Press Release

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

December 27, 2022

Abstract

Antisense oligonucleotides (ASOs) are promising therapeutics for intractable central nervous system (CNS) diseases. For this clinical application, neurotoxicity is one of critical limitations. Therefore, an evaluation of this neurotoxicity from a behavioral perspective is important to reveal symptomatic dysfunction of 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 effects of modulators against receptors or channels, which regulate calcium influx of neurons, on the ASO-neurotoxicity. Modulators promoting calcium influx mitigated, on the contrary, 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 the present 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.

Journal Article

JOURNALMolecular Therapy - Nucleic Acids

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

DOIhttps://doi.org/10.1016/j.omtn.2022.12.010

Correspondence to

Takanori Yokota, MD, PhD, Professor
Kotaro Yoshioka,Specially Appointed Assistant Professor

Department of Neurology and Neurological Science,
Graduate School of Medical and Dental Sciences,
Tokyo Medical and Dental University (TMDU)
E-mail: tak-yokota.nuro(at)tmd.ac.jp
E-mail: kotanuro(at)tmd.ac.jp       

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