Ornithine transcarbamylase deficiency (OTCD) is a metabolic and genetic disease caused by dysfunction of the hepatocytic urea cycle. To develop new drugs or therapies for OTCD, it is ideal to use models that are more closely related to human metabolism and pathology. Primary human hepatocytes (HHs) isolated from two patients (a 6‐month‐old boy and a 5‐year‐old girl) and a healthy donor were transplanted into host mice (hemi‐, hetero‐OTCD mice, and control mice, respectively). HHs were isolated from these mice and used for serial transplantation into the next host mouse or for in vitro experiments. Histological, biochemical, and enzyme activity analyses were performed. Cultured HHs were treated with ammonium chloride or therapeutic drugs. Replacement rates exceeded 80% after serial transplantation in both OTCD mice. These highly humanized OTCD mice showed characteristics similar to OTCD patients that included increased blood ammonia levels and urine orotic acid levels enhanced by allopurinol. Hemi‐OTCD mice showed defects in OTC expression and significantly low enzymatic activities, while hetero‐OTCD mice showed residual OTC expression and activities. A reduction in ammonium metabolism was observed in cultured HHs from OTCD mice, and treatment with the therapeutic drug reduced the ammonia levels in the culture medium. In conclusion, we established in vivo OTC mouse models with hemi‐ and hetero‐patient HHs. HHs isolated from the mice were useful as an in vitro model of OTCD. These OTC models could be a source of valuable patient‐derived hepatocytes that would enable large scale and reproducible experiments using the same donor.

中文翻译：

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鸟氨酸转氨甲酰酶缺乏症患者移植人肝细胞的人源化肝脏小鼠模型

鸟氨酸转氨甲酰酶缺乏症（OTCD）是一种由肝细胞尿素循环功能障碍引起的代谢和遗传疾病。为 OTCD 开发新的药物或疗法，最好使用与人体代谢和病理学更密切相关的模型。从两名患者（一名 6 个月大的男孩和一名 5 岁的女孩）和一名健康供体中分离的原代人肝细胞（HHs）被移植到宿主小鼠（分别为半、异源 OTCD 小鼠和对照小鼠）中）。从这些小鼠中分离出 HHs 并用于连续移植到下一个宿主小鼠中或用于体外实验。进行了组织学、生化和酶活性分析。用氯化铵或治疗药物处理培养的 HH。两只 OTCD 小鼠连续移植后的替代率超过 80%。这些高度人源化的 OTCD 小鼠显示出与 OTCD 患者相似的特征，包括血氨水平升高和别嘌呤醇增强的尿乳清酸水平。Hemi-OTCD 小鼠表现出 OTC 表达缺陷和酶活性显着降低，而异质 OTCD 小鼠表现出残留的 OTC 表达和活性。在来自 OTCD 小鼠的培养的 HHs 中观察到铵代谢减少，用治疗药物治疗降低了培养基中的氨水平。总之，我们建立了具有半身和异种患者 HH 的体内 OTC 小鼠模型。从小鼠中分离的 HH 可用作 OTCD 的体外模型。这些 OTC 模型可能是有价值的患者来源肝细胞的来源，可以使用同一供体进行大规模和可重复的实验。