PDF(Pubmed)
Abstract：
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.
摘要：
严重的联合免疫缺陷（SCID）包括一系列导致免疫系统严重恶化的遗传性疾病。在与SCID相关的关键基因中，RAG1和IL2RG起着至关重要的作用。IL2RG是必不可少的发展，分化,和T的功能，B,和NK细胞，而RAG1通过在淋巴细胞成熟过程中促进V（D）J重组而对适应性免疫至关重要。携带这些基因突变的动物模型在其免疫系统中表现出明显的缺陷。非人灵长类动物（NHP）由于其与人类的遗传和生理相似性，因此非常适合生物医学研究的模型。胞嘧啶碱基编辑器（CBEs）是精确有效地修饰基因组单碱基突变的强大工具。它们的成功实施已经在人类细胞中得到证明，老鼠,和作物种类。这项研究概述了通过使用CBE4max系统使IL2RG和RAG1基因失活来创建免疫缺陷猴模型。基本编辑的猴子表现出严重受损的免疫系统，其特征是淋巴细胞减少，淋巴器官萎缩，和成熟T细胞的缺乏。此外，这些基本编辑的猴子能够承载和支持人类乳腺癌细胞的生长，导致肿瘤形成。总之,我们已经成功开发了一种免疫缺陷猴模型,该模型能够使用CBE4max系统促进肿瘤生长.这些免疫缺陷猴作为推进生物医学和转化研究的有价值的工具显示出巨大的潜力。
