Safety and Efficacy of Human Clinical Trials Using Kidney-on-a-Chip Microphysiological Systems

使用芯片肾微生理系统进行人体临床试验的安全性和有效性

基本信息

批准号：
10037553
负责人：
Jonathan Himmelfarb
金额：
$ 81.87万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10037553
关键词：
Accounting Address Affect Animal Model Architecture Autosomal Dominant Polycystic Kidney Bioinformatics Biological Models Biology Biomedical Engineering Biomedical Research Biometry Blood Vessels Cause of Death Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Clinical Clinical Trials Clinical Trials Design Clustered Regularly Interspaced Short Palindromic Repeats Complex Computational Biology Data Development Devices Disease Disease model Engineering Etiology Expenditure Failure Focal Segmental Glomerulosclerosis Funding Gene Expression Profiling Genes Genetic Genomics Goals Heterogeneity Histologic Histopathology Human Human Genetics Image In Vitro Individual Internal Medicine Kidney Kidney Diseases Kidney Failure Medicare Microfluidics Modeling Modernization Molecular Molecular Profiling Molecular and Cellular Biology Natural History Nephrology Nephrons Nephrotic Syndrome Organoids Outcome Pathogenesis Pathology Pathway interactions Patients Pharmacology and Toxicology Phenotype Physiological Physiological Processes Physiology Pluripotent Stem Cells Polycystic Kidney Diseases Public Health Publishing Randomized Clinical Trials Rare Diseases Reporting Resources Safety Structure System Taxonomy Technology Testing Therapeutic Tissue Microarray Translating Triad Acrylic Resin Tubular formation United States National Institutes of Health base biomarker discovery biomarker evaluation clinical phenotype clinically relevant cohort design drug development effective therapy glomerular filtration in vitro Model in vivo insight kidney cell kidney vascular structure materials science medical specialties microphysiology system model development multidisciplinary novel novel therapeutics organ on a chip outcome prediction patient response patient stratification phenotypic data precision medicine profiles in patients protocol development response response to injury stem cell biology success targeted therapy trials therapeutic evaluation tool

项目摘要

ABSTRACT Kidney diseases are an expanding public health problem, currently affecting 37 million people and are the 9th leading cause of death in the US, while disproportionately accounting for ~27% of Medicare expenditures. Unfortunately, the number of randomized clinical trials has been fewer than all other specialties of internal medicine with very low success rates, likely due to the structural and functional complexity of the kidney. The multicellular architecture and unusual triad of physiological processes characterized by glomerular filtration, tubular secretion, and tubular reabsorption have limited the ability of animal models to recapitulate the diversity of etiologies, mechanisms, and heterogenous manifestations of most human kidney diseases. Additionally, until recently there has been a lack of in vitro models that recapitulate critical aspects of kidney physiology, mimic the unique complexities of specific nephron segments, or assess reparative mechanisms in response to injury. In response to this critical unmet need, our group has pioneered the development of `human kidney on a chip' microphysiological systems (MPS). Our integrated approach for in vitro disease modeling includes differentiating human kidney cells and organoids from diseased patient-derived inducible pluripotent stem cells (iPSCs), CRISPR gene editing, single cell transcriptional profiling and engineered MPS platforms for both living human kidney vascular networks and tubular units. This approach has already led us to achieve new mechanistic insights into the pathogenesis of autosomal dominant polycystic kidney disease (PKD, the leading monogenetic cause of kidney failure) and potential new therapeutic pathways. In parallel, significant efforts led by us are underway in the Nephrotic Syndrome Study Network (known as NEPTUNE) and the Kidney Precision Medicine Project, NIH funded Consortia designed to address the functional heterogeneity of kidney disease by rigorous molecular, histologic and phenotypic characterization of kidney diseases. The NCATS Rare Disease Clinical Network NEPTUNE is testing the precision medicine concept by matching individual molecular profiles from patients to targeted therapy trials. We now propose to leverage these field-leading tools to inform clinical trial design and planning, accounting for human genetic and clinical response heterogeneity for PKD and Focal Segmental Glomerulosclerosis (FSGS), the form of nephrotic syndrome with the most severe patient consequences. Based on our data, we hypothesize that kidney-on-a-chip MPS will manifest patient-specific phenotypic responses in vitro commensurate with clinical trial outcomes in vivo, establishing a robust molecular and cellular basis for kidney precision medicine approaches. We have established a multidisciplinary investigative team with all the field-leading expertise needed to address all technical and experimental challenges.

抽象的肾脏疾病是一个日益严重的公共卫生问题，目前影响着 3700 万人，是第九大公共卫生问题。是美国主要的死亡原因，同时不成比例地占医疗保险支出的 27%。不幸的是，随机临床试验的数量少于内科所有其他专业。成功率非常低的药物，可能是由于肾脏结构和功能的复杂性。这多细胞结构和以肾小球滤过为特征的不寻常的生理过程三联体，肾小管分泌和肾小管重吸收限制了动物模型重现多样性的能力大多数人类肾脏疾病的病因、机制和异质性表现。此外，直到最近，还缺乏概括肾脏生理学关键方面的体外模型，模仿特定肾单位段的独特复杂性，或评估响应的修复机制以致受伤。为了满足这一未满足的关键需求，我们的团队率先开发了“人类肾脏” 芯片上的微生理系统（MPS）。我们的体外疾病建模综合方法包括将人肾细胞和类器官与患病患者来源的诱导多能干细胞区分开来 (iPSC)、CRISPR 基因编辑、单细胞转录分析和工程 MPS 平台活的人类肾脏血管网络和管状单位。这种方法已经引导我们实现了新的目标对常染色体显性多囊肾病（PKD，领先的肾衰竭的单基因原因）和潜在的新治疗途径。与此同时，重大努力由我们领导的肾病综合征研究网络（称为 NEPTUNE）和肾脏正在进行中 NIH 资助的精准医学项目旨在解决肾脏功能异质性问题通过对肾脏疾病进行严格的分子、组织学和表型表征来诊断疾病。国家CATS 罕见病临床网络 NEPTUNE 正在通过匹配个人来测试精准医疗概念从患者的分子概况到靶向治疗试验。我们现在建议利用这些领域领先的为临床试验设计和规划提供信息、考虑人类遗传和临床反应的工具多囊肾 (PKD) 和局灶节段性肾小球硬化 (FSGS) 的异质性，这是肾病综合征的一种形式最严重的患者后果。根据我们的数据，我们假设肾芯片 MPS 将在体外表现出与体内临床试验结果相称的患者特异性表型反应，为肾脏精准医学方法奠定坚实的分子和细胞基础。我们有建立了一个多学科调查团队，拥有解决所有问题所需的所有领域领先的专业知识技术和实验挑战。