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Generation of in situ CRISPR-mediated primary and metastatic cancer from monkey liver
Liping Zhong1, Yong Huang1, Jian He1
1National Center for International Research of Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China.
Abstract:
Non-human primates (NHPs) represent the most valuable animals for drug discovery. However, the current main challenge remains that the NHP has not yet been used to develop an efficient translational medicine platform simulating human diseases, such as cancer. This study generated an in situ gene-editing approach to induce efficient loss-of-function mutations of Pten and p53 genes for rapid modeling primary and metastatic liver tumors using the CRISPR/Cas9 in the adult cynomolgus monkey. Under ultrasound guidance, the CRISPR/Cas9 was injected into the cynomolgus monkey liver through the intrahepatic portal vein. The results showed that the ultrasound-guided CRISPR/Cas9 resulted in indels of the Pten and p53 genes in seven out of eight monkeys. The best mutation efficiencies for Pten and p53 were up to 74.71% and 74.68%, respectively. Furthermore, the morbidity of primary and extensively metastatic (lung, spleen, lymph nodes) hepatoma in CRISPR-treated monkeys was 87.5%. The ultrasound-guided CRISPR system could have great potential to successfully pursue the desired target genes, thereby reducing possible side effects associated with hitting non-specific off-target genes, and significantly increasing more efficiency as well as higher specificity of in situ gene editing in vivo, which holds promise as a powerful, yet feasible tool, to edit disease genes to build corresponding human disease models in adult NHPs and to greatly accelerate the discovery of new drugs and save economic costs.
Insights
Researchers developed a novel gene-editing technique in non-human primates to create accurate models of human liver cancer. This CRISPR/Cas9 approach efficiently targets Pten and p53 genes, accelerating drug discovery and reducing costs.
Area of Science:
- * Biomedical research
- * Gene editing technology
- * Translational medicine
Background:
- * Non-human primates (NHPs) are crucial for drug discovery but lack efficient models for human diseases like cancer.
- * Current challenges include developing translational medicine platforms that accurately simulate human conditions in NHPs.
Purpose of the Study:
- * To establish an in situ gene-editing method for rapid modeling of primary and metastatic liver tumors in adult cynomolgus monkeys.
- * To utilize CRISPR/Cas9 to induce loss-of-function mutations in Pten and p53 genes, simulating human hepatoma.
Main Methods:
- * An ultrasound-guided CRISPR/Cas9 system was injected into the cynomolgus monkey liver via the intrahepatic portal vein.
- * Gene editing targeted the Pten and p53 genes to create mutations (indels).
Main Results:
- * Ultrasound-guided CRISPR/Cas9 successfully induced Pten and p53 gene mutations in 7 of 8 monkeys.
- * Achieved mutation efficiencies of up to 74.71% for Pten and 74.68% for p53.
- * Observed an 87.5% morbidity rate for primary and metastatic hepatoma in treated monkeys.
Conclusions:
- * The ultrasound-guided CRISPR system demonstrates high efficiency and specificity for in situ gene editing in vivo.
- * This approach holds significant potential for creating accurate human disease models in NHPs.
- * Facilitates accelerated drug discovery and reduces economic costs in preclinical research.
