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DOI | 10.1038/s41467-019-08539-w |
Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity | |
Janas, Maja M.; Schlegel, Mark K.; Harbison, Carole E.; Yilmaz, Vedat O.; Jiang, Yongfeng; Parmar, Rubina; Zlatev, Ivan; Castoreno, Adam; Xu, Huilei; Shulga-Morskaya, Svetlana; Rajeev, Kallanthottathil G.; Manoharan, Muthiah; Keirstead, Natalie D.; Maier, Martin A.; Jadhav, Vasant | |
2019-02-08 | |
发表期刊 | NATURE COMMUNICATIONS |
ISSN | 2041-1723 |
出版年 | 2018 |
卷号 | 9 |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | 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. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000425383000003 |
WOS关键词 | RNA ; OLIGONUCLEOTIDE ; EXPRESSION ; DELIVERY ; IMPACT |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/204208 |
专题 | 资源环境科学 |
作者单位 | Alnylam Pharmaceut, 300 Third St, Cambridge, MA 02142 USA |
推荐引用方式 GB/T 7714 | Janas, Maja M.,Schlegel, Mark K.,Harbison, Carole E.,et al. Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity[J]. NATURE COMMUNICATIONS,2019,9. |
APA | Janas, Maja M..,Schlegel, Mark K..,Harbison, Carole E..,Yilmaz, Vedat O..,Jiang, Yongfeng.,...&Jadhav, Vasant.(2019).Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.NATURE COMMUNICATIONS,9. |
MLA | Janas, Maja M.,et al."Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity".NATURE COMMUNICATIONS 9(2019). |
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