Strategies for In Vivo Screening and Mitigation of Hepatotoxicity Associated with Antisense Drugs.

ABSTRACT: Antisense oligonucleotide (ASO) gapmers downregulate gene expression by inducing enzyme-dependent degradation of targeted RNA and represent a promising therapeutic platform for addressing previously undruggable genes. Unfortunately, their therapeutic application, particularly that of the more potent chemistries (e.g., locked-nucleic-acid-containing gapmers), has been hampered by their frequent hepatoxicity, which could be driven by hybridization-mediated interactions. An early de-risking of this liability is a crucial component of developing safe, ASO-based drugs. To rank ASOs based on their effect on the liver, we have developed an acute screen in the mouse that can be applied early in the drug development cycle. A single-dose (3-day) screen with streamlined endpoints (i.e., plasma transa

SUBMITTER: Kamola PJ 

PROVIDER: S-EPMC5537172 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature