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

摘要 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，排在第9位。 在美国是主要的死因，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一直少于所有其他专业的内部 成功率非常低的药物，可能是由于肾脏的结构和功能复杂所致。这个 以肾小球滤过为特征的多细胞结构和不同寻常的三重生理过程， 肾小管分泌和肾小管重吸收限制了动物模型概括多样性的能力。 大多数人类肾脏疾病的病因、机制和异质性表现。另外， 直到最近，还缺乏概括肾脏生理学关键方面的体外模型， 模仿特定肾单位节段的独特复杂性，或评估修复机制 致伤。为了满足这一关键的未得到满足的需求，我们团队率先开发了人类肾脏 芯片上的微生理系统(MPS)。我们用于体外疾病建模的集成方法包括 从疾病患者来源的可诱导多能干细胞中分化出人肾细胞和类器官 (IPSCs)、CRISPR基因编辑、单细胞转录图谱和工程MPS平台 活体人肾血管网和肾小管单位。这种方法已经带领我们实现了新的 常染色体显性遗传性多囊肾病发病机制的机制探讨 肾功能衰竭的单基因原因)和潜在的新治疗途径。同时，做出了重大努力 由我们领导的研究正在肾病综合征研究网络(称为海王星)和肾脏 美国国立卫生研究院资助的旨在解决肾脏功能异质性的精密医学项目 肾脏疾病的严格分子、组织学和表型特征。NCATS 罕见病临床网络海王星通过匹配个体来测试精准医学概念 从患者到靶向治疗试验的分子图谱。我们现在建议利用这些领域领先的 为临床试验设计和计划提供信息的工具，考虑到人类遗传和临床反应 PKD和局灶节段性肾小球硬化(FSGS)的异质性，肾病综合征的形式 最严重的病人后果。根据我们的数据，我们假设芯片上的肾脏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建立强有力的分子和细胞基础。我们有 建立了一支拥有所有领域领先专业知识的多学科调查团队，以解决 技术和实验挑战。

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.