The central nervous system (CNS) is a very promising tissue for the use of antisense oligonucleotides (ASOs), with one drug approved and six others in clinical trials. Nevertheless, we have found that the administration of ASOs to the CNS often causes acute toxicity. In this talk, we use a novel assay to quantify ASO-induced acute toxicity, explore its mechanism, and identify both modification and formulation approaches that provide ASOs with improved therapeutic index in both small (mouse) and large (sheep) brains.
