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[摘要]
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。
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[Abstract]
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.
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