N-乙酰半乳糖胺及其衍生物作为小干扰核糖核酸和反义寡核苷酸递送载体的研究进展

Advances in N-acetylgalactosamine and its derivatives as delivery vehicles of small interfering RNA and antisense oligonucleotides

近年来,使用N-乙酰半乳糖胺(GalNAc)缀合物靶向去唾液酸糖蛋白受体来递送寡核苷酸至肝细胞已成为治疗性寡核苷酸领域的突破方法。与传统的寡核苷酸递送方法相比,GalNAc偶联技术是一种更简单的肝脏递送方法,表现出肝靶向特异性、高效性、安全性以及可规模化制备等优势,具有深入开发的研究价值和临床应用的广阔前景。利用GalNAc偶联技术开发的givosiran已被美国FDA批准用于治疗急性肝卟啉症,此外还有7种缀合物处于注册审评或Ⅲ期临床试验中,另外至少还有21种GalNAc核酸缀合物处于临床开发的早期阶段。但国内GalNAc偶联技术相关研究基础比较薄弱,也无相关产品上市,属于“卡脖子”技术,因此本综述重点介绍了GalNAc及其衍生物作为小干扰核糖核酸(siRNA)和反义寡核苷酸(ASO)这2种寡核苷酸递送载体的研究进展,以期为国内GalNAc缀合物的开发提供参考。

In recent years,the use of N-acetylgalactosamine(GalNAc) conjugates to target asialoglycoprotein receptors and further deliver oligonucleotides to hepatocytes has become a breakthrough approach in the field of therapeutic oligonucleotides.Compared with traditional delivery methods of nucleic acid drugs,GalNAc-nucleic acid conjugation is a simple method of liver delivery.It exhibits liver targeting specificity,high efficiency,high safety,large-scale preparation and many other advantages,thus has research value of in-depth development and broad prospects for clinical application.Givosiran,developed using GalNAc conjugation,has been approved by FDA for the treatment of acute hepatic porphyria,and there are 7 other conjugates are in registration review or phase Ⅲ clinical trials,and at least 21 GalNAc nucleic acid conjugates are in the early stages of clinical development.However,the relevant research foundation of GalNAc conjugation in China is relatively weak,and no related products are on the market,making it a neck-stuck technology in China.Therefore,this review focuses on GalNAc and its derivatives as nucleic acid drug delivery vehicles and their application progress in small interfering RNA(siRNA) and antisense oligonucleotides(ASO).This review provides reference for the development of domestic GalNAc conjugates.