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Exploring novel therapeutic chemistries in exon-skipping for duchenne muscular dystrophy
Journal article   Peer reviewed

Exploring novel therapeutic chemistries in exon-skipping for duchenne muscular dystrophy

L.T. Bao, P. Herdewijn, V.V. Filichev, S.D. Wilton, S. Fletcher and R.N. Veedu
Journal of Gene Medicine, Vol.20(1)
2018
DOI: https://doi.org/10.1002/jgm.3003
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Abstract

Duchenne muscular dystrophy (DMD) is a muscle wasting, invariably fatal genetic disease caused protein truncating mutations, commonly frame‐shifting deletions of one or more exons in the dystrophin gene that abolish functional dystrophin expression. Induced exon‐skipping therapy using splice‐switching antisense oligonucleotides (AO) has been explored in the treatment of DMD and is currently the only treatment that has been shown to unequivocally slow progression of the disease over several years. In this study, we explored novel nucleic acid chemistries such as anhydrohexitol nucleic acid (HNA), cyclohexenyl nucleic acid (CeNA), altritol nucleic acid (ANA) and Twisted Intercalating Nucleic Acids (TINA) and evaluating their exon‐skipping efficacy in vitro in the H2K mdx mouse cell line. We have designed, synthesised and tested the AOs to induce exon 23 skipping in Dmd pre‐mRNA. We also characterized critical properties of the AOs such as melting temperature with complementary RNA, stability against enzymatic activity, and cytotoxicity by WST‐1 assays. Overall, our results showed that all modified‐AOs efficiently induced exon 23 skipping in H2K cells in vitro, showed high nuclease resistance and no obvious toxicity. In addition, HNA, CeNA and ANA‐modified AOs also limited the unfavourable dual exon 22/23 skipping product. In conclusion, our study highlights the importance of exploring novel antisense chemistries in improving the scope of exon‐skipping therapy, and further systematic investigation of locked nucleic acid (LNA)‐modified AO‐based exon‐skipping is currently underway.

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