小柯机器人

美国Verve治疗公司Sekar Kathiresan研究组发现，PCSK9的体内CRISPR碱基编辑可持久降低灵长类动物的胆固醇。2021年5月19日，国际知名学术期刊《自然》发表了这一成果。

研究人员证明，使用脂质纳米颗粒在体内传递的CRISPR碱基编辑器可以有效、精确地修饰食蟹猴（Macaca fascicularis）中与疾病相关的基因。研究人员观察到单次输注脂质纳米颗粒后肝脏中的PCSK9接近完全敲低，同时血液中PCSK9和低密度脂蛋白胆固醇的水平分别降低了约90％和约60％。单剂量治疗后，所有这些变化至少稳定了8个月。除了支持“一劳永逸”的方法来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（全球死亡的主要原因）之外，这些结果还概念性验证：如何有效地使用CRISPR碱基编辑器在肝脏以及潜在的其他器官中的治疗靶基因中进行精确的单核苷酸改变 。

据了解，基因编辑技术，包括CRISPR–Cas核酸酶和CRISPR碱基编辑器，具有永久修饰患者致病基因的潜力。在临床试验中向患者体内施用基因编辑器之前，在非人类灵长类动物的靶器官中进行持久编辑测试是关键的一步。

附：英文原文

Title: In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates

Author: Kiran Musunuru, Alexandra C. Chadwick, Taiji Mizoguchi, Sara P. Garcia, Jamie E. DeNizio, Caroline W. Reiss, Kui Wang, Sowmya Iyer, Chaitali Dutta, Victoria Clendaniel, Michael Amaonye, Aaron Beach, Kathleen Berth, Souvik Biswas, Maurine C. Braun, Huei-Mei Chen, Thomas V. Colace, John D. Ganey, Soumyashree A. Gangopadhyay, Ryan Garrity, Lisa N. Kasiewicz, Jennifer Lavoie, James A. Madsen, Yuri Matsumoto, Anne Marie Mazzola, Yusuf S. Nasrullah, Joseph Nneji, Huilan Ren, Athul Sanjeev, Madeleine Shay, Mary R. Stahley, Steven H. Y. Fan, Ying K. Tam, Nicole M. Gaudelli, Giuseppe Ciaramella, Leslie E. Stolz, Padma Malyala, Christopher J. Cheng, Kallanthottathil G. Rajeev, Ellen Rohde, Andrew M. Bellinger, Sekar Kathiresan

Issue&Volume: 2021-05-19

Abstract: Gene-editing technologies, which include the CRISPR–Cas nucleases1,2,3 and CRISPR base editors4,5, 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.

DOI: 10.1038/s41586-021-03534-y

Source: https://www.nature.com/articles/s41586-021-03534-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html