文献检索文档翻译深度研究
Suppr Zotero 插件Zotero 插件
邀请有礼套餐&价格历史记录

新学期,新优惠

限时优惠:9月1日-9月22日

30天高级会员仅需29元

1天体验卡首发特惠仅需5.99元

了解详情
不再提醒
插件&应用
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
高级版
套餐订阅购买积分包
AI 工具
文献检索文档翻译深度研究
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利:CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2025

采用瞬时碱基编辑方法治疗小鼠的代谢性肝病。

Treatment of a metabolic liver disease in mice with a transient prime editing approach.

作者信息

Rothgangl Tanja, Tálas András, Ioannidi Eleonora I, Weber Yanik, Böck Desirée, Matsushita Mai, Villiger Elina Andrea, Schmidheini Lukas, Moon Woohyun J, Lin Paulo J C, Fan Steven H Y, Marquart Kim F, Schwerdel Cornelia, Rimann Nicole, Faccin Erica, Villiger Lukas, Muramatsu Hiromi, Vadovics Máté, Cremonesi Alessio, Kulcsár Péter István, Thöny Beat, Kopf Manfred, Häberle Johannes, Pardi Norbert, Tam Ying K, Schwank Gerald

机构信息

Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.

Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.

出版信息

Nat Biomed Eng. 2025 May 20. doi: 10.1038/s41551-025-01399-4.


DOI:10.1038/s41551-025-01399-4
PMID:40394220
Abstract

Prime editing is a versatile genome editing technology that circumvents the need for DNA double-strand break formation and homology-directed repair, making it particularly suitable for in vivo correction of pathogenic mutations. Here we developed liver-specific prime editing approaches with temporally restricted prime editor (PE) expression. We first established a dual-delivery approach where the prime editor guide RNA is continuously expressed from adeno-associated viral vectors and only the PE is transiently delivered as nucleoside-modified mRNA encapsulated in lipid nanoparticles (LNP). This strategy achieved 26.2% editing with PEmax and 47.4% editing with PE7 at the Dnmt1 locus using a single 2 mg kg dose of mRNA-LNP. When targeting the pathogenic Pah mutation in a phenylketonuria mouse model, gene correction rates reached 4.3% with PEmax and 20.7% with PE7 after three doses of 2 mg kg mRNA-LNP, effectively reducing blood L-phenylalanine levels from over 1,500 µmol l to below the therapeutic threshold of 360 µmol l. Encouraged by the high efficiency of PE7, we next explored a simplified approach where PE7 mRNA was co-delivered with synthetic prime editor guide RNAs encapsulated in LNP. This strategy yielded 35.9% editing after two doses of RNA-LNP at the Dnmt1 locus and 8.0% editing after three doses of RNA-LNP at the Pah locus, again reducing L-phenylalanine levels below 360 µmol l. These findings highlight the therapeutic potential of mRNA-LNP-based prime editing for treating phenylketonuria and other genetic liver diseases, offering a scalable and efficient platform for future clinical translation.

摘要

碱基编辑是一种多功能的基因组编辑技术,它无需形成DNA双链断裂和同源定向修复,这使得它特别适合于在体内纠正致病突变。在此,我们开发了具有时间限制的碱基编辑器(PE)表达的肝脏特异性碱基编辑方法。我们首先建立了一种双递送方法,其中碱基编辑器引导RNA从腺相关病毒载体持续表达,而只有PE作为封装在脂质纳米颗粒(LNP)中的核苷修饰mRNA被瞬时递送。使用2mg/kg单剂量的mRNA-LNP,该策略在Dnmt1位点实现了PEmax编辑效率为26.2%,PE7编辑效率为47.4%。在苯丙酮尿症小鼠模型中靶向致病的Pah突变时,在给予三剂2mg/kg mRNA-LNP后,PEmax的基因校正率达到4.3%,PE7的基因校正率达到20.7%,有效地将血液L-苯丙氨酸水平从超过1500µmol/l降低到360µmol/l的治疗阈值以下。受PE7高效率的鼓舞,我们接下来探索了一种简化方法,即PE7 mRNA与封装在LNP中的合成碱基编辑器引导RNA共同递送。该策略在Dnmt1位点给予两剂RNA-LNP后产生了35.9%的编辑效率,在Pah位点给予三剂RNA-LNP后产生了8.0%的编辑效率,同样将L-苯丙氨酸水平降低到360µmol/l以下。这些发现突出了基于mRNA-LNP的碱基编辑在治疗苯丙酮尿症和其他遗传性肝脏疾病方面的治疗潜力,为未来的临床转化提供了一个可扩展且高效的平台。

