RNA干扰
小干扰RNA
核糖核酸
寡核苷酸
药理学
基因沉默
细胞生物学
化学
生物化学
生物
基因
作者
Maja M. Janas,Mark K. Schlegel,Carole Harbison,Vedat O. Yilmaz,Yongfeng Jiang,Rubina Parmar,Ivan Zlatev,Adam Castoreno,Huilei Xu,Svetlana Shulga-Morskaya,Kallanthottathil G. Rajeev,Muthiah Manoharan,Natalie Keirstead,Martin A. Maier,Vasant Jadhav
标识
DOI:10.1038/s41467-018-02989-4
摘要
Small interfering RNAs (siRNAs) conjugated to a trivalent N-acetylgalactosamine (GalNAc) ligand are being evaluated in investigational clinical studies for a variety of indications. The typical development candidate selection process includes evaluation of the most active compounds for toxicity in rats at pharmacologically exaggerated doses. The subset of GalNAc-siRNAs that show rat hepatotoxicity is not advanced to clinical development. Potential mechanisms of hepatotoxicity can be associated with the intracellular accumulation of oligonucleotides and their metabolites, RNA interference (RNAi)-mediated hybridization-based off-target effects, and/or perturbation of endogenous RNAi pathways. Here we show that rodent hepatotoxicity observed at supratherapeutic exposures can be largely attributed to RNAi-mediated off-target effects, but not chemical modifications or the perturbation of RNAi pathways. Furthermore, these off-target effects can be mitigated by modulating seed-pairing using a thermally destabilizing chemical modification, which significantly improves the safety profile of a GalNAc-siRNA in rat and may minimize the occurrence of hepatotoxic siRNAs across species.
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