Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity

Maja M. Janas, Mark K. Schlegel, Carole E. Harbison, Vedat O. Yilmaz, Yongfeng Jiang, Rubina Parmar, Ivan Zlatev, Adam Castoreno, Huilei Xu, Svetlana Shulga-Morskaya, Kallanthottathil G. Rajeev, Muthiah Manoharan, Natalie D. Keirstead, Martin A. Maier and Vasant Jadhav ()
Additional contact information
Maja M. Janas: Alnylam Pharmaceuticals
Mark K. Schlegel: Alnylam Pharmaceuticals
Carole E. Harbison: Alnylam Pharmaceuticals
Vedat O. Yilmaz: Alnylam Pharmaceuticals
Yongfeng Jiang: Alnylam Pharmaceuticals
Rubina Parmar: Alnylam Pharmaceuticals
Ivan Zlatev: Alnylam Pharmaceuticals
Adam Castoreno: Alnylam Pharmaceuticals
Huilei Xu: Alnylam Pharmaceuticals
Svetlana Shulga-Morskaya: Alnylam Pharmaceuticals
Kallanthottathil G. Rajeev: Alnylam Pharmaceuticals
Muthiah Manoharan: Alnylam Pharmaceuticals
Natalie D. Keirstead: Alnylam Pharmaceuticals
Martin A. Maier: Alnylam Pharmaceuticals
Vasant Jadhav: Alnylam Pharmaceuticals

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-02989-4

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