Abstract

Single stranded antisense oligonucleotides (ASO) represent a novel therapeutic modality that opens new space to address previously undruggable targets. In spite of their proven efficacy, the development of promising ASO drug candidates has been limited by reported cases of ASO-associated organ toxicity, primarily seen in tissues of accumulation, mainly liver and kidney after systemic administration and CNS for IT administered drugs. We have developed in vitro screening assays using relevant rodent and human cell models to deselect ASOs with potential safety liabilities prior to in vivo testing. This procedure results in a reduced attrition rate in in vivo safety studies and allows assessment of translatability of effects in rodents to humans early on.