高效扩增和 CRISPR-Cas9 介导的患者衍生肝细胞基因校正用于治疗遗传性肝病

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING Cell stem cell Pub Date : 2024-05-20 DOI:10.1016/j.stem.2024.04.022
Kun Zhang, Ping Wan, Liren Wang, Zhen Wang, Fangzhi Tan, Jie Li, Xiaolong Ma, Jin Cen, Xiang Yuan, Yang Liu, Zhen Sun, Xi Cheng, Yuanhua Liu, Xuhao Liu, Jiazhi Hu, Guisheng Zhong, Dali Li, Qiang Xia, Lijian Hui
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引用次数: 0

摘要

事实证明,在实体器官(尤其是肝脏)中进行基于细胞的体外基因治疗在技术上具有挑战性。在此,我们报告了肝细胞疗法临床应用的可行策略。我们首先通过大规模扩增患者肝细胞生成高质量的自体肝细胞。此外,增殖的患者来源肝细胞与通过筛选确定的 AAV2.7m8 变体一起,实现了 CRISPR-Cas9 介导的高效靶向整合,实现了对 FAH 或 OTC 中致病突变的功能性校正。重要的是,这些经过编辑的肝细胞能在损伤的小鼠肝脏中进行高水平的再填充和成熟,并在移植后成功治疗了酪氨酸血症小鼠。我们的研究结合了体外大规模细胞扩增和基因编辑患者来源的可移植肝细胞,这为治疗人类肝病提供了潜力。
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Efficient expansion and CRISPR-Cas9-mediated gene correction of patient-derived hepatocytes for treatment of inherited liver diseases

Cell-based ex vivo gene therapy in solid organs, especially the liver, has proven technically challenging. Here, we report a feasible strategy for the clinical application of hepatocyte therapy. We first generated high-quality autologous hepatocytes through the large-scale expansion of patient-derived hepatocytes. Moreover, the proliferating patient-derived hepatocytes, together with the AAV2.7m8 variant identified through screening, enabled CRISPR-Cas9-mediated targeted integration efficiently, achieving functional correction of pathogenic mutations in FAH or OTC. Importantly, these edited hepatocytes repopulated the injured mouse liver at high repopulation levels and underwent maturation, successfully treating mice with tyrosinemia following transplantation. Our study combines ex vivo large-scale cell expansion and gene editing in patient-derived transplantable hepatocytes, which holds potential for treating human liver diseases.

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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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