经mRNA工程设计的CRISPR-Cas表观遗传编辑器可以使基因沉默在体内持续且高效
Chao Xu1, Chen Zeng1, Mengge Wang1
1Institute of Advanced Biotechnology, Institute of Homeostatic Medicine, and School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
Innovation (Cambridge (Mass.))
|March 6, 2026
概括
我们开发了小型的mRNA传递表观遗传编辑器 (EEs),用于长期的基因沉默,而无需改变DNA. 这些编辑器通过脂质纳米颗粒 (LNP) 传递,有效降低小鼠的胆固醇超过180天.
科学领域:
- 基因编辑和表观遗传学
- 治疗性输送系统治疗性输送系统
- 分子和遗传医学是分子和遗传医学.
背景情况:
- 可编程表观遗传编辑器 (EEs) 提供了长期基因调制的治疗潜力,而无需改变DNA.
- 目前基于CRISPR的表观基因组编辑器由于其大分子尺寸而面临交付挑战,这阻碍了临床翻译.
- 高效的体内输送对于表观遗传编辑技术的治疗应用至关重要.
研究的目的:
- 为了设计紧的mRNA传递表观遗传编辑器 (CRISPR OFF-EE),以改善体内传递.
- 在临床前模型中评估这些新型编辑器的有效性和耐用性.
- 评估工程表观遗传编辑器的安全性和特异性.
主要方法:
- 使用Streptococcus pyogenes Cas9 (SpCas9),int-split-SpCas9和较小的Cas-SF01.01的紧型表观遗传编辑器的合理设计和工程.
- 优化mRNA架构和脂质纳米粒子 (LNP) 配方,以实现高效的输送.
- 在小鼠体内给予mRNA输出的针对PCSK9的OFF-EE,以评估PCSK9和LDL-C水平的降低.
主要成果:
- 一次静脉内输入优化OFF-EE V2mRNA的LNP给药导致循环PCSK9 (~83.2%) 和LDL-C (~51.4%) 持续减少至少180天.
- 与基于SpCas9的编辑器相比,基于SF01的EE表现出优异的特异性,减少了目标外甲基化.
- 优化的LNP配方表现出良好的安全性,主要具有肝脏特异性活性.
结论:
- 已经建立了一个强大的和多功能平台,用于使用暂时交付的,工程的mRNA编辑器进行体内表观遗传沉默.
- 这些紧的mRNA输送的EEs对推进体内疗法具有重大前景.
- 这些发现支持精确和持久的表观遗传沉默治疗遗传疾病的潜力.
相关概念视频
01:28CRISPR/Cas9 Genome Editing
2.2K
The CRISPR-Cas system serves as a bacterial defense mechanism against invading genetic elements such as viruses and plasmids, forming the foundation for its adaptation as a powerful genome-editing tool. Originally discovered in prokaryotes, this system has been repurposed to revolutionize genetic engineering across a wide range of organisms, including plants, animals, and humans. The core component, Cas9, is an endonuclease derived from Streptococcus pyogenes, capable of introducing...
2.2K
01:59CRISPR
58.5K
Genome editing technologies allow scientists to modify an organism’s DNA via the addition, removal, or rearrangement of genetic material at specific genomic locations. These types of techniques could potentially be used to cure genetic disorders such as hemophilia and sickle cell anemia. One popular and widely used DNA-editing research tool that could lead to safe and effective cures for genetic disorders is the CRISPR-Cas9 system. CRISPR-Cas9 stands for Clustered Regularly Interspaced...
58.5K
02:15Experimental RNAi
8.1K
RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
8.1K
02:53CRISPR and crRNAs
19.4K
Bacteria and archaea are susceptible to viral infections just like eukaryotes; therefore, they have developed a unique adaptive immune system to protect themselves. Clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins (CRISPR-Cas) are present in more than 45% of known bacteria and 90% of known archaea.
The CRISPR-Cas system stores a copy of foreign DNA in the host genome and uses it to identify the foreign DNA upon reinfection. CRISPR-Cas has three different...
The CRISPR-Cas system stores a copy of foreign DNA in the host genome and uses it to identify the foreign DNA upon reinfection. CRISPR-Cas has three different...
19.4K