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.

项目总结