploration, relative to vehicle controls and in relation with the coinciding rise of ALT and ALP, clinical DILI biomarkers, in order to isolate those with the highest log-fold change and specificity at low or moderate ALT. To successfully carry out the studies and ensure the project’s success, we have assembled a team of experts in advanced, OXPHOS-competent cell cultures (LB), and predictive screening of drug-induced livery injury (Dr. Salman Khetani, UIC).

药物诱导的肝损伤（DILI）是患者，临床医生，FDA和制药行业的关注点 作为临床药物流失和营业后药物提取的主要原因。根据FDA的说法 在过去的50年中，一直是与安全有关的药物提取的最常见原因。作为潜力 解决该问题的解决方案，智商-MPS隶属于国际创新和质量联盟 药物开发强调了有必要有资格的人肝微生物生理系统（MPS） 使用一组务实的工程和质量要求的DILI使用上下文（COU） 实施标准操作程序。在正在进行的NCATS SBIR中，Lena Biosciences（LB） 开发和商业化了一个符合这些的SLAS标准化的灌注器官面板议员 先决条件。该SBIR的最终目标是通过革命性的合成血红蛋白限定国会议员， 鲜血替代，使用FDA CDER和IQ-MPS分支机构的指导进行DILI COU。 我们最近的出版物（Front。Mol。Biosci。2020）表明，MPS恢复了细胞氧化物的代谢 潜水员，灌注的3D肝模型，通过线粒体传输显着增加细胞呼吸 链，CYP450药物代谢所需的氧化以及整体所需的OXPHOS ATP产生 细胞功能，以及从分子在整个细胞膜上的主动转运到细胞器的所有细胞过程 功能。细胞氧化还原稳态的能力竞争模型将在体内样细胞敏感性对 药物及其反应性代谢产物和自由基，以及药物诱导的氧化和硝化胁迫， 导致细胞抗氧化剂防御的丧失，以全面地表征DILI威胁，定位 国会议员充分满足DILI COU的生物学资格先决条件。 尽管已经报道了许多导致DILI的因素，但迄今为止，尚无共识 这些用于使用原代人细胞进行体外测试的因素，以及最多的体外测定类型 与预防DILI有关。因此，在此SBIR中，我们将专注于测试该药物的化合物 行业发现最难去风险，检查氧化细胞应激在细胞序列中的作用 导致DILI的事件，通过一组电池对DILI后遗症提供机制信息的见解 分离触发因素并识别因果关系的测定法，并解决临时和对数折叠的变化 生物标志物，包括用于临床探索的FDA指定的生物标志物，相对于车辆控制和IN 与ALT和ALP的重合升高，临床DILI生物标志物的关系，以分离患有 低或中等替代处的最高对数折变和特异性。 为了成功进行研究并确保项目的成功，我们组建了一个专家团队 在晚期，具有OXPHOS功能的细胞培养物（LB）和药物诱导的肝损伤的预测性筛查（Dr. Salman Khetani，UIC）。