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Template-independent genome editing and repairing correct frameshift disease in vivo

By Lian Liu, Kuan Li, Linzhi Zou, Hanqing Hou, Qun Hu, Shuang Liu, Shufeng Wang, Yangzhen Wang, Jie Li, Chenmeng Song, Jiaofeng Chen, Changri Li, Haibo Du, Jun-Liszt Li, Fangyi Chen, Zhigang Xu, Wenzhi Sun, Qianwen Sun, Wei Xiong

Posted 15 Nov 2020
bioRxiv DOI: 10.1101/2020.11.13.381160

Frameshift mutation caused by small insertions/deletions (indels) often generate truncated and non-functional proteins, which underlies 22% inherited Mendelian disorders in humans. However, there is no efficient in vivo gene therapy strategy available to date, especially in postmitotic systems. Here, we leveraged the non-homologous end joining (NHEJ) mediated non-random editing profiles to compensate the frameshift mutation in a USH1F mouse model - av3j. After treatment by the selected gRNA, about 50% editing products showed reading-frame restoration, and more than 70% targeted hair cells recovered mechanotransduction. In vivo treatment ameliorated the hearing and balance symptoms in homozygous mutant mice. Furthermore, a scale-up analysis of 114 gRNAs targeting 40 frameshift deafness mutations reveals that 65% loci have at least one gRNA with predicted therapeutic potential. Together, our study demonstrates that the NHEJ-mediated frame restoration is a simple and highly efficient therapeutic strategy for small-indel induced frameshift mutations. ### Competing Interest Statement The authors have declared no competing interest.

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