Multi-organ human-on-a-chip system to address overdose and acute and chronic efficacy and off-target toxicity

多器官人体芯片系统解决用药过量、急慢性疗效和脱靶毒性问题

• 批准号: 10351973
• 负责人: James J Hickman
• 金额: $ 238.14万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-27 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351973
• 关键词: Multi; organ; human; chip; system

Project Summary Addiction to pain medications, especially opiates, has become a major health problem and systems to guide the understanding of repeat overdose treatments are needed. Our proposal seeks to build overdose models for four drugs (fentanyl, methadone, codeine, and morphine) in a multi-organ system and evaluate the acute and repeat dose, or chronic effects, of overdose treatments such as Naloxone on overdose recovery, efficacy as well as off-target toxicity for cardiac, muscle, kidney and liver. We have developed a low cost system using human cells in a pumpless multi-organ platform that allows continuous recirculation of a blood surrogate for up to 28 days. This system emulates the distribution of a parental compound and the formation of metabolites among all “organ” compartments and predicts potential toxicity and efficacy of drugs better than in vitro single human organ or animal models. We will develop two different overdose models for both male and female phenotypes based on nociceptors and B?tzinger Complex (B?tC) neurons as they contain µ-opioid receptors but are thought to have different roles in response to overdose and treatment. We will also integrate functional immune components in the UH3 Phase that has been demonstrated to enable organ specific or systemic monocyte actuation. In addition, models for cardiomyopathy and an infection model will be utilized to more accurately represent the effects of therapeutics on comorbidities. We will establish a PKPD in vitro model of overdose and treatment to enable prediction in clinical environments for a range of variables including age and drug-drug interactions. Once established the system could be used to evaluate novel pain therapeutics for efficacy and off-target toxicity as well as additional overdose treatments in future studies. Interconnected systems with continuous recirculation of a blood surrogate allows both the parent compound and its metabolites to be evaluated in the same system since it is a low volume platform. This interconnected system is better suited for preclinical drug testing than single organ systems for the same reason that human and animal models are currently the gold standards for toxicity and efficacy determination as they allow communication between the organ systems in the body. To construct a well defined system we will use a common serum free medium with microelectrode arrays and cantilever systems that are integrated on chip that allow for noninvasive electronic and mechanical readouts of organ function. UCF and Hesperos in collaboration with clinicians seek to radically change established practice in drug discovery by bypassing animal experiments and extensive clinical trials to provide treatments for diseases and clinical conditions such as overdose. We have already been working with regulatory authorities to prepare for eventual acceptance of the systems for regular use in INDs. Since Hesperos is already offering multi-organ evaluations as a service to the pharmaceutical industry and clinicians there is a direct translational element in the proposal.

项目概要 止痛药成瘾，尤其是阿片类药物成瘾，已成为一个主要的健康问题和指导系统 需要了解重复用药过量治疗的情况，我们的建议旨在建立用药过量模型。 四种药物（芬太尼、美沙酮、可待因和吗啡）在多器官系统中的作用，并评估急性和 纳洛酮等过量治疗的重复剂量或慢性影响对过量恢复、疗效以及 作为对心脏、肌肉、肾脏和肝脏的脱靶毒性，我们开发了一种利用人体的低成本系统。 无泵多器官平台中的细胞允许血液代用品连续再循环长达 28 该系统模拟母体化合物的分布和代谢物在所有化合物中的形成。 “器官”区室并比体外单个人体器官更好地预测药物的潜在毒性和疗效 我们将针对男性和女性表型开发两种不同的过量模型。 作用于伤害感受器和 B?tzinger Complex (B?tC) 神经元，因为它们含有 µ-阿片受体，但被认为 在应对药物过量和治疗方面发挥不同的作用，我们还将整合功能性免疫成分。 已被证明能够实现器官特异性或全身性单核细胞激活的 UH3 阶段。 此外，将利用心肌病模型和感染模型来更准确地表示 我们将建立 PKPD 过量和治疗的体外模型。 能够在临床环境中预测一系列变量，包括年龄和药物相互作用。 建立的系统可用于评估新型疼痛疗法的功效和脱靶毒性 以及未来研究中的额外过量治疗与连续再循环的互连系统。 血液替代品允许在同一系统中评估母体化合物及其代谢物 由于它是一个小容量平台，因此该互连系统比临床前药物测试更适合。 出于同样的原因，人类和动物模型是目前单器官系统的黄金标准 毒性和功效测定，因为它们允许体内器官系统之间的通信。 构建一个明确的系统，我们将使用带有微电极阵列的常见无血清培养基和 集成在芯片上的悬臂系统，允许非侵入性电子和机械读数 UCF 和 Hesperos 合作，寻求从根本上改变既定做法。 通过绕过动物实验和广泛的临床试验来进行药物发现，以提供疾病治疗方法 我们已经与监管机构合作做好准备。 由于 Hesperos 已经提供多器官，因此接受系统在 IND 中的常规使用。 评估作为为制药行业和上级提供的服务，其中存在直接转化因素 该提案。