Unknown

Dataset Information

0

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.

SUBMITTER: Janas MM 

PROVIDER: S-EPMC5818625 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications


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 w  ...[more]

Similar Datasets

2018-01-11 | GSE108823 | GEO
| S-EPMC8377513 | biostudies-literature
| PRJNA428745 | ENA
| S-EPMC5023400 | biostudies-literature
| S-EPMC6731179 | biostudies-literature
| S-EPMC8228246 | biostudies-literature
| S-EPMC8565336 | biostudies-literature
| S-EPMC3909712 | biostudies-literature
| S-EPMC10465356 | biostudies-literature
| S-EPMC5570069 | biostudies-literature