N-乙酰半乳糖胺偶联小干扰RNA类药物的非临床毒性研究进展

小干扰核糖核酸（siRNA）作为核苷酸类药物，通过RNA干扰（RNAi）特异性诱导基因沉默而发挥作用，在代谢性疾病、抗感染及肿瘤等领域被广泛应用。目前已获批上市4款基于N-乙酰半乳糖胺（GalNAc）偶联技术siRNA药物，汇总分析已上市GalNAc偶联药物的非临床毒性特征及临床不良反应，初步明确非临床研究中毒性常见类型，包括脱靶与非脱靶毒性等。结合GalNAc-siRNA类药物非临床研究实践，了解可预测的脱靶毒性及对于非临床安全性评价中的毒性关注点，以期为GalNAc-siRNA药物临床研究提供参考。

Advances in non-clinical toxicity of N-acetylgalactosamine-conjugated small interfering RNA drugs

Small interfering RNA (siRNA), nucleotide drugs, are interfering with gene silencing specifically through RNA interference (RNAi) and have been widely applied in metabolic diseases, anti-infection and tumor indications. Currently, four siRNA drugs based on N-acetylgalactosamine (GalNAc) conjugated technology have been approved for market. In this paper, we summarized the non-clinical toxicity characteristics and clinical adverse reactions of approved GalNAc drugs, by clarifying the common types of toxicity in non-clinical studies identified, including off-target toxicity and non-off-target toxicity. Combined with the practice of non-clinical studies on GalNAc-siRNA drugs, the predictable off-target toxicity and toxicity concerns in non-clinical safety evaluation were understood to provide references for clinical trials.