Cas12a chRDNA介导的体内基因组编辑实现高特异性功能基因敲除
Cas12a chRDNA-mediated in vivo genome editing for high specificity functional gene disruption
CRISPR基因编辑需要向导分子精准定位目标DNA，但传统全RNA向导可能误伤其他位点。本研究使用含RNA和DNA混合片段的向导（chRDNA），配合Cas12a核酸酶，用脂质纳米颗粒（LNP，一种包裹核酸并送入体内的脂质载体）静脉注射到野生型小鼠。结果单次给药即高效敲除了Pcsk9、Angptl3和Ttr三个临床相关基因，血浆中对应蛋白几乎完全下降，胆固醇也降低，且未检出脱靶编辑，高剂量下无肝毒性、无慢性细胞因子释放、非肝组织无编辑。作者认为这是安全、高特异、强效的体内编辑工具，但结果来自动物，尚需人体验证。
为什么推荐给您：chRDNA提高Cas12a体内编辑特异性并同时敲除三基因，属有转化前景的新平台技术。
不需要生物学背景，多打比方
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摘要Abstract
CRISPR hybrid guides containing a combination of RNA and DNA nucleotides (CRISPR hybrid RNA-DNA or chRDNA) enhance both Cas9 and Cas12a nuclease specificity and reduce off-target editing in vitro. CRISPR-Cas9 with all-RNA crRNA guides has been implemented for in vivo intervention of familial hypercholesterolemia, an inherited autosomal dominant disorder exhibiting high circulating low-density lipoprotein cholesterol, and transthyretin amyloidosis, a progressive life-threatening disease characterized by accumulation of misfolded transthyretin protein leading to neurodegeneration or cardiomyopathy. We targeted three clinically validated genes, Pcsk9, Angptl3, and Ttr, that address these indications using our Cas12a chRDNA genome-editing technology delivered in lipid nanoparticles (LNP). A single intravenous dose of LNP-encapsulated Cas12a mRNA with a chRDNA guide led to high editing efficiencies without detectable off-target editing, corresponding with near-complete reduction of all three targeted plasma proteins in wild-type mice. Additionally, Pcsk9 and Angptl3 knockouts were accompanied by reductions of plasma cholesterol. No liver toxicity, chronic cytokine release, off-target editing, or on-target editing in non-hepatic tissue was observed in rodents administered high doses. We propose that LNP-delivered Cas12a mRNA and chRDNA is a safe, highly specific, and powerful tool for genome editing in vivo.