胞苷
胞苷脱氨酶
DNA
核糖核酸
转录组
基因组编辑
RNA编辑
分子生物学
生物
碱基对
计算生物学
遗传学
基因组
基因表达
生物化学
基因
酶
作者
Lukas Villiger,Tanja Rothgangl,Dominik Witzigmann,Rurika Oka,Paulo J.C. Lin,Weihong Qi,Sharan Janjuha,Christian Berk,Femke Ringnalda,Mitchell Beattie,Markus Stoffel,Beat Thöny,Jonathan Hall,Hubert Rehrauer,Ruben van Boxtel,Ying K. Tam,Gerald Schwank
标识
DOI:10.1038/s41551-020-00671-z
摘要
Base editors are RNA-programmable deaminases that enable precise single-base conversions in genomic DNA. However, off-target activity is a concern in the potential use of base editors to treat genetic diseases. Here, we report unbiased analyses of transcriptome-wide and genome-wide off-target modifications effected by cytidine base editors in the liver of mice with phenylketonuria. The intravenous delivery of intein-split cytidine base editors by dual adeno-associated viruses led to the repair of the disease-causing mutation without generating off-target mutations in the RNA and DNA of the hepatocytes. Moreover, the transient expression of a cytidine base editor mRNA and a relevant single-guide RNA intravenously delivered by lipid nanoparticles led to ~21% on-target editing and to the reversal of the disease phenotype; there were also no detectable transcriptome-wide and genome-wide off-target edits. Our findings support the feasibility of therapeutic cytidine base editing to treat genetic liver diseases. Cytidine base editors delivered to the liver of mice with phenylketonuria via adeno-associated viruses or lipid nanoparticles do not lead to detectable off-target edits in the RNA and DNA of hepatocytes.
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