Generation of inactivated IL2RG and RAG1 monkeys with severe combined immunodeficiency using base editing.

Sep 04, 2023

Experts: 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

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.

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ABOUT THE EXPERTS

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

Xiao Zheng

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Department of Pathophysiology, School of Medicine, Jinan University, 510632, Guangzhou, China.

Chunhui Huang

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Department of Pathophysiology, School of Medicine, Jinan University, 510632, Guangzhou, China.

Yingqi Lin

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Department of Pathophysiology, School of Medicine, Jinan University, 510632, Guangzhou, China.

Bofeng Han

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Yizhi Chen

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Caijuan Li

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Department of Pathophysiology, School of Medicine, Jinan University, 510632, Guangzhou, China.

Jiawei Li

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Department of Pathophysiology, School of Medicine, Jinan University, 510632, Guangzhou, China.

Yongyan Ding

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Xichen Song

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Wei Wang

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Weien Liang

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Jianhao Wu

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Jiaxi Wu

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Jiale Gao

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Chengxi Wei

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Xudong Zhang

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China.

Zhuchi Tu

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China. atuwater@163.com.

Sen Yan

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632, Guangzhou, China. 231yansen@163.com.

Department of Pathophysiology, School of Medicine, Jinan University, 510632, Guangzhou, China. 231yansen@163.com.