Enhancement of the Inhibitory Activity of oatp Antisense Oligonucleotides by Incorporation of 2‘-<i>O</i>,4‘-<i>C</i>-Ethylene-Bridged Nucleic Acids (ENA) without a Loss of Subtype Selectivity

Takagi, M.; Morita, Koji; Nakai, Daisuke; Nakagomi, Rie; Tokui, Taro; Koizumi, Makoto

doi:10.1021/bi035847x

Cited by 19 publications

(19 citation statements)

References 45 publications

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“…We have confirmed the intracellular antisense activity of ENA oligonucleotides against organic anion transporting polypeptide (oatp). [10] The ENA oligonucleotides also exhibit excellent triplex formation with dsDNA. [11] They could be used for exon skipping to bind dystrophin pre-mRNA and inhibit its splicing reaction.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of VEGF mRNA by 2′-O,4′−C−Ethylene-Bridgednucleicacids (ENA®) Antisense Oligonucleotides and Their Influence on Off-Target Gene Expressions

Morita

Yamate²,

Kurakata³

et al. 2006

Nucleosides, Nucleotides and Nucleic Acids

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We investigated 2'-O,4'-C-ethylene-bridged nucleic acids (ENA) antisense oligonucleotides (AONs) for vascular endothelial growth factor (VEGF) in human lung carcinoma A549 cells. An ENA/DNA gapmer AON with RNase H-mediated activity was virtually stable in rat plasma and exhibited more than 90% inhibition of VEGF mRNA production. Moreover, 22 genes that are likely to bind to the AON were found in the GenBank database by BLAST and CLUSTAL W searches. Three of these genes were actually inhibited by the ENA AON. In shorter ENA AONs with fewer matched sequences of these genes, inhibitiory activities were decreased and off-target effects were improved. These results indicate that ENA AONs act in a sequence-specific manner and could be used as effective antisense drugs.

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Section: Introductionmentioning

confidence: 99%

Inhibition of VEGF mRNA by 2′-O,4′−C−Ethylene-Bridgednucleicacids (ENA®) Antisense Oligonucleotides and Their Influence on Off-Target Gene Expressions

Morita

Yamate²,

Kurakata³

et al. 2006

Nucleosides, Nucleotides and Nucleic Acids

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“…It has been demonstrated that fully modified ASOs (i.e., with 2 0 ribose modifications at all nucleotide positions) act predominantly by inhibiting mRNA translation [Crooke, 1999;Fulford et al, 2000]. However, modified ASOs with six to eight DNA bases in the center lacking ribose modification at the 2 0 position (known as ''GAPmers'') efficiently activate RNase H to degrade the target mRNA Zamaratski et al, 2001;ten Asbroek et al, 2002]. Like unmodified and fully modified ASOs, GAPmers form stable duplexes with target mRNA, although the stability is decreased with increasing length of the alkyl chain and with an increasing number of modified nucleotides in a sequence.…”

Section: Asr Chemistries Aso Chemistrymentioning

confidence: 99%

Antisense applications for biological control

Pan

Clawson

2006

J. Cell. Biochem.

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Although Nature's antisense approaches are clearly impressive, this Perspectives article focuses on the experimental uses of antisense reagents (ASRs) for control of biological processes. ASRs comprise antisense oligonucleotides (ASOs), and their catalytically active counterparts ribozymes and DNAzymes, as well as small interfering RNAs (siRNAs). ASOs and ribozymes/DNAzymes target RNA molecules on the basis of Watson-Crick base pairing in sequence-specific manner. ASOs generally result in destruction of the target RNA by RNase-H mediated mechanisms, although they may also sterically block translation, also resulting in loss of protein production. Ribozymes and DNAzymes cleave target RNAs after base pairing via their antisense flanking arms. siRNAs, which contain both sense and antisense regions from a target RNA, can mediate target RNA destruction via RNAi and the RISC, although they can also function at the transcriptional level. A considerable number of ASRs (mostly ASOs) have progressed into clinical trials, although most have relatively long histories in Phase I/II settings. Clinical trial results are surprisingly difficult to find, although few ASRs appear to have yet established efficacy in Phase III levels. Evolution of ASRs has included: (a) Modifications to ASOs to render them nuclease resistant, with analogous modifications to siRNAs being developed; and (b) Development of strategies to select optimal sites for targeting. Perhaps the biggest barrier to effective therapies with ASRs is the "Delivery Problem." Various liposomal vehicles have been used for systemic delivery with some success, and recent modifications appear to enhance systemic delivery, at least to liver. Various nanoparticle formulations are now being developed which may also enhance delivery. Going forward, topical applications of ASRs would seem to have the best chances for success. In summary, modifications to ASRs to enhance stability, improve targeting, and incremental improvements in delivery vehicles continue to make ASRs attractive as molecular therapeutics, but their advance toward the bedside has been agonizingly slow.

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“…17,19,20) ENA-DNA-ENA gapmer-designed oligonucleotides that can undergo RNase H-mediated degradation are used as AONs. When ENA-modified AONs against vascular endothelial growth factor (VEGF) mRNA were introduced into human cancer A549 cells in the presence of a cationic polymer, more than 90% inhibition of VEGF mRNA production was observed after RT-PCR analysis.…”

Section: Application Of Ena Oligonucleotides As Antisense Moleculesmentioning

confidence: 99%

“…19,20) When several ENA residues were incorporated into AONs, the inhibitory activity of these oatp AONs was enhanced. Moreover, these ENA AONs did not lose their oatp-subtype selectivity.…”

Section: Application Of Ena Oligonucleotides As Antisense Moleculesmentioning

confidence: 99%

Enhancement of the Inhibitory Activity of oatp Antisense Oligonucleotides by Incorporation of 2‘-O,4‘-C-Ethylene-Bridged Nucleic Acids (ENA) without a Loss of Subtype Selectivity

Cited by 19 publications

References 45 publications

Inhibition of VEGF mRNA by 2′-O,4′−C−Ethylene-Bridgednucleicacids (ENA®) Antisense Oligonucleotides and Their Influence on Off-Target Gene Expressions

Inhibition of VEGF mRNA by 2′-O,4′−C−Ethylene-Bridgednucleicacids (ENA®) Antisense Oligonucleotides and Their Influence on Off-Target Gene Expressions

Antisense applications for biological control

2'-O,4'-C-Ethylene-Bridged Nucleic Acids (ENA) as Next-Generation Antisense and Antigene Agents

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