title: Rescue of ATP7B function in hepatocyte-like cells from Wilson's disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin.
abstract: Directed hepatocyte differentiation from human induced pluripotent stem cells (iPSCs) potentially provides a unique platform for modeling liver genetic diseases and performing drug-toxicity screening in vitro. Wilson's disease is a genetic disease caused by mutations in the ATP7B gene, whose product is a liver transporter protein responsible for coordinated copper export into bile and blood. Interestingly, the spectrum of ATP7B mutations is vast and can influence clinical presentation (a variable spectrum of hepatic and neural manifestations), though the reason is not well understood. We describe the generation of iPSCs from a Chinese patient with Wilson's disease that bears the R778L Chinese hotspot mutation in the ATP7B gene. These iPSCs were pluripotent and could be readily differentiated into hepatocyte-like cells that displayed abnormal cytoplasmic localization of mutated ATP7B and defective copper transport. Moreover, gene correction using a self-inactivating lentiviral vector that expresses codon optimized-ATP7B or treatment with the chaperone drug curcumin could reverse the functional defect in vitro. Hence, our work describes an attractive model for studying the pathogenesis of Wilson's disease that is valuable for screening compounds or gene therapy approaches aimed to correct the abnormality. In the future, once relevant safety concerns (including the stability of the mature liver-like phenotype) and technical issues for the transplantation procedure are solved, hepatocyte-like cells from similarly genetically corrected iPSCs could be an option for autologous transplantation in Wilson's disease.
authors: Stem Cell and Cancer Biology Group, Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, People’s Republic of China.
authors: Shiqiang
authors: S
authors: Zhang
authors: Shen
authors: S
authors: Chen
authors: Wen
authors: W
authors: Li
authors: Xiangpeng
authors: X
authors: Guo
authors: Ping
authors: P
authors: Zhao
authors: Jianyong
authors: J
authors: Xu
authors: Yan
authors: Y
authors: Chen
authors: Qiong
authors: Q
authors: Pan
authors: Xiaorong
authors: X
authors: Liu
authors: Daniela
authors: D
authors: Zychlinski
authors: Hai
authors: H
authors: Lu
authors: Micky D
authors: MD
authors: Tortorella
authors: Axel
authors: A
authors: Schambach
authors: Yan
authors: Y
authors: Wang
authors: Duanqing
authors: D
authors: Pei
authors: Miguel A
authors: MA
authors: Esteban