title: DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing.
abstract: Antisense oligonucleotides (ASOs) are recognized therapeutic agents for the modulation of specific genes at the post-transcriptional level. Similar to any medical drugs, there are opportunities to improve their efficacy and safety. Here we develop a short DNA/RNA heteroduplex oligonucleotide (HDO) with a structure different from double-stranded RNA used for short interfering RNA and single-stranded DNA used for ASO. A DNA/locked nucleotide acid gapmer duplex with an α-tocopherol-conjugated complementary RNA (Toc-HDO) is significantly more potent at reducing the expression of the targeted mRNA in liver compared with the parent single-stranded gapmer ASO. Toc-HDO also improves the phenotype in disease models more effectively. In addition, the high potency of Toc-HDO results in a reduction of liver dysfunction observed in the parent ASO at a similar silencing effect. HDO technology offers a novel concept of therapeutic oligonucleotides, and the development of this molecular design opens a new therapeutic field.
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan [2] Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Nishina
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan [2] Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
authors.forename: Wenying
authors.initials: W
authors.lastname: Piao
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan [2] Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
authors.forename: Kie
authors.initials: K
authors.lastname: Yoshida-Tanaka
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan [2] Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Sujino
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan [2] Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishina
authors.affiliation: Bioorganic Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita-shi, Osaka 565-0871, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nitta
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan [2] Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Yoshioka
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan [2] Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kuwahara
authors.affiliation: Bioorganic Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita-shi, Osaka 565-0871, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yasuhara
authors.affiliation: Bioorganic Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita-shi, Osaka 565-0871, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Baba
authors.affiliation: The Corporation for Production and Research of Laboratory Primates, 1-16-2 Sakura, Tsukuba-shi, Ibaraki 305-0003, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Ono
authors.affiliation: Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kanjiro
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, California 92010, USA.
authors.forename: Punit P
authors.initials: PP
authors.lastname: Seth
authors.affiliation: Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, California 92010, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Low
authors.affiliation: Department of Life Science and Medical Ethics, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, California 92010, USA.
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: 1] Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [2] Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
authors.affiliation: 1] Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan [2] Bioorganic Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita-shi, Osaka 565-0871, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Obika
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan [2] Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Yokota
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D006937:Hypercholesterolemia / Q000139:chemically induced; D008252:Macaca fascicularis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009692:Nucleic Acid Heteroduplexes / Q000502:physiology*; D009841:Oligonucleotides; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D024502:alpha-Tocopherol / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001055:Apolipoproteins B; D004041:Dietary Fats; D009692:Nucleic Acid Heteroduplexes; D009841:Oligonucleotides; D012333:RNA, Messenger; D024502:alpha-Tocopherol