Safeguarding genome integrity during gene-editing therapy in a mouse model of age-related macular degeneration

Jianhang Yin, Kailun Fang, Yanxia Gao, Liqiong Ou, Shaopeng Yuan, Changchang Xin, Weiwei Wu, Wei-wei Wu, Jiaxu Hong, Hui Yang () and Jiazhi Hu ()
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Jianhang Yin: Peking University
Kailun Fang: Chinese Academy of Sciences
Yanxia Gao: Chinese Academy of Sciences
Liqiong Ou: Peking University
Shaopeng Yuan: Peking University
Changchang Xin: Peking University
Weiwei Wu: Chinese Academy of Sciences
Wei-wei Wu: Chinese Academy of Sciences
Jiaxu Hong: Fudan University
Hui Yang: Chinese Academy of Sciences
Jiazhi Hu: Peking University

Nature Communications, 2022, vol. 13, issue 1, 1-8

Abstract: Abstract Ensuring genome safety during gene editing is crucial for clinical translation of the high-efficient CRISPR-Cas9 toolbox. Therefore, the undesired events including chromosomal translocations, vector integrations, and large deletions arising during therapeutic gene editing remain to be adequately addressed or tackled in vivo. Here, we apply CRISPR-Cas9TX in comparison to CRISPR-Cas9 to target Vegfa for the treatment of age-related macular degeneration (AMD) disease in a mouse model. AAV delivery of both CRISPR-Cas9 and CRISPR-Cas9TX can efficiently inhibit laser-induced neovascularization. Importantly, Cas9TX almost eliminates chromosomal translocations that occur at a frequency of approximately 1% in Cas9-edited mouse retinal cells. Strikingly, the widely observed AAV integration at the target Vegfa site is also greatly reduced from nearly 50% of edited events to the background level during Cas9TX editing. Our findings reveal that chromosomal structural variations routinely occur during in vivo genome editing and highlight Cas9TX as a superior form of Cas9 for in vivo gene disruption.

Date: 2022
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DOI: 10.1038/s41467-022-35640-4

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