RT Journal Article
SR Electronic
T1 Template-independent genome editing and repairing correct frameshift disease <em>in vivo</em>
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.13.381160
DO 10.1101/2020.11.13.381160
A1 Lian Liu
A1 Kuan Li
A1 Linzhi Zou
A1 Hanqing Hou
A1 Qun Hu
A1 Shuang Liu
A1 Shufeng Wang
A1 Yangzhen Wang
A1 Jie Li
A1 Chenmeng Song
A1 Jiaofeng Chen
A1 Changri Li
A1 Haibo Du
A1 Jun-Liszt Li
A1 Fangyi Chen
A1 Zhigang Xu
A1 Wenzhi Sun
A1 Qianwen Sun
A1 Wei Xiong
YR 2020
UL http://biorxiv.org/content/early/2020/11/15/2020.11.13.381160.abstract
AB 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 strategies 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 StatementThe authors have declared no competing interest.