Journal article
Alpha-l-Locked nucleic acid-modified antisense oligonucleotides induce efficient splice modulation in vitro
International Journal of Molecular Sciences, Vol.21(7), Article 2434
2020
Abstract
Alpha-l-Locked nucleic acid (α-l-LNA) is a stereoisomeric analogue of locked nucleic acid (LNA), which possesses excellent biophysical properties and also exhibits high target binding affinity to complementary oligonucleotide sequences and resistance to nuclease degradations. Therefore, α-l-LNA nucleotides could be utilised to develop stable antisense oligonucleotides (AO), which can be truncated without compromising the integrity and efficacy of the AO. In this study, we explored the potential of α-l-LNA nucleotides-modified antisense oligonucleotides to modulate splicing by inducing Dmd exon-23 skipping in mdx mouse myoblasts in vitro. For this purpose, we have synthesised and systematically evaluated the efficacy of α-l-LNA-modified 2′-O-methyl phosphorothioate (2′-OMePS) AOs of three different sizes including 20mer, 18mer and 16mer AOs in parallel to fully-modified 2′-OMePS control AOs. Our results demonstrated that the 18mer and 16mer truncated AO variants showed slightly better exon-skipping efficacy when compared with the fully-23 modified 2′-OMePS control AOs, in addition to showing low cytotoxicity. As there was no previous report on using α-l-LNA-modified AOs in splice modulation, we firmly believe that this initial study could be beneficial to further explore and expand the scope of α-l-LNA-modified AO therapeutic molecules.
Details
- Title
- Alpha-l-Locked nucleic acid-modified antisense oligonucleotides induce efficient splice modulation in vitro
- Authors/Creators
- P. Raguraman (Author/Creator) - Murdoch UniversityT. Wang (Author/Creator) - Murdoch UniversityL. Ma (Author/Creator) - Henan UniversityP.T. Jørgensen (Author/Creator) - University of Southern DenmarkJ. Wengel (Author/Creator) - University of Southern DenmarkR.N. Veedu (Author/Creator) - Murdoch University
- Publication Details
- International Journal of Molecular Sciences, Vol.21(7), Article 2434
- Publisher
- MPDI
- Identifiers
- 991005542905007891
- Copyright
- © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
UN Sustainable Development Goals (SDGs)
This output has contributed to the advancement of the following goals:
Source: InCites
Metrics
53 File views/ downloads
23 Record Views
InCites Highlights
These are selected metrics from InCites Benchmarking & Analytics tool, related to this output
- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 2 Chemistry
- 2.170 Nucleic Acids Chemistry
- 2.170.988 Oligonucleotide Modifications
- Web Of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary
- ESI research areas
- Chemistry