美国威尔康奈尔医学院Lukas E. Dow团队近期取得重要工作进展，他们研究使用受调控的体内碱基编辑器生成精确的临床前癌症模型。相关研究成果2023年8月10日在线发表于《自然—生物技术》杂志上。

据介绍，尽管单核苷酸变异（SNV）构成了大多数癌症相关的遗传变化，并且已被全面分类，它们对肿瘤发生和发展的影响知之甚少。

为了探讨与癌症相关SNV的功能，研究人员开发了一种用于时间和可调节的体内碱基编辑的小鼠系统。诱导型碱基编辑（iBE）小鼠在四环素应答元件的控制下携带单个表达优化的胞嘧啶碱基编辑转基因，并能够在体内广泛的组织中实现强大的多西环素依赖性表达。与基于质粒或合成的引导RNA相结合，iBE驱动肠道、肺和胰腺类器官中单个或多个SNV的有效工程化。

总之，对碱基编辑器活性的时间调节允许在体外和体内控制顺序基因组编辑，并且将sgRNA直接递送到靶组织有利于促进原位临床前癌症模型的产生。

附：英文原文

Title: Generation of precision preclinical cancer models using regulated in vivo base editing

Author: Katti, Alyna, Vega-Prez, Adrin, Foronda, Miguel, Zimmerman, Jill, Zafra, Maria Paz, Granowsky, Elizabeth, Goswami, Sukanya, Gardner, Eric E., Diaz, Bianca J., Simon, Janelle M., Wuest, Alexandra, Luan, Wei, Fernandez, Maria Teresa Calvo, Kadina, Anastasia P., Walker, John A., Holden, Kevin, Lowe, Scott W., Snchez Rivera, Francisco J., Dow, Lukas E.

Issue&Volume: 2023-08-10

Abstract: Although single-nucleotide variants (SNVs) make up the majority of cancer-associated genetic changes and have been comprehensively catalogued, little is known about their impact on tumor initiation and progression. To enable the functional interrogation of cancer-associated SNVs, we developed a mouse system for temporal and regulatable in vivo base editing. The inducible base editing (iBE) mouse carries a single expression-optimized cytosine base editor transgene under the control of a tetracycline response element and enables robust, doxycycline-dependent expression across a broad range of tissues in vivo. Combined with plasmid-based or synthetic guide RNAs, iBE drives efficient engineering of individual or multiple SNVs in intestinal, lung and pancreatic organoids. Temporal regulation of base editor activity allows controlled sequential genome editing ex vivo and in vivo, and delivery of sgRNAs directly to target tissues facilitates generation of in situ preclinical cancer models.

DOI: 10.1038/s41587-023-01900-x

Source: https://www.nature.com/articles/s41587-023-01900-x