Previous studies have shown that human liver stem-like cells (HLSCs) may undergo differentiation in vitro into urea producing hepatocytes and in vivo may sustain liver function in models of experimentally induced acute liver injury. The aim of this study was to assess the safety of HLSCs intrahepatic administration in inherited neonatal-onset hyperammonemia. The study was approved by the Agenzia Italiana del Farmaco on favorable opinion of the Italian Institute of Health as an open-label, prospective, uncontrolled, monocentric Phase I study (HLSC 01–11, EudraCT-No. 2012–002120-33). Three patients affected by argininosuccinic aciduria (patient 1) and methylmalonic acidemia (patients 2 and 3) and included in the liver transplantation list were enrolled. In all patients, HLSCs were administered by percutaneous intrahepatic injections (once a week for two consecutive weeks) within the first months of life. The first patient received 125,000 HLSCs x gram of liver/dose while the other two patients received twice this dose. No immunosuppression was administered since HLSCs possess immunomodulatory activities. None of the patients experienced infections, hyperammonemia decompensation, or other adverse events during the whole observation period. No donor specific antibodies (DSA) against HLSCs were detected. Patients were metabolic stable despite an increase (~30%) in protein intake. Two patients underwent liver transplantation after 19 and 11 months respectively, and after explantation, the native livers showed no histological alterations. In conclusion, percutaneous intrahepatic administration of HLSCs was safe in newborn with inherited neonatal-onset hyperammonemia. These data pave the way for Phase II studies in selected inherited and acquired liver disorders.

中文翻译：

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患有遗传性新生儿发作性高氨血症的婴儿的肝干细胞肝内给药：I期研究。

先前的研究表明，人肝干样细胞（HLSC）可能在体外分化为产生尿素的肝细胞，并且在实验诱导的急性肝损伤模型中，体内可能维持肝功能。这项研究的目的是评估HLSCs肝内给药在遗传性新生儿高氨血症中的安全性。这项研究得到了意大利卫生研究院的青睐，并获得了意大利卫生研究院的认可，它是一项开放性，前瞻性，不受控制的单中心I期研究（HLSC 01-11，EudraCT-No.2012-002120-33）。纳入了三例受精氨酸琥珀酸尿症（患者1）和甲基丙二酸血症（患者2和3）影响并被列入肝移植清单的患者。在所有患者中 在生命的头几个月内，经皮肝内注射（每周一次，连续两周）给予HLSC。第一名患者接受了125,000 HLSC x克肝/剂量，而其他两名患者接受了该剂量的两倍。自HLSC以来未进行免疫抑制具有免疫调节活性。在整个观察期间，没有患者发生感染，高氨血症代偿失调或其他不良事件。没有检测到针对HLSC的供体特异性抗体（DSA）。尽管蛋白质摄入增加（〜30％），患者仍处于代谢稳定状态。两名患者分别在19个月和11个月后进行了肝移植，并且在移出后，天然肝脏未显示出组织学改变。总之，经皮肝内给药HLSCs对于新生儿遗传性高氨血症新生儿是安全的。这些数据为选定的遗传性和获得性肝病的II期研究铺平了道路。