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

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-c...

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Main Authors: Masahiro Ohara (Author), Tetsuya Nagata (Author), Rintaro Iwata Hara (Author), Kie Yoshida-Tanaka (Author), Nozomi Toide (Author), Kazunori Takagi (Author), Kazuki Sato (Author), Tomoya Takenaka (Author), Masanori Nakakariya (Author), Kenichi Miyata (Author), Yusuke Maeda (Author), Kazuko Toh (Author), Takeshi Wada (Author), Takanori Yokota (Author)
Format: Book
Published: Elsevier, 2024-09-01T00:00:00Z.
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Summary: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.
Item Description:2162-2531
10.1016/j.omtn.2024.102289

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