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在猪模型中无指导Cas9诱导的安全风险的体内评估

Weikai Ge^1,2,3,4, Shixue Gou^1,2,4, Xiaozhu Zhao^1,5

¹China-New Zealand Joint Laboratory on Biomedicine and Health, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China.

Signal transduction and targeted therapy

|July 18, 2024

概括

没有指导的CRISPR/Cas9 (集群定期间隔的短时间Palindromic重复/Cas9) 可以在体内引起基因组损伤和转录组改变. 在猪中长期表达Cas9导致不良表型和突变率的增加,突出了基因治疗的安全性问题.

科学领域:

遗传学是一个遗传学.
分子生物学分子生物学
基因治疗基因治疗

背景情况:

克里斯普尔/卡斯9基因疗法对遗传性疾病具有前景.
关于无导向Cas9的安全性存在担忧,特别是其体内效应.
以前的体外研究表明,无导向的Cas9可以导致基因组不稳定.

研究的目的:

评估无导向Cas9.9的体内安全风险.
评估生物体中由无导向Cas9诱导的基因组损伤和转录组变化.
为了确定Cas9体内表达的长期后果.

主要方法:

使用了可诱导多西环素的表达Cas9的猪进行体内评估.
监测基因组损伤和转录组改变.
与观察到的影响相关的Cas9表达水平.
评估随着时间的推移的表型变化和突变率.

主要成果:

在体内诱导的无导向Cas9表达引起了基因组损伤和转录组变化.
损伤严重程度与Cas9蛋白表达水平相关.
长时间的Cas9表达导致体重减轻和异常的表型.
观察到全基因组和瘤驱动基因突变的增加,表明瘤风险增加.

结论:

在猪体内对无导向Cas9的体内评估显示了重大安全风险.
单独Cas9的有害影响需要在临床基因治疗中仔细考虑和监测.
进一步的研究和安全措施对于CRISPR/Cas9技术的安全临床应用至关重要.

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