Multi-Tissue MAFLD Chip for Mechanism-Based Drug Testing

用于基于机制的药物测试的多组织 MAFLD 芯片

• 批准号: 10484325
• 负责人: Murat Cirit
• 金额: $ 31.48万
• 依托单位: JAVELIN BIOTECH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10484325
• 关键词: Address; Adipose tissue; Adult; Affect; Animal Model; Animals; Area; Autopsy; Benchmarking; Biochemical Pathway; Biological; Bioreactors; Biotechnology; Businesses; Cells; Clinical; Collaborations; Combined Modality Therapy; Complex; Data; Developed Countries; Development; Disease; Disease Progression; Disease model; Drug Combinations; Drug Industry; Drug Targeting; Elements; Ethics; Etiology; Exhibits; FDA approved; Failure; Fee-for-Service Plans; Fibrosis; Functional disorder; Gene Expression; Genetic; Human; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; In Vitro; Inflammation; Insulin Resistance; Lipolysis; Literature; Liver; Liver diseases; Metabolic; Microfluidics; Modeling; Molecular; Molecular Disease; Molecular Target; Morbidity - disease rate; Multiomic Data; Organ; Outcome; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phenotype; Physiological; Play; Pre-Clinical Model; Process; Program Development; Role; Sales; Signal Transduction; Steatohepatitis; Systems Biology; Technology; Testing; Therapeutic; TimeLine; Tissue Microarray; Tissues; Treatment Efficacy; Visceral; adipokines; base; combinatorial; cost; design; disease phenotype; drug development; drug discovery; drug efficacy; drug mechanism; drug testing; efficacy evaluation; genome-wide; gut dysbiosis; gut-liver axis; hemodynamics; human tissue; improved; in vitro Model; insight; lead optimization; metabolic-associated fatty liver disease; metabolomics; microbial; microphysiology system; mortality; multiple omics; network models; non-alcoholic fatty liver disease; novel; phase III trial; phenotypic biomarker; platform as a service; pre-clinical; success; targeted treatment; therapeutic target; transcriptomics

Project Summary Metabolic-associated fatty liver disease (MAFLD) is a pathophysiological spectrum disorder affecting 20- 40% of adults in developed countries. MAFLD etiology is complex, influenced by multiple organs, environmental, and genetic factors in what is referred to as the “multiple parallel-hit model” of disease. Dysregulated metabolic signals axes (e.g., gut-liver and liver-adipose) and pathways (e.g., peripheral insulin resistance (IR)) are elements of the multi-hit model that drive the development and progression of MAFLD hallmarks including steatosis, steatohepatitis, and fibrosis. As of today, there are no FDA-approved therapies specific for MAFLD/NAFLD. Dozens of companies have invested in MAFLD drug development programs competing to be first-to-market with a treatment. However, recent high-profile failures of Phase III trials highlight the challenge to win approval for monotherapies to treat MAFLD. Given the pathological complexity of MAFLD and the limited efficacy of mono-therapeutic approaches, the pharmaceutical industry has begun to develop strategies for combinatorial therapies that will engage several targets/pathways simultaneously to improve the clinical outcomes. One of the major challenges in the identification of drug combinations to treat MAFLD is the limitation of the current preclinical drug discovery platforms for complex diseases. While animal models are commonly used in late drug discovery phase, they are not suitable for “exploratory” combinatorial studies due to cost and ethical concerns. On the other hand, current in vitro models of MAFLD are designed to investigate liver only pathophysiologies. To address this limitation, we propose developing an interconnected liver-adipose MAFLD tissue chip to test drugs and drug combinations targeting mechanistic drivers of disease in the context of the gut-liver-adipose (GLA) signaling axis. This drug testing platform combines a liver-adipose microphysiological system (MPS) that recreates key aspects of the multi-hit hypothesis of MAFLD in the context of GLA signaling axis, and systems biology (SB)-based workflows to evaluate mono- and combinatorial therapies’ efficacy and mechanism of action. The drugs and drug combination will be tested on tissue chips for their efficacy and the results, both phenotypic and multi-omics, will be used with our systems biology-based computational workflow - genome-scale metabolic network models (GEMs) to gain mechanistic insights. GEMs will be constructed and validated using transcriptomics and metabolomics data, respectively. We believe that our platform will enable mechanism-based drug efficacy evaluation for mono- and combination therapies at the preclinical discovery stage prior to animal studies. This will reduce the cost and timeline to identify combination therapies for MAFLD and improve long-term clinical outcomes.

项目概要 代谢相关脂肪肝病 (MAFLD) 是一种影响 20- 发达国家40%的成年人MAFLD病因复杂，受多器官、环境、 以及所谓的“多重平行打击模型”疾病中的遗传因素。 信号轴（例如，肠道-肝脏和肝脏-脂肪）和途径（例如，外周胰岛素抵抗（IR）） 推动 MAFLD 标志发展和进步的多重命中模型的要素包括 脂肪变性、脂肪性肝炎和纤维化。 截至目前，数十家公司还没有 FDA 批准的针对 MAFLD/NAFLD 的疗法。 已投资 MAFLD 药物开发项目，竞相率先将治疗方法推向市场。 最近引人注目的 III 期试验失败凸显了单一疗法获得批准所面临的挑战 鉴于 MAFLD 的病理复杂性和单一治疗方法的疗效有限， 制药行业已开始制定组合疗法战略，该战略将涉及多个领域 同时调整目标/途径以改善临床结果。 确定治疗 MAFLD 的药物组合的主要挑战之一是药物组合的局限性 目前针对复杂疾病的临床前药物发现平台通常使用动物模型。 在药物发现后期，由于成本和伦理原因，它们不适合“探索性”组合研究 另一方面，目前的 MAFLD 体外模型仅用于研究肝脏。 病理生理学。 为了解决这一限制，我们建议开发一种互连的肝脏脂肪 MAFLD 组织芯片 针对肠道-肝脏-脂肪背景下疾病的机械驱动因素的测试药物和药物组合 (GLA) 信号轴。该药物测试平台结合了肝脏脂肪微生理系统 (MPS)， 在 GLA 信号轴和系统的背景下重建 MAFLD 多重打击假设的关键方面 基于生物学 (SB) 的工作流程，用于评估单一疗法和组合疗法的功效和作用机制。 该药物组合将在组织芯片上测试其功效和结果，包括表型 和多组学，将与我们基于系统生物学的计算工作流程 - 基因组规模代谢一起使用 将使用网络模型（GEM）来构建和验证以获得机制见解。 分别是转录组学和代谢组学数据。 我们相信，我们的平台将能够实现基于机制的单一药物和药物疗效评估。 在动物研究之前的临床前发现阶段进行联合疗法，这将降低成本和效果。 确定 MAFLD 联合疗法并改善长期临床结果的时间表。