Department of Laboratory Medicine, Karolinska Institute, 141 52 Stockholm, Sweden.
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40 138 Bologna, Italy.
Int J Mol Sci. 2021 Jan 26;22(3):1217. doi: 10.3390/ijms22031217.
Urea cycle disorders are enzymopathies resulting from inherited deficiencies in any genes of the cycle. In severe cases, currently available therapies are marginally effective, with liver transplantation being the only definitive treatment. Donor liver availability can limit even this therapy. Identification of novel therapeutics for genetic-based liver diseases requires models that provide measurable hepatic functions and phenotypes. Advances in stem cell and genome editing technologies could provide models for the investigation of cell-based genetic diseases, as well as the platforms for drug discovery. This report demonstrates a practical, and widely applicable, approach that includes the successful reprogramming of somatic cells from a patient with a urea cycle defect, their genetic correction and differentiation into hepatic organoids, and the subsequent demonstration of genetic and phenotypic change in the edited cells consistent with the correction of the defect. While individually rare, there is a large number of other genetic-based liver diseases. The approach described here could be applied to a broad range and a large number of patients with these hepatic diseases where it could serve as an in vitro model, as well as identify successful strategies for corrective cell-based therapy.
尿素循环障碍是由于循环中任何基因的遗传缺陷导致的酶病。在严重的情况下，目前可用的治疗方法效果有限，肝移植是唯一的根治性治疗方法。供肝的可用性甚至可以限制这种治疗方法。为遗传性肝病寻找新的治疗方法需要提供可测量的肝功能和表型的模型。干细胞和基因组编辑技术的进步可以为基于细胞的遗传疾病的研究提供模型，以及药物发现的平台。本报告展示了一种实用且广泛适用的方法，包括成功地对尿素循环缺陷患者的体细胞进行重编程，对其进行基因修正，并分化为肝类器官，随后证明编辑细胞中的遗传和表型变化与缺陷的修正一致。虽然个体罕见，但仍有大量其他遗传性肝病。这里描述的方法可以应用于广泛的、大量的这些肝脏疾病患者，既可以作为体外模型，也可以确定成功的基于细胞的治疗纠正策略。
