阿达尔
RNA编辑
引导RNA
核糖核酸
生物
计算生物学
生物信息学
基因组编辑
遗传学
作者
Philipp Reautschnig,Nicolai Wahn,Jacqueline Wettengel,Annika E. Schulz,Ngadhnjim Latifi,Paul Vogel,Tae-Won Kang,Laura S. Pfeiffer,Christine Zarges,Ulrike Naumann,Lars Zender,Jin Billy Li,Thorsten Stafforst
标识
DOI:10.1038/s41587-021-01105-0
摘要
RNA base editing represents a promising alternative to genome editing. Recent approaches harness the endogenous RNA-editing enzyme adenosine deaminase acting on RNA (ADAR) to circumvent problems caused by ectopic expression of engineered editing enzymes, but suffer from sequence restriction, lack of efficiency and bystander editing. Here we present in silico-optimized CLUSTER guide RNAs that bind their target messenger RNAs in a multivalent fashion, achieve editing with high precision and efficiency and enable targeting of sequences that were not accessible using previous gRNA designs. CLUSTER gRNAs can be genetically encoded and delivered using viruses, and are active in a wide range of cell lines. In cell culture, CLUSTER gRNAs achieve on-target editing of endogenous transcripts with yields of up to 45% without bystander editing. In vivo, CLUSTER gRNAs delivered to mouse liver by hydrodynamic tail vein injection edited reporter constructs at rates of up to 10%. The CLUSTER approach opens avenues for drug development in the field of RNA base editing.
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