无需双链断裂或供体 DNA 的搜索-替换基因组编辑
Search-and-replace genome editing without double-strand breaks or donor DNA
许多致病基因变异难以被高效、精准地修复。研究人员开发出一种名为先导编辑（prime editing）的基因组编辑新方法。该方法将一种失去切割活性的 Cas9 蛋白与逆转录酶融合，配合一种特殊设计的引导 RNA，能直接在指定 DNA 位点写入新的遗传信息，无需造成 DNA 双链断裂或提供外源 DNA 模板。在人类细胞中，研究人员成功实现了超过 175 种编辑，包括插入、删除以及全部 12 种点突变，并高效修正了镰状细胞病和泰-萨克斯病的致病突变。先导编辑的副产物更少，脱靶编辑也远低于传统 Cas9 核酸酶。这项技术大幅扩展了基因组编辑的能力，理论上可修正约 89% 的已知人类致病遗传变异。
为什么推荐给您：全新基因组编辑模态，无需双链断裂即可实现多种精准编辑，是里程碑式技术突破。
不需要生物学背景，多打比方
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摘要Abstract
Most genetic variants that contribute to disease1 are challenging to correct efficiently and without excess byproducts2-5. Here we describe prime editing, a versatile and precise genome editing method that directly writes new genetic information into a specified DNA site using a catalytically impaired Cas9 endonuclease fused to an engineered reverse transcriptase, programmed with a prime editing guide RNA (pegRNA) that both specifies the target site and encodes the desired edit. We performed more than 175 edits in human cells, including targeted insertions, deletions, and all 12 types of point mutation, without requiring double-strand breaks or donor DNA templates. We used prime editing in human cells to correct, efficiently and with few byproducts, the primary genetic causes of sickle cell disease (requiring a transversion in HBB) and Tay-Sachs disease (requiring a deletion in HEXA); to install a protective transversion in PRNP; and to insert various tags and epitopes precisely into target loci. Four human cell lines and primary post-mitotic mouse cortical neurons support prime editing with varying efficiencies. Prime editing shows higher or similar efficiency and fewer byproducts than homology-directed repair, has complementary strengths and weaknesses compared to base editing, and induces much lower off-target editing than Cas9 nuclease at known Cas9 off-target sites. Prime editing substantially expands the scope and capabilities of genome editing, and in principle could correct up to 89% of known genetic variants associated with human diseases.