Journal Article

DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing

Obika, Satoshi, Miyata, Kanjiro, Nishina, Tomoko, Nishina, Kazutaka, Yokota, Takanori, Yoshida-Tanaka, Kie, Yoshioka, Kotaro, Low, Audrey, Sujino, Yumiko, Yamamoto, Tsuyoshi, Bennett, C. Frank, Ono, Fumiko, Seth, Punit P., Mizusawa, Hidehiro, Kataoka, Kazunori, Yoshida, Masayuki, Miyake, Koichi, Kuwahara, Hiroya, Piao, Wenying, Yasuhara, Hidenori, Baba, Takeshi, Nitta, Keiko

2015

Overview

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. Antisense oligonucleotides (ASOs) can repress the expression of specific genes. Here, the authors show that a DNA/RNA heteroduplex oligonucleotide (HDO) with a structure different from ASOs is more potent in suppressing target gene expression, and causes a less adverse effect in mouse liver.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/61 / 38/71 / 38/77 / 38/90 / 631/337/176/2016 / 631/61/338 / 631/61/391 / alpha-Tocopherol - chemistry / alpha-Tocopherol - pharmacology / Animals / Apolipoproteins B - genetics / Apolipoproteins B - metabolism / Base Sequence / Deoxyribonucleic acid / Dietary Fats - administration & dosage / Dietary Fats - adverse effects / DNA / Drug dosages / Gene Silencing - physiology / Humanities and Social Sciences / Humans / Hypercholesterolemia - chemically induced / Ligands / Lipids / Macaca fascicularis / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / multidisciplinary / Nucleic Acid Heteroduplexes - physiology / Oligonucleotides / RNA, Messenger - genetics / RNA, Messenger - metabolism / Science / Science (multidisciplinary)