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

药物性肝损伤(DILI)是患者、临床医生、FDA和制药行业关注的问题 作为临床药物损耗和上市后药物停药的主要原因。根据FDA的说法，帝力 在过去的50年里，它是与安全相关的药物停用最常见的原因。作为一种潜力 问题的解决方案，智商-MPS附属于#年国际创新和质量联盟 药物开发强调了对人类肝脏微生理系统(MPS)进行鉴定的必要性 帝力使用环境(CUU)和一套实用的MPS工程和质量要求 落实到标准操作程序中。在正在进行的NCATS SBIR期间，Lena Biosciences(LB) 开发并商业化SLAS标准化的灌流器官面板MPS，以满足以下要求 必备条件。这种SBIR的最终目标是用一种革命性的合成血红蛋白来鉴定MPS， 血液替代品，在FDA CDER和IQ-MPS附属机构的指导下用于迪丽库。 我们最近出版的出版物(Front.摩尔。比奥西。2020)表明，MPS恢复了细胞的氧化代谢 多样化的、灌流的3D肝脏模型，通过线粒体电子传递显著增加细胞呼吸 链，药物代谢所需的CYP450氧化，以及整体所需的OXPHOS ATP产生 细胞的功能，以及所有的细胞过程，从分子通过细胞膜到细胞器的主动运输 功能。细胞氧化还原动态平衡的OXPHOS活性模型将在体内提供类细胞对 药物及其活性代谢物和自由基，以及药物引起的氧化和亚硝化应激 导致细胞抗氧化防御丧失，全面表征帝力威胁，定位 MPS要充分满足迪丽考的生物资格先决条件。 虽然有许多因素对帝力的影响进行了报道，但到目前为止还没有关于 这些因素用于使用原代人类细胞进行体外测试，并对大多数体外测试类型进行 与帝力预防相关。因此，在这篇SBIR中，我们将重点测试那些药物 业界发现最难去风险的，是检查氧化细胞应激在细胞序列中的作用 导致帝力的事件，通过使用一组 分析以隔离触发因素(S)并确定因果关系，并解决时间和对数倍的变化 生物标志物，包括FDA指定的用于临床探索的生物标志物，相对于车辆控制和 与ALT、ALP同步升高及临床DILI生物标志物的关系 低或中度ALT的对数倍数变化和特异度最高。 为了成功地进行研究，确保项目的成功，我们组建了一个专家团队 在晚期，OXPHOS活性细胞培养(LB)和药物诱导的制服损伤的预测性筛查(Dr。 萨尔曼·赫塔尼，UIC)。

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).