DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing
| Autor: | Wenying Piao, Takanori Yokota, Hiroya Kuwahara, Satoshi Obika, Masayuki Yoshida, Tsuyoshi Yamamoto, Koichi Miyake, Punit P. Seth, Kie Yoshida-Tanaka, C. Frank Bennett, Kazunori Kataoka, Hidehiro Mizusawa, Tomoko Nishina, Takeshi Baba, Kanjiro Miyata, Keiko Nitta, Fumiko Ono, Audrey Low, Kotaro Yoshioka, Yumiko Sujino, Kazutaka Nishina, Hidenori Yasuhara |
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| Rok vydání: | 2015 |
| Předmět: |
Small interfering RNA
Hypercholesterolemia alpha-Tocopherol Oligonucleotides General Physics and Astronomy Mice Transgenic Biology Article General Biochemistry Genetics and Molecular Biology Mice chemistry.chemical_compound Animals Humans Gene silencing Gene Silencing RNA Messenger Gene Apolipoproteins B Mice Knockout Messenger RNA Multidisciplinary Base Sequence Oligonucleotide Nucleic Acid Heteroduplexes RNA General Chemistry Dietary Fats Molecular biology Mice Inbred C57BL Macaca fascicularis RNA silencing chemistry DNA |
| Zdroj: | Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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