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.

项目摘要 代谢相关性脂肪肝（MAFLD）是一种影响20- 30岁儿童的病理生理学谱系疾病。 发达国家40%的成年人。MAFLD病因复杂，受多器官、环境、 和遗传因素，这被称为疾病的“多重平行打击模型”。代谢失调 信号轴（例如，肠-肝和肝-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打击模式的要素，包括 脂肪变性、脂肪性肝炎和纤维化。 到目前为止，还没有FDA批准的MAFLD/NAFLD特异性治疗方法。数十家公司 已经投资于MAFLD药物开发项目，竞争成为第一个上市的治疗。然而，在这方面， 最近备受瞩目的III期试验失败突出了获得批准的单一疗法治疗的挑战， MAFLD。鉴于MAFLD的病理复杂性和单一治疗方法的有限功效， 制药工业已经开始开发组合疗法的策略， 同时实现目标/途径，以改善临床结果。 鉴定治疗MAFLD的药物组合的主要挑战之一是药物组合的局限性。 目前用于复杂疾病的临床前药物发现平台。虽然动物模型通常用于 在后期药物发现阶段，由于成本和伦理原因，它们不适合于“探索性”组合研究 性问题另一方面，目前MAFLD的体外模型被设计为仅研究肝脏 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， 在肠-肝-脂肪系统的背景下靶向疾病的机制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信号传导轴的背景下重新创建MAFLD的多击假设的关键方面， 生物学（SB）为基础的工作流程，以评估单一和组合疗法的疗效和作用机制。 药物和药物组合将在组织芯片上测试其功效和结果， 和多组学，将与我们的系统生物学为基础的计算工作流程-基因组规模的代谢 网络模型（GEM），以获得机械的见解。GEM将使用 转录组学和代谢组学数据。 我们相信，我们的平台将使基于机制的药物疗效评价的单， 在动物研究之前的临床前发现阶段的联合治疗。这将降低成本， 确定MAFLD联合治疗和改善长期临床结局的时间轴。