Gene-editing technologies, which include the CRISPR–Cas nucleases^1,2,3 and CRISPR base editors^4,5, have the potential to permanently modify disease-causing genes in patients⁶. The demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes in living cynomolgus monkeys (Macaca fascicularis). We observed a near-complete knockdown of PCSK9 in the liver after a single infusion of lipid nanoparticles, with concomitant reductions in blood levels of PCSK9 and low-density lipoprotein cholesterol of approximately 90% and about 60%, respectively; all of these changes remained stable for at least 8 months after a single-dose treatment. In addition to supporting a ‘once-and-done’ approach to the reduction of low-density lipoprotein cholesterol and the treatment of atherosclerotic cardiovascular disease (the leading cause of death worldwide⁷), our results provide a proof-of-concept for how CRISPR base editors can be productively applied to make precise single-nucleotide changes in therapeutic target genes in the liver, and potentially in other organs.

基因编辑技术，包括 CRISPR–Cas 核酸酶^1,2,3和 CRISPR 碱基编辑器^4,5，有可能永久修改患者的致病基因⁶。在非人类灵长类动物的靶器官中进行持久编辑的证明是在临床试验中将基因编辑器体内管理给患者之前的关键步骤。在这里，我们证明了使用脂质纳米颗粒在体内传递的 CRISPR 碱基编辑器可以有效且精确地修改活食蟹猴（食蟹猴）中的疾病相关基因。我们观察到PCSK9几乎完全击倒单次输注脂质纳米颗粒后，肝脏中的 PCSK9 和低密度脂蛋白胆固醇水平分别降低约 90% 和约 60%；在单剂量治疗后，所有这些变化至少在 8 个月内保持稳定。除了支持降低低密度脂蛋白胆固醇和治疗动脉粥样硬化性心血管疾病（全球主要死因⁷）的“一劳永逸”方法外，我们的研究结果还提供了一个概念验证CRISPR 碱基编辑器可以有效地用于在肝脏中以及可能在其他器官中对治疗靶基因进行精确的单核苷酸改变。