In Vivo Base Editing of Post-mitotic Sensory Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Jun 7

PMID 29872041

Citations 122

Authors

Wei-Hsi Yeh

Hao Chiang

Holly A Rees

Albert S B Edge

David R Liu

Affiliations

Soon will be listed here.

Abstract

Programmable nucleases can introduce precise changes to genomic DNA through homology-directed repair (HDR). Unfortunately, HDR is largely restricted to mitotic cells, and is typically accompanied by an excess of stochastic insertions and deletions (indels). Here we present an in vivo base editing strategy that addresses these limitations. We use nuclease-free base editing to install a S33F mutation in β-catenin that blocks β-catenin phosphorylation, impedes β-catenin degradation, and upregulates Wnt signaling. In vitro, base editing installs the S33F mutation with a 200-fold higher editing:indel ratio than HDR. In post-mitotic cells in mouse inner ear, injection of base editor protein:RNA:lipid installs this mutation, resulting in Wnt activation that induces mitosis of cochlear supporting cells and cellular reprogramming. In contrast, injection of HDR agents does not induce Wnt upregulation. These results establish a strategy for modifying posttranslational states in signaling pathways, and an approach to precision editing in post-mitotic tissues.

Citing Articles

From bench to bedside: cutting-edge applications of base editing and prime editing in precision medicine.

Xu W, Zhang S, Qin H, Yao K J Transl Med. 2024; 22(1):1133.

PMID: 39707395 PMC: 11662623. DOI: 10.1186/s12967-024-05957-3.

Safer and efficient base editing and prime editing via ribonucleoproteins delivered through optimized lipid-nanoparticle formulations.

Holubowicz R, Du S, Felgner J, Smidak R, Choi E, Palczewska G Nat Biomed Eng. 2024; 9(1):57-78.

PMID: 39609561 PMC: 11754100. DOI: 10.1038/s41551-024-01296-2.

Mechanism of Genome Editing Tools and Their Application on Genetic Inheritance Disorders.

Oh D Glob Med Genet. 2024; 11(4):319-329.

PMID: 39583120 PMC: 11405120. DOI: 10.1055/s-0044-1790558.

CasRx-based Wnt activation promotes alveolar regeneration while ameliorating pulmonary fibrosis in a mouse model of lung injury.

Shen S, Wang P, Wu P, Huang P, Chi T, Xu W Mol Ther. 2024; 32(11):3974-3989.

PMID: 39245939 PMC: 11573616. DOI: 10.1016/j.ymthe.2024.09.008.

Rational design of base, sugar and backbone modifications improves ADAR-mediated RNA editing.

Lu G, Shivalila C, Monian P, Yu H, Harding I, Briem S Nucleic Acids Res. 2024; 52(17):10068-10084.

PMID: 39149897 PMC: 11417349. DOI: 10.1093/nar/gkae681.

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