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碱基编辑:治疗进展与机制洞察

Prime editing: therapeutic advances and mechanistic insights.

作者信息

Murray Joss B, Harrison Patrick T, Scholefield Janine

机构信息

Department of Physiology, University College Cork, Cork, Ireland.

Division of Pulmonary Medicine, Cincinnati Children's Hospital, Cincinnati, OH, USA.

出版信息

Gene Ther. 2025 Mar;32(2):83-92. doi: 10.1038/s41434-024-00499-1. Epub 2024 Nov 28.

Abstract

We are often confronted with a simple question, "which gene editing technique is the best?"; the simple answer is "there isn't one". In 2021, a year after prime editing first made its mark, we evaluated the landscape of this potentially transformative advance in genome engineering towards getting treatments to the clinic [1]. Nearly 20% of the papers we cited were still in pre-print at the time which serves to indicate how early-stage the knowledge base was at that time. Now, three years later, we take a look at the landscape and ask what has been learnt to ensure this tech is broadly accessible, highlighting some key advances, especially those that push this towards the clinic. A big part of the appeal of prime editing is its ability to precisely edit DNA without double stranded breaks, and to install any of the 12 possible single-nucleotide conversion events as well as small insertions and/or deletions, or essentially any combination thereof. Over the last few decades, other transformative and Nobel prize-winning technologies that rely on Watson-Crick base-pairing such as PCR, site-directed mutagenesis, RNA interference, and one might say, "classic" CRISPR, were swiftly adopted across labs around the world because of the speed with which mechanistic rules governing their efficiency were determined. Whilst this perspective focuses on the context of gene therapy applications of prime editing, we also further look at the recent studies which have increased our understanding of the mechanism of PEs and simultaneously improved the efficiency and diversity of the PE toolbox.

摘要

我们常常会面临一个简单的问题

“哪种基因编辑技术是最好的?”;简单的答案是“没有一种”。2021年,在碱基编辑首次崭露头角一年后,我们评估了基因组工程这一潜在变革性进展迈向临床应用的情况[1]。我们引用的论文中近20%在当时仍处于预印本阶段,这表明当时的知识库处于多么早期的阶段。现在,三年过去了,我们审视这一领域,询问学到了什么以确保这项技术能够广泛应用,突出一些关键进展,尤其是那些推动其迈向临床的进展。碱基编辑的一大吸引力在于它能够精确编辑DNA而不产生双链断裂,并能够实现12种可能的单核苷酸转换事件中的任何一种以及小片段插入和/或缺失,或者基本上是它们的任何组合。在过去几十年里,其他依赖沃森-克里克碱基配对的变革性且获得诺贝尔奖的技术,如聚合酶链反应(PCR)、定点诱变、RNA干扰,以及可以说“经典”的CRISPR,由于确定其效率的机制规则速度很快,在世界各地的实验室中迅速得到采用。虽然这一观点聚焦于碱基编辑在基因治疗应用中的背景,但我们也进一步审视了最近的研究,这些研究增进了我们对碱基编辑器机制的理解,同时提高了碱基编辑工具箱的效率和多样性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4e0/11946880/eff74b7bf344/41434_2024_499_Fig1_HTML.jpg

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