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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.

摘要