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

Autor:	Kamola PJ; Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK; GlaxoSmithKline R&D, Ware SG12 0DP, UK; GlaxoSmithKline R&D, Stevenage SG1 2NY, UK; Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Harwell Science and Innovation Campus, Oxfordshire OX11 0RQ, UK. Electronic address: piotr.kamola@riken.jp., Maratou K; GlaxoSmithKline R&D, Stevenage SG1 2NY, UK., Wilson PA; GlaxoSmithKline R&D, Stevenage SG1 2NY, UK., Rush K; GlaxoSmithKline R&D, Ware SG12 0DP, UK., Mullaney T; GlaxoSmithKline R&D, Ware SG12 0DP, UK., McKevitt T; GlaxoSmithKline R&D, Ware SG12 0DP, UK., Evans P; GlaxoSmithKline R&D, Ware SG12 0DP, UK., Ridings J; GlaxoSmithKline R&D, Ware SG12 0DP, UK., Chowdhury P; GlaxoSmithKline R&D, Ware SG12 0DP, UK., Roulois A; GlaxoSmithKline R&D, Ware SG12 0DP, UK., Fairchild A; GlaxoSmithKline R&D, Ware SG12 0DP, UK., McCawley S; GlaxoSmithKline R&D, Ware SG12 0DP, UK., Cartwright K; GlaxoSmithKline R&D, Ware SG12 0DP, UK., Gooderham NJ; Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK., Gant TW; Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Harwell Science and Innovation Campus, Oxfordshire OX11 0RQ, UK., Moores K; GlaxoSmithKline R&D, Stevenage SG1 2NY, UK., Hughes SA; GlaxoSmithKline R&D, Stevenage SG1 2NY, UK., Edbrooke MR; GlaxoSmithKline R&D, Stevenage SG1 2NY, UK., Clark K; GlaxoSmithKline R&D, Stevenage SG1 2NY, UK., Parry JD; GlaxoSmithKline R&D, Ware SG12 0DP, UK.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2017 Sep 15; Vol. 8, pp. 383-394. Date of Electronic Publication: 2017 Jul 08.
DOI:	10.1016/j.omtn.2017.07.003
Abstrakt:	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 transaminase levels and liver weights) was observed to be predictive of ASO hepatotoxicity ranking established based on a repeat-dose (15 day) study. Furthermore, to study the underlying mechanisms of liver toxicity, we applied transcriptome profiling and pathway analyses and show that adverse in vivo liver phenotypes correlate with the number of potent, hybridization-mediated off-target effects (OTEs). We propose that a combination of in silico OTE predictions, streamlined in vivo hepatotoxicity screening, and a transcriptome-wide selectivity screen is a valid approach to identifying and progressing safer compounds. (Copyright © 2017 GSK R&D. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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