Abstract
In the development of antisense oligonucleotides (ASO) drugs for central nervous system (CNS) diseases, nonspecific acute CNS toxicities in non-clinical animal studies have been reported; however, such studies are often evaluated by a different route of administration than the clinical route due to the difficulty of the administration technique in animals. Therefore, as a preliminary study, we administered a toxic ASO, which have been reported to induce convulsions by intracerebroventricular (ICV) dosing to mice, to rats by ICV or lumber intrathecal (IT) dosing and compared the dose levels at convulsion occurrence and the concentrations of the toxic ASO in the brain. Since such toxic ASOs have been reported to suppress neuronal activity in in vitro studies, we also examined electrophysiological evaluation using microelectrode arrays (MEA) in rat primary cortical neurons. In the in vivo study, convulsions were noted in rats at 600 μg/head or higher of ICV dosing, and no convulsions up to 2400 μg/head of IT dosing, but the ASO concentrations in the brain were 41-150 μg/g brain and 24 μg/g brain, respectively. This suggests that the difference in brain concentrations of the ASO might have a significant effect on the convulsion occurrences. In vitro MEA evaluation at 3, 30, and 300 μM, the ASO showed spike inhibition at 3 μM and eliminated spikes at 30 μM or higher. In a follow-up to day 8 of the ASO treatment, spike activity was abolished even at 3 μM.
During this presentation, I will show details of the above results.
