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Evaluation of exon skipping using novel chemically-modified antisense oligonucleotides

Veedu, R.N. (2018) Evaluation of exon skipping using novel chemically-modified antisense oligonucleotides. Journal of Gene Medicine, 20 (1).

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Antisense oligonucleotides (AOs) have gained significant interest in recent years towards the development of therapeutics against several diseases. AOs can be used to regulate the function of RNAs by skipping or retaining a specific exon inmessenger RNAs (mRNAs) during the RNA splicing process within the nucleus. To improve the pharmacodynamics of AOs, chemical modifications are normally used. Towards this, a number of nucleic acid analogues have been developed in recent years.On September 19th 2016, Eteplirsen, an AO with Phosphorodiamidate morpholino (PMO) chemistry targeting DMD exon‐51 has been conditionally approved by the US FDA for the treatment of Duchenne muscular dystrophy (DMD). We have investigated the potential of various chemically‐modified exon‐skipping AOs to induce exon‐23 skipping in DMD as model towards improving exon‐skipping efficacy. Very recently, we developed a novel analogue of PMO called morpholino nucleic acid (MNA) as the current PMO is not compatible with standard oligonucleotide chemistries, and large‐scale production is difficult making PMO very expensive. We investigated the potential of MNA to induce exon‐23 skipping in DMD, and found that the MNA‐modified AO efficiently induced exon‐23 skipping in mdx mice myotubes. We also investigated the potential of various other chemistries such as anhydrohexitol nucleic acid (HNA), althreitol nucleic acid (ANA), cyclohexenyl nucleic acid (CeNA), ortho‐twisted intercalating nucleic acids (oTINA) and locked nucleic acids (LNA) to induce exon‐23 skipping in DMD, and observed that these modifications can also yield efficient exon‐23 skipping.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Comparative Genomics
Publisher: John Wiley & Sons
Copyright: © 2018 John Wiley & Sons, Ltd.
Other Information: Abstract taken from Joint 10th Australasian Gene and Cell Therapy Society (AGCTS) and Australasian Society for Stem Cell Research (ASSCR) Annual Scientific Meeting
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