A vascularized patient-derived iPSC liver acinus microphysiology system as an innovative precision medicine platform for optimizing clinical trial design for nonalcoholic fatty liver disease

血管化的患者来源的iPSC肝腺泡微生理学系统（vLAMPS）是一种 创新的精准医学平台，用于优化非酒精性脂肪肝的临床试验设计 肝病（NAFLD）。非酒精性脂肪肝（NAFLD）是一种主要的健康危机， 批准的治疗方法和许多临床失败。据估计，NAFLD的患病率 从2015年占美国人口的25%（约8300万）增加到2030年的1亿多， 伴随非酒精性脂肪性肝炎（NASH）的增加，NASH是肝硬化的进行性形式。 疾病，可导致肝硬化伴肝功能衰竭和肝细胞癌（HCC）。尽管 由于其公共卫生的重要性，目前还没有FDA批准的治疗任何阶段的 NAFLD。NAFLD/NASH是一种复杂的异质性疾病， 途径。有效药物治疗的发展受到有限的 临床前药物测试模型的实用性。简单的细胞培养和动物模型不能 概括了人类NASH表型的谱。突出这些物种 差异，具有高风险NASH相关遗传多态性的敲入小鼠模型， PNPLA 3 I148 M，发生肝脂肪变性，但不重现所见的进行性疾病 在人类身上。此外，NASH进展风险的异质性、个体遗传性、 调节纤维化进展风险的变异，以及NAFLD相关代谢产物的存在， 合并症，如2型糖尿病（T2 DM），增加了额外的复杂性。我们将 实施vLAMPS以初始表征“正常”和NAFLD/NASH vLAMPS 从原代人肝细胞（肝细胞、肝窦内皮细胞、星状细胞）产生 和Kupffer细胞），然后用诱导多能干细胞（iPSC）再现结果。 我们最终将从我们的研究中的患者中产生四种细胞类型的患者特异性iPSC。 NAFLD诊所创建患者特异性vLAMPS。我们将测试两个群组：1）患有 2）具有野生型PNPLA 3的患者，以鉴定以下患者： 对两种已经或正在进行临床试验的NAFLD药物和两种对照药物有反应， 毒品重要的是，这种模式规避了高危患者被 入组大型长期研究，失败的可能性很高，同时 取消参加其他潜在有益研究/治疗的资格。这种方法将证明 通过丰富最有可能受益于 治疗，并在未来，超过一个目前的研究药物被批准后， 精准医疗，以确定最有效的治疗高风险亚组。

A vascularized patient-derived iPSC liver acinus microphysiology system (vLAMPS) is an innovative precision medicine platform for optimizing clinical trial design for nonalcoholic fatty liver disease (NAFLD). Non-alcoholic fatty liver disease (NAFLD) is a major health crisis with no approved therapeutics and many failures in the clinic. The prevalence of NAFLD is estimated to increase from 25% of the US population in 2015 (~83 million) to over 100 million by 2030, accompanied by an increase in nonalcoholic steatohepatitis (NASH), the progressive form of the disease, that can lead to cirrhosis with liver failure and hepatocellular carcinoma (HCC). Despite its public health importance, there is currently no FDA-approved therapy for any stage of NAFLD. NAFLD/NASH is a complex heterogeneous disorder involving multiple molecular pathways. Development of efficacious pharmacotherapy has been hampered by the limited utility of preclinical drug testing models. Simple cell culture and animal models do not recapitulate the spectrum of NASH phenotypes in humans. Highlighting these species differences, knock-in murine models with the high-risk NASH-associated genetic polymorphism, PNPLA3 I148M, develop hepatic steatosis but do not recapitulate the progressive disease seen in humans. Additionally, heterogeneity in risk of progression of NASH, individual genetic variations modulating risk of fibrosis progression, and presence of NAFLD-associated metabolic comorbidities such as Type 2 diabetes mellitus (T2DM), adds additional complexity. We will implement the vLAMPS to initially characterize both a “normal” and a NAFLD/NASH vLAMPS generated from primary human liver cells (hepatocytes, liver sinusoidal endothelial cells, stellate and Kupffer cells) and then reproduce the results with induced pluripotent stem cells (iPSCs). We will ultimately generate patient-specific iPSCs of the four cell types from patients in our NAFLD clinic to create patient-specific vLAMPS. We will test two cohorts: 1) patients with the PNPLA3 I 148M variant and 2) patients with the wild-type PNPLA3 to identify the patients who respond to two NAFLD drugs that have or are now going through clinical trials and two control drugs. Importantly, this paradigm circumvents the conundrum of high-risk patients being enrolled in large prolonged studies with a high likelihood of failure being simultaneously disqualified from other potentially beneficial studies/treatments. This approach will prove transformational for clinical trial design by enriching for subjects most likely to benefit from a therapy, and in the future, after more than one currently investigational drugs are approved, for precision medicine to identify the most efficacious therapy for high-risk subgroups.