Academic Journal
Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity
| العنوان: | Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity |
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| المؤلفون: | 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 |
| المصدر: | Nature Communications ; volume 9, issue 1 ; ISSN 2041-1723 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2018 |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41467-018-02989-4 |
| الاتاحة: | http://dx.doi.org/10.1038/s41467-018-02989-4 https://www.nature.com/articles/s41467-018-02989-4 https://www.nature.com/articles/s41467-018-02989-4.pdf |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.6A3E530C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-018-02989-4 |
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