Change of intracellular calcium level causes acute neurotoxicity by antisense oligonucleotides via CSF route

Chunyan Jia; Su Su Lei Mon; Ying Yang; Maho Katsuyama; Kie Yoshida-Tanaka; Tetsuya Nagata; Kotaro Yoshioka; Takanori Yokota

Molecular Therapy: Nucleic Acids (Mar 2023)

Change of intracellular calcium level causes acute neurotoxicity by antisense oligonucleotides via CSF route

Chunyan Jia,
Su Su Lei Mon,
Ying Yang,
Maho Katsuyama,
Kie Yoshida-Tanaka,
Tetsuya Nagata,
Kotaro Yoshioka,
Takanori Yokota

Affiliations

Chunyan Jia: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Su Su Lei Mon: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Ying Yang: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Maho Katsuyama: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Kie Yoshida-Tanaka: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Tetsuya Nagata: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Kotaro Yoshioka: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Corresponding author: Kotaro Yoshioka, Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Takanori Yokota: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Corresponding author: Takanori Yokota, Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

Journal volume & issue: Vol. 31
pp. 182 – 196

Abstract

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Antisense oligonucleotides (ASOs) are promising therapeutics for intractable central nervous system (CNS) diseases. For this clinical application, neurotoxicity is one of the critical limitations. Therefore, an evaluation of this neurotoxicity from a behavioral perspective is important to reveal symptomatic dysfunction of the CNS and elucidate the underlying molecular mechanism. We here exploited a behavioral analysis method to categorize and quantify the acute neurotoxicity of mice administered with toxic ASOs via intracerebroventricular injection. The toxic ASOs were found to reduce consciousness and locomotor function in mice in a dose-dependent manner. Mechanistically, we analyzed the effects of modulators against receptors or channels, which regulate calcium influx of neurons, on the ASO neurotoxicity. Modulators promoting calcium influx mitigated, whereas those hindering calcium influx increased, in vivo neurotoxicity of ASOs in mice. In an in vitro assay to evaluate intracellular free calcium levels using rat primary cortical neurons, toxic ASOs reduced the calcium levels. The findings of this study demonstrated the behavioral characteristics of ASO-induced neurotoxicity and revealed that changes in intracellular free calcium levels are a part of the mechanism underlying the neurotoxic effects of ASO.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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