使用基因编辑技术生成严重联合免疫缺陷的IL2RG和RAG1猴模型
Generation of inactivated IL2RG and RAG1 monkeys with severe combined immunodeficiency using base editing.
发表日期：2023 Sep 04
作者：
Xiao Zheng, Chunhui Huang, Yingqi Lin, Bofeng Han, Yizhi Chen, Caijuan Li, Jiawei Li, Yongyan Ding, Xichen Song, Wei Wang, Weien Liang, Jianhao Wu, Jiaxi Wu, Jiale Gao, Chengxi Wei, Xudong Zhang, Zhuchi Tu, Sen Yan
来源：
Cellular & Molecular Immunology
摘要：
严重并发性免疫缺陷症（SCID）是一系列遗传性疾病的总称，会导致免疫系统严重退化。在与SCID相关的关键基因中，RAG1和IL2RG起着重要作用。IL2RG对T、B和NK细胞的发育、分化和功能具有至关重要的作用，而RAG1通过在淋巴细胞成熟期促进V(D)J重组，对适应性免疫发挥重要贡献。携带这些基因突变的动物模型在其免疫系统方面显示明显缺陷。非人灵长类动物（NHPs）由于与人类在基因和生理上的相似性而极为适合生物医学研究。胞嘧啶碱基编辑酶（CBEs）可作为精确有效地修饰基因组中的单碱基突变的强大工具。人类细胞、小鼠和作物品种中已经成功应用了这些工具。本研究概述了使用CBE4max系统通过失活IL2RG和RAG1基因来创建一种免疫缺陷的猴模型。碱基编辑的猴子表现出免疫系统严重受损，包括淋巴细胞减少、淋巴器官萎缩和成熟T细胞的缺乏。此外，这些碱基编辑的猴子能够容纳并支持人乳腺癌细胞的生长，导致肿瘤形成。总之，我们成功地发展了一种能够促进肿瘤生长的免疫缺陷猴子模型，该模型利用了CBE4max系统。这些免疫缺陷猴子展示了成为推动生物医学和转化研究的有价值工具的巨大潜力。© 2023. 西南医科大学华西医院。
Severe combined immunodeficiency (SCID) encompasses a range of inherited disorders that lead to a profound deterioration of the immune system. Among the pivotal genes associated with SCID, RAG1 and IL2RG play crucial roles. IL2RG is essential for the development, differentiation, and functioning of T, B, and NK cells, while RAG1 critically contributes to adaptive immunity by facilitating V(D)J recombination during the maturation of lymphocytes. Animal models carrying mutations in these genes exhibit notable deficiencies in their immune systems. Non-human primates (NHPs) are exceptionally well-suited models for biomedical research due to their genetic and physiological similarities to humans. Cytosine base editors (CBEs) serve as powerful tools for precisely and effectively modifying single-base mutations in the genome. Their successful implementation has been demonstrated in human cells, mice, and crop species. This study outlines the creation of an immunodeficient monkey model by deactivating both the IL2RG and RAG1 genes using the CBE4max system. The base-edited monkeys exhibited a severely compromised immune system characterized by lymphopenia, atrophy of lymphoid organs, and a deficiency of mature T cells. Furthermore, these base-edited monkeys were capable of hosting and supporting the growth of human breast cancer cells, leading to tumor formation. In summary, we have successfully developed an immunodeficient monkey model with the ability to foster tumor growth using the CBE4max system. These immunodeficiency monkeys show tremendous potential as valuable tools for advancing biomedical and translational research.© 2023. West China Hospital, Sichuan University.