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Issue 92, 2016
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Evaluation of anhydrohexitol nucleic acid, cyclohexenyl nucleic acid and D-altritol nucleic acid-modified 2′-O-methyl RNA mixmer antisense oligonucleotides for exon skipping in vitro

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Abstract

Antisense oligonucleotide (AO) mediated exon skipping has been widely explored as a therapeutic strategy for several diseases, in particular, for rare genetic disorders such as Duchenne muscular dystrophy (DMD). To date, the potential of anhydrohexitol nucleic acid (HNA), cyclohexenyl nucleic acid (CeNA) and altritol nucleic acid (ANA) has not been explored in exon skipping. For the first time, in this study we designed and synthesised HNA, CeNA and ANA-modified 2′-O-methyl (2′-OMe) mixmer AOs on a phosphorothioate (PS) backbone, and evaluated their potential to induce exon 23 skipping in mdx mouse myotubes, as a model system. Our results clearly showed that all three AO candidates modified with HNA, CeNA and ANA could efficiently induce Dmd exon 23 skipping in vitro in parallel to the fully modified 2′-OMePS AO with reduced dual exon 22/23 skipping. In addition, they showed high nuclease resistance and no cytotoxicity compared to the 2′-OMePS AO, demonstrating the applicability of HNA, CeNA and ANA nucleotide-modified AOs in exon skipping.

Graphical abstract: Evaluation of anhydrohexitol nucleic acid, cyclohexenyl nucleic acid and d-altritol nucleic acid-modified 2′-O-methyl RNA mixmer antisense oligonucleotides for exon skipping in vitro

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Publication details

The article was received on 12 Sep 2016, accepted on 20 Oct 2016 and first published on 21 Oct 2016


Article type: Communication
DOI: 10.1039/C6CC07447B
Citation: Chem. Commun., 2016,52, 13467-13470
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    Evaluation of anhydrohexitol nucleic acid, cyclohexenyl nucleic acid and D-altritol nucleic acid-modified 2′-O-methyl RNA mixmer antisense oligonucleotides for exon skipping in vitro

    B. T. Le, S. Chen, M. Abramov, P. Herdewijn and R. N. Veedu, Chem. Commun., 2016, 52, 13467
    DOI: 10.1039/C6CC07447B

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