Recently, Yan Sen/Tu Chi, a researcher at Jinan University, and others successfully constructed an immunodeficient monkey model that can support tumor growth using the cytosine base editor (CBE) 4max system. The results were published online in Signal Transduction and Targeted Therapy.
Schematic of the construction of a single-base edited cynomolgus monkey. Photo courtesy of the research team
Nonhuman primates are generally considered to have good phylogenetic correlations with humans and share many physiological similarities. Close genetic and physiological similarity to humans makes non-human primates an excellent model for biomedical research. At the same time, neurodegenerative diseases tend to produce severe immune cell changes, so it is important to study neurodegenerative diseases using immunodeficiency models.
CBE is a powerful tool for editing single-base mutations and has been used to introduce single-base mutations into the genome. Therefore, it is of great significance to use this technology to perform base editing of IL2RG and RAG1 genes at the same time to explore whether the inactivation of IL2RG and RAG1 genes in cynomolgus monkeys can produce immunodeficient monkey models with immunodeficiency phenotypes.
The researchers mutated the IL2RG and RAG1 genes in the embryos of cynomolgus monkeys by single-base editing, and injected CBE4max mRNA and gRNA into the embryos of cynomolgus monkeys, and successfully obtained base editing monkeys by embryo transfer to surrogate mother monkeys. Histopathological testing of base-editing monkeys also validated the generation of immunodeficiency phenotypes. At the same time, the immune system of base-edited monkeys was severely compromised. The results of whole genome sequencing showed that no significant off-target effects occurred in base-edited monkeys. In addition, human breast cancer cells survive and develop tumors in immunodeficient monkeys. These results show that inactivation of IL2RG and RAG1 genes using single-base editing techniques in cynomolgus monkeys can yield base-edited monkey models with distinct immunodeficiency phenotypes.
“This study successfully generated IL2RG and RAG1 gene mutant monkeys with severe combined immunodeficiency using the CBE4max base-editing system.” Yan Sen, co-corresponding author of the paper, said that these immunodeficient monkeys are valuable tools for preclinical research and bridge the gap between small animal models and humans. Their utilization can significantly increase the effectiveness of preclinical research. (Source: China Science News Zhu Hanbin)
Related paper information:https://www.nature.com/articles/s41392-023-01544-y
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