News

The results of joint research with Luxna Biotec, Inc published in “Nucleic Acid Therapeutics”

2025.04.25

Hepatotoxicity Reduction Profiles of Antisense Oligonucleotides Containing Amido-Bridged Nucleic Acid and 2′-O,4′-C-Spirocyclopropylene Bridged Nucleic Acid

Publication

Amide-bridged nucleic acid (AmNA) and 2′-O,4′-C-spirocyclopropylene-bridged nucleic acid (scpBNA) are bridged nucleic acid analogs with high complementary binding affinity and nuclease resistance. AmNA and scpBNA overcome the hepatotoxicity caused by phosphorothioate-modified gapmers, but the mechanism remains unclear. In this study, we found that antisense oligonucleotides (ASOs) combining AmNA, scpBNA, and phosphodiester (PO) linkages significantly reduced mouse hepatotoxicity. Histopathological findings of the liver observed in the LNA and AmNA-scpBNA groups were attenuated in the AmNA-scpBNA-PO group. Bioinformatics analysis suggested that the reduction in hepatotoxicity may involve the expression changes of mitochondrial-related genes, Atp5o and Sdhb. This study demonstrated that AmNA, scpBNA, and PO modifications could reduce hepatotoxicity and improve the potential of ASOs.
This study is joint research with Luxna Biotech Co., Ltd, and Axcelead DDP performed the pathological analysis and transcriptome analysis. We conducted immunohistochemical analysis using our proprietary anti-PS-ASO antibodies to evaluate the distribution of administered ASOs in liver tissue. In addition, transcriptomic analysis was performed to identify gene expression changes and investigate their potential association with ASO-induced hepatotoxicity. Furthermore, electron microscopy enabled the detection of ultrastructural alterations in tissues and cells triggered by ASO administration.

Axcelead DDP Solution
At Axcelead DDP, we accelerate nucleic acid drug discovery by providing solutions for the visualization and safety evaluation of nucleic acid therapeutics. We offer comprehensive support across all stages of nucleic acid drug discovery—from sequence design and delivery technologies to ADME, efficacy, and safety evaluations. If you are exploring nucleic acid drug development, we invite you to consult with us.

Joined Axcelead Drug Discovery Partners, Inc. in 2017. I am responsible for bioinformatics analysis of mainly transcriptome data.

After graduating from the Department of Veterinary Medicine, Faculty of Agriculture, University of Tokyo, I worked at Takeda Pharmaceutical before joining Axcelead Drug Discovery Partners.

After joining the Drug Safety Research Institute at Takeda Pharmaceutical Company Limited, I transferred to Axcelead Drug Discovery Partners Inc. in 2017.
I’m mainly in charge of clinical pathology for non-clinical trials.

Joined Takeda in 2007, transferred to Axcelead Drug Discovery Partners in 2017 to lead the Integrated Pathology Group, concurrently serving as GM Animal Group Lead from 2024.

After working at Global Takeda, I led the Pathology Department at Axcelead Drug Discovery Partners, Inc. where I’m responsible for consultation and project management on non-clinical safety for small molecules and new modalities.