文献类型：期刊文献

英文题名：Alpha-l-Locked Nucleic Acid-Modified Antisense Oligonucleotides Induce Efficient Splice Modulation In Vitro

作者：Raguraman, Prithi[1,2];Wang, Tao[1,2];Ma, Lixia[3];Jorgensen, Per Trolle[4];Wengel, Jesper[4];Veedu, Rakesh N.[1,2,4]

第一作者：Raguraman, Prithi

通讯作者：Veedu, RN[1];Veedu, RN[2];Veedu, RN[3]

机构：[1]Murdoch Univ, Ctr Mol Med & Innovat Therapeut, Perth, WA 6150, Australia;[2]Perron Inst Neurol & Translat Sci, Perth, WA 6005, Australia;[3]Henan Univ Econ & Law, Sch Stat, Zhengzhou 450001, Peoples R China;[4]Univ Southern Denmark, Nucle Acid Ctr, Dept Phys & Chem & Pharm, DK-5230 Odense M, Denmark

第一机构：Murdoch Univ, Ctr Mol Med & Innovat Therapeut, Perth, WA 6150, Australia

通讯机构：[1]corresponding author), Murdoch Univ, Ctr Mol Med & Innovat Therapeut, Perth, WA 6150, Australia;[2]corresponding author), Perron Inst Neurol & Translat Sci, Perth, WA 6005, Australia;[3]corresponding author), Univ Southern Denmark, Nucle Acid Ctr, Dept Phys & Chem & Pharm, DK-5230 Odense M, Denmark.

年份：2020

卷号：21

期号：7

外文期刊名：INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

收录：;Scopus(收录号：2-s2.0-85083042064);WOS:【SCI-EXPANDED(收录号:WOS:000535574200176)】；

基金：P. R thanks the MIPS funding scheme of Murdoch University. R.N.V. acknowledges the funding provided by McCusker Charitable Foundation and the Perron Institute for Neurological and Translational Science. J.W. acknowledges the support from the European Union's Horizon 2020 research and innovation program under grant agreement No 810685.

语种：英文

外文关键词：alpha-l-LNA; locked nucleic acids; antisense oligonucleotides; DMD

摘要：Alpha-l-Locked nucleic acid (alpha-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, alpha-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 alpha-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 alpha-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 alpha-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 alpha-l-LNA-modified AO therapeutic molecules.