相似文献

[1]
Treatment of a metabolic liver disease in mice with a transient prime editing approach.

Nat Biomed Eng. 2025-5-20

[2]
In vivo prime editing of a metabolic liver disease in mice.

Sci Transl Med. 2022-3-16

[3]
Treatment of a metabolic liver disease by in vivo genome base editing in adult mice.

Nat Med. 2018-10-8

[4]
Prime Editing by Lipid Nanoparticle Co-delivery of Chemically Modified pegRNA and Prime Editor mRNA.

GEN Biotechnol. 2023-12

[5]
Delivery of nucleic acid based genome editing platforms via lipid nanoparticles: Clinical applications.

Adv Drug Deliv Rev. 2024-8

[6]
Comparative analysis of lipid Nanoparticle-Mediated delivery of CRISPR-Cas9 RNP versus mRNA/sgRNA for gene editing in vitro and in vivo.

Eur J Pharm Biopharm. 2024-3

[7]
Highly efficient generation of isogenic pluripotent stem cell models using prime editing.

Elife. 2022-9-7

[8]
A base editing strategy using mRNA-LNPs for in vivo correction of the most frequent phenylketonuria variant.

HGG Adv. 2024-1-11

[9]
A truncated reverse transcriptase enhances prime editing by split AAV vectors.

Mol Ther. 2022-9-7

[10]
Non-viral Delivery of Zinc Finger Nuclease mRNA Enables Highly Efficient In Vivo Genome Editing of Multiple Therapeutic Gene Targets.

Mol Ther. 2019-3-7

引用本文的文献

[1]
Optimized Ribonucleoprotein Complexes Enhance Prime Editing Efficiency in Zebrafish.

Animals (Basel). 2025-8-6

本文引用的文献

[1]
Prime Editing by Lipid Nanoparticle Co-delivery of Chemically Modified pegRNA and Prime Editor mRNA.

GEN Biotechnol. 2023-12

[2]
Increasing intracellular dNTP levels improves prime editing efficiency.

Nat Biotechnol. 2025-4

[3]
Publisher Correction: Machine learning prediction of prime editing efficiency across diverse chromatin contexts.

Nat Biotechnol. 2025-5

[4]
Enhancing prime editing in hematopoietic stem and progenitor cells by modulating nucleotide metabolism.

Nat Biotechnol. 2025-4

[5]
Improving prime editing with an endogenous small RNA-binding protein.

Nature. 2024-4

[6]
Efficient in vivo prime editing corrects the most frequent phenylketonuria variant, associated with high unmet medical need.

Am J Hum Genet. 2023-12-7

[7]
Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne's Muscular Dystrophy.

N Engl J Med. 2023-9-28

[8]
Targeted genome editing with a DNA-dependent DNA polymerase and exogenous DNA-containing templates.

Nat Biotechnol. 2024-7

[9]
State-of-the-art 2023 on gene therapy for phenylketonuria.

J Inherit Metab Dis. 2024-1

[10]
Rapid and definitive treatment of phenylketonuria in variant-humanized mice with corrective editing.

Nat Commun. 2023-6-10

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

推荐工具

医学文档翻译智能文献检索