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Naked antisense double-stranded DNA oligonucleotide efficiently suppresses BCR-ABL positive leukemic cells

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Summary

Oligonucleotide-based gene silencing, using molecules such as antisense oligonucleotides (ASOs), small interfering RNA, and aptamers, is widely studied. Another approach uses DNA/RNA heteroduplex oligonucleotides (HDOs). Here, we developed an antisense double-stranded DNA oligonucleotide (ADO) by modification of the complementary RNA in an HDO to generate DNA for increasing resistance to nucleases. Naked BCR-ABL-targeting ADO was significantly more potent than siRNA at reducing BCR-ABL chimeric mRNA expression in chronic myeloid leukemia (CML) cell lines. Further, naked BCR-ABL-targeting ADO suppressed BCR-ABL protein levels in a dose-dependent manner, inhibited CML cell proliferation, and augmented the inhibitory effects of imatinib mesylate. In conclusion, ADO technology is an attractive method for therapeutic application.

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Acknowledgements

The authors thank Satomi Nakagawara for her excellent technical assistance.

Funding

This research was partially supported by JSPS KAKENHI Grant Number 16 K09851 to Y. Kubota.

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Authors and Affiliations

  1. Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan

    Toshimi Hoshiko, Yasushi Kubota & Shinya Kimura

  2. Department of Transfusion Medicine, Saga University Hospital, Saga, 849-8501, Japan

    Yasushi Kubota

  3. Rena Therapeutics Inc., Tokyo, 100-0004, Japan

    Takuya Akisawa, Kazuaki Tanigawara & Junichi Yano

  4. Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine, Saga University, Saga, 849-8501, Japan

    Tatsuro Watanabe & Shinya Kimura

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  1. Toshimi Hoshiko
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  2. Yasushi Kubota
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  3. Takuya Akisawa
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  4. Tatsuro Watanabe
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  7. Shinya Kimura
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Correspondence to Yasushi Kubota.

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S. Kimura reports grants from Rena Therapeutics Inc., during the conduct of the study. The remaining authors declare that they have no conflicts of interest.

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Hoshiko, T., Kubota, Y., Akisawa, T. et al. Naked antisense double-stranded DNA oligonucleotide efficiently suppresses BCR-ABL positive leukemic cells. Invest New Drugs 38, 1012–1019 (2020). https://doi.org/10.1007/s10637-019-00862-9

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  • DOI: https://doi.org/10.1007/s10637-019-00862-9

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