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

Published: Nov. 15, 2020, 11:02 a.m.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.13.381160v1?rss=1 Authors: Liu, L., Li, K., Zou, L., Hou, H., Hu, Q., Liu, S., Wang, S., Wang, Y., Li, J., Song, C., Chen, J., Li, C., Du, H., Li, J.-L., Chen, F., Xu, Z., Sun, W., Sun, Q., Xiong, W. Abstract: 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. Copy rights belong to original authors. Visit the link for more info