Evaluation of guide-free Cas9-induced genomic damage and transcriptome changes in pig embryos

Ge, Weikai; Zhao, Xiaozhu; Gou, Shixue; Jin, Qin; Chen, Fangbing; Ouyang, Zhen; Lai, Chengdan; Cui, Tao; Mai, Baoyi; Lu, Sijia; Zhong, Kexin; Liang, Yanhui; Chen, Tao; Wu, Han; Li, Nan; Ye, Yinghua; Lai, Liangxue; Wang, Kepin

doi:10.1016/j.omtn.2023.102035

Molecular Therapy - Nucleic Acids

2023

DOI: 10.1016/j.omtn.2023.102035

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Evaluation of guide-free Cas9-induced genomic damage and transcriptome changes in pig embryos

Weikai Ge,

Xiaozhu Zhao,

Shixue Gou

et al.

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2024

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A compact, versatile drug-induced splicing switch system with minimal background expression

Chi,

Lu,

et al. 2024

Cell Reports Methods

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A compact, versatile drug-induced splicing switch system with minimal background expression

Chi,

Lu,

et al. 2024

Cell Reports Methods

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In vivo evaluation of guide-free Cas9-induced safety risks in a pig model

Ge,

Gou,

Zhao

et al. 2024

Sig Transduct Target Ther

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The CRISPR/Cas9 system has shown great potential for treating human genetic diseases through gene therapy. However, there are concerns about the safety of this system, specifically related to the use of guide-free Cas9. Previous studies have shown that guide-free Cas9 can induce genomic instability in vitro. However, the in vivo safety risks associated with guide-free Cas9 have not been evaluated, which is necessary for the development of gene therapy in clinical settings. In this study, we used doxycycline-inducible Cas9-expressing pigs to evaluate the safety risks of guide-free Cas9 in vivo. Our findings demonstrated that expression of guide-free Cas9 could induce genomic damages and transcriptome changes in vivo. The severity of the genomic damages and transcriptome changes were correlate with the expression levels of Cas9 protein. Moreover, prolonged expression of Cas9 in pigs led to abnormal phenotypes, including a significant decrease in body weight, which may be attributable to genomic damage-induced nutritional absorption and metabolic dysfunction. Furthermore, we observed an increase in whole-genome and tumor driver gene mutations in pigs with long-term Cas9 expression, raising the risk of tumor occurrence. Our in vivo evaluation of guide-free Cas9 in pigs highlights the necessity of considering and monitoring the detrimental effects of Cas9 alone as genome editing via the CRISPR/Cas9 system is implemented in clinical gene therapy. This research emphasizes the importance of further study and implementation of safety measures to ensure the successful and safe application of the CRISPR/Cas9 system in clinical practice.

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Evaluation of guide-free Cas9-induced genomic damage and transcriptome changes in pig embryos

Cited by 2 publications

References 50 publications

A compact, versatile drug-induced splicing switch system with minimal background expression

A compact, versatile drug-induced splicing switch system with minimal background expression

In vivo evaluation of guide-free Cas9-induced safety risks in a pig model

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