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Journal of Nucleic Acids
Volume 2012 (2012), Article ID 707323, 7 pages
Research Article

Superior Silencing by 2′,4′-BNANC-Based Short Antisense Oligonucleotides Compared to 2′,4′-BNA/LNA-Based Apolipoprotein B Antisense Inhibitors

1Applied Biopharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
2Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan
3BNA Inc, 7-7-20 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan

Received 13 June 2012; Revised 17 August 2012; Accepted 18 August 2012

Academic Editor: Masayasu Kuwahara

Copyright © 2012 Tsuyoshi Yamamoto et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The duplex stability with target mRNA and the gene silencing potential of a novel bridged nucleic acid analogue are described. The analogue, , - antisense oligonucleotides (AONs) ranging from 10- to 20-nt-long, targeted apolipoprotein B. , - was directly compared to its conventional bridged (or locked) nucleic acid ( , -BNA/LNA)-based counterparts. Melting temperatures of duplexes formed between , - -based antisense oligonucleotides and the target mRNA surpassed those of 2′,4′-BNA/LNA-based counterparts at all lengths. An in vitro transfection study revealed that when compared to the identical length , -BNA/LNA-based counterpart, the corresponding , - -based antisense oligonucleotide showed significantly stronger inhibitory activity. This inhibitory activity was more pronounced in shorter (13-, 14-, and 16-mer) oligonucleotides. On the other hand, the 2′,4′-BNANC-based 20-mer AON exhibited the highest affinity but the worst value, indicating that very high affinity may undermine antisense potency. These results suggest that the potency of AONs requires a balance between reward term and penalty term. Balance of these two parameters would depend on affinity, length, and the specific chemistry of the AON, and fine-tuning of this balance could lead to improved potency. We demonstrate that , - may be a better alternative to conventional , -BNA/LNA, even for “short” antisense oligonucleotides, which are attractive in terms of drug-likeness and cost-effective bulk production.