DNA/RNA heteroduplex technology with cationic oligopeptide reduces class-related adverse effects of nucleic acid drugs

Masahiro Ohara; Tetsuya Nagata; Rintaro Iwata Hara; Kie Yoshida-Tanaka; Nozomi Toide; Kazunori Takagi; Kazuki Sato; Tomoya Takenaka; Masanori Nakakariya; Kenichi Miyata; Yusuke Maeda; Kazuko Toh; Takeshi Wada; Takanori Yokota

Molecular Therapy: Nucleic Acids (Sep 2024)

DNA/RNA heteroduplex technology with cationic oligopeptide reduces class-related adverse effects of nucleic acid drugs

Masahiro Ohara,
Tetsuya Nagata,
Rintaro Iwata Hara,
Kie Yoshida-Tanaka,
Nozomi Toide,
Kazunori Takagi,
Kazuki Sato,
Tomoya Takenaka,
Masanori Nakakariya,
Kenichi Miyata,
Yusuke Maeda,
Kazuko Toh,
Takeshi Wada,
Takanori Yokota

Affiliations

Masahiro Ohara: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; NucleoTIDE and PepTIDE Drug Discovery Center, 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 Science, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Corresponding author: Tetsuya Nagata, MD, PhD, 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.
Rintaro Iwata Hara: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Corresponding author: Rintaro Iwata Hara, PhD, 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.
Kie Yoshida-Tanaka: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Nozomi Toide: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Kazunori Takagi: Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan
Kazuki Sato: Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan
Tomoya Takenaka: Takeda Pharmaceutical Company Limited, Kanagawa 251-8555, Japan
Masanori Nakakariya: Takeda Pharmaceutical Company Limited, Kanagawa 251-8555, Japan
Kenichi Miyata: Takeda Pharmaceutical Company Limited, Kanagawa 251-8555, Japan
Yusuke Maeda: Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan
Kazuko Toh: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Takeshi Wada: Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan
Takanori Yokota: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Corresponding author: Takanori Yokota, MD, PhD, 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. 35, no. 3
p. 102289

Abstract

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Antisense oligonucleotides (ASOs) are a therapeutic modality for incurable diseases. However, systemic injection of gapmer-type ASOs causes class-related toxicities, including prolongation of activated partial thromboplastin time (aPTT) and thrombocytopenia. We previously reported that cholesterol-conjugated DNA/RNA heteroduplex oligonucleotides (Chol-HDOs) exhibit significantly enhanced gene-silencing effects compared to ASOs, even in the central nervous system, by crossing the blood-brain barrier. In the present study, we initially evaluated the effect of the HDO structure on class-related toxicities. The HDO structure ameliorated the class-related toxicities associated with ASOs, but they remained to some extent. As a further antidote, we have developed artificial cationic oligopeptides, L-2,4-diaminobutanoic acid oligomers (DabOs), which bind to the phosphates in the major groove of the A-type double-helical structure of HDOs. The DabO/Chol-HDO complex showed significantly improved aPTT prolongation and thrombocytopenia in mice while maintaining gene-silencing efficacy. Moreover, the conjugation with DabOs effectively prevented cerebral infarction, a condition frequently observed in mice intravenously injected with high-dose Chol-HDO. These approaches, combining HDO technology with DabOs, offer distinct advantages over conventional strategies in reducing toxicities. Consequently, the DabO/HDO complex represents a promising platform for overcoming the class-related toxicities associated with therapeutic ASOs.

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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