RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
TriLink BioTechnologies, San Diego, CA, USA.
Nat Commun. 2020 Apr 24;11(1):1979. doi: 10.1038/s41467-020-15892-8.
CRISPR-Cas9-associated base editing is a promising tool to correct pathogenic single nucleotide mutations in research or therapeutic settings. Efficient base editing requires cellular exposure to levels of base editors that can be difficult to attain in hard-to-transfect cells or in vivo. Here we engineer a chemically modified mRNA-encoded adenine base editor that mediates robust editing at various cellular genomic sites together with moderately modified guide RNA, and show its therapeutic potential in correcting pathogenic single nucleotide mutations in cell and animal models of diseases. The optimized chemical modifications of adenine base editor mRNA and guide RNA expand the applicability of CRISPR-associated gene editing tools in vitro and in vivo.
CRISPR-Cas9 相关的碱基编辑是一种有前途的工具，可以在研究或治疗环境中纠正致病的单核苷酸突变。有效的碱基编辑需要细胞暴露于碱基编辑器的水平，而在难以转染的细胞或体内，这可能很难达到。在这里，我们设计了一种化学修饰的 mRNA 编码腺嘌呤碱基编辑器，它与中度修饰的向导 RNA 一起介导各种细胞基因组位点的强大编辑，并在疾病的细胞和动物模型中展示了其纠正致病单核苷酸突变的治疗潜力。腺嘌呤碱基编辑器 mRNA 和向导 RNA 的优化化学修饰扩展了 CRISPR 相关基因编辑工具在体外和体内的适用性。
