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IPSC肝腺泡微生理学系统(VLAMPS)是一种 优化非酒精性脂肪临床试验设计的创新精准医学平台 肝病(NAFLD)。非酒精性脂肪性肝病(NAFLD)是一种主要的健康危机，没有 批准的治疗方法和临床上的许多失败。据估计，非酒精性脂肪肝的患病率为 从2015年占美国人口的25%(约8300万)增加到2030年的1亿以上， 伴随着非酒精性脂肪性肝炎(NASH)的增加，进行性形式的 疾病，可导致肝硬变并肝功能衰竭和肝细胞癌。尽管 它的公共卫生重要性，目前还没有FDA批准的治疗任何阶段的 NAFLD。NAFLD/NASH是一种涉及多个分子的复杂的异质性疾病 小路。有效药物治疗的发展一直受到有限的限制 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 概括一下人类的NASH表型谱。突出这些物种 差异，敲入具有高风险NASH相关基因多态的小鼠模型， PNPLA3 I148M，发生肝脏脂肪变性，但不能概括所见的进展性疾病 在人类身上。此外，NASH进展风险的异质性、个体基因 调节纤维化进展风险的变异和NAFLD相关代谢的存在 合并症，如2型糖尿病(T2 DM)，增加了复杂性。我们会 实施vLAMPS以初始地描述“正常”和NAFLD/NASH vLAMPS 由原代人肝细胞(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(IPSCs)重现结果。 我们最终将从我们的患者中生成四种细胞类型的患者特定的IPSCs NAFLD诊所创建特定于患者的vLAMPS。我们将测试两个队列：1)患有 PNPLA3I148M变异体和2)携带野生型PNPLA3的患者 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的反应 毒品。重要的是，这一范例绕过了高危患者 参加大规模的长期研究，同时失败的可能性很高 被取消了其他可能有益的研究/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，以及在未来，在一种以上目前正在研究的药物获得批准后，用于 精准医学为高危人群确定最有效的治疗方法。

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.