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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Janas MM,Schlegel MK,Harbison CE,Yilmaz VO,Jiang Y,Parmar R,Zlatev I,Castoreno A,Xu H,Shulga-Morskaya S,Rajeev KG,Manoharan M,Keirstead ND,Maier MA,Jadhav V

doi

10.1038/s41467-018-02989-4

subject

Has Abstract

pub_date

2018-02-19 00:00:00

pages

723

issue

1

issn

2041-1723

pii

10.1038/s41467-018-02989-4

journal_volume

9

pub_type

杂志文章

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