Host: The Japanese Society of Toxicology
Name : The 50th Annual Meeting of the Japanese Society of Toxicology
Date : June 19, 2023 - June 21, 2023
Oligonucleotides (ONs) are preparations consisting of natural or chemically modified nucleotides. ONs can directly target intracellular molecules such as mRNA and non-coding RNA without mediated gene expression. In order to create a highly safe ONs, it is necessary to evaluate appropriately based on the toxicity characteristics of ONs and optimize the compound. Toxicity of ONs can be classified into on-target toxicity due to excessive pharmacological effects caused by hybridization to the target sequence, off-target toxicity in a narrow sense based on effects caused by hybridization to other than the target sequence, and hybridization-independent off-target toxicity based on the chemical property of ONs or effects other than ONs components. Based on these toxicity mechanisms, hepatotoxicity and nephrotoxicity are major issues for ONs administered systemically, e.g. subcutaneously or intravenously, and central nervous system toxicity are major issues for ONs administered centrally, e.g. intrathecally. Although various candidates of ONs can be easily designed based on the target genes, the cost of synthesis is higher than that of small molecules. Therefore, it is desirable to screen the initial toxicity of ONs in a stepwise and effective manner for a large number of candidate sequences. In this topic, based on our findings for Gapmer-type antisense oligonucleotide, we’d like to introduce each strategy for (1) Safety specifications before and at the time of sequence design, (2) Early exploratory toxicity screening, and (3) Late exploratory toxicity screening.
