Intramuscular Evaluation of Chimeric Locked Nucleic Acid/2′<i>O</i>Methyl-Modified Antisense Oligonucleotides for Targeted Exon 23 Skipping in Mdx Mice

Duchenne muscular dystrophy (DMD) is a fatal disorder characterised by progressive muscle wasting. It is caused by mutations in the dystrophin gene, which disrupt the open reading frame leading to the loss of functional dystrophin protein in muscle fibres. Antisense oligonucleotide (AON)-mediated sk...

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Autores principales:	Michaella Georgiadou, Melina Christou, Kleitos Sokratous, Jesper Wengel, Kyriaki Michailidou, Kyriacos Kyriacou, Andrie Koutsoulidou, Nikolaos P. Mastroyiannopoulos, Leonidas A. Phylactou
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	DMD exon skipping antisense oligonucleotides LNA/2′<i>O</i>Me mdx Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/859912fa29444673b665f4b3783ea3bc
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spelling	oai:doaj.org-article:859912fa29444673b665f4b3783ea3bc2021-11-25T18:39:28ZIntramuscular Evaluation of Chimeric Locked Nucleic Acid/2′<i>O</i>Methyl-Modified Antisense Oligonucleotides for Targeted Exon 23 Skipping in Mdx Mice10.3390/ph141111131424-8247https://doaj.org/article/859912fa29444673b665f4b3783ea3bc2021-10-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1113https://doaj.org/toc/1424-8247Duchenne muscular dystrophy (DMD) is a fatal disorder characterised by progressive muscle wasting. It is caused by mutations in the dystrophin gene, which disrupt the open reading frame leading to the loss of functional dystrophin protein in muscle fibres. Antisense oligonucleotide (AON)-mediated skipping of the mutated exon, which allows production of a truncated but partially functional dystrophin protein, has been at the forefront of DMD therapeutic research for over two decades. Nonetheless, novel nucleic acid modifications and AON designs are continuously being developed to improve the clinical benefit profile of current drugs in the DMD pipeline. We herein designed a series of 15mer and 20mer AONs, consisting of 2′<i>O</i>-Methyl (2′<i>O</i>Me)- and locked nucleic acid (LNA)-modified nucleotides in different percentage compositions, and assessed their efficiency in inducing exon 23 skipping and dystrophin restoration in locally injected muscles of mdx mice. We demonstrate that LNA/2′<i>O</i>Me AONs with a 30% LNA composition were significantly more potent in inducing exon skipping and dystrophin restoration in treated mdx muscles, compared to a previously tested 2′<i>O</i>Me AON and LNA/2′<i>O</i>Me chimeras with lower or higher LNA compositions. These results underscore the therapeutic potential of LNA/2′<i>O</i>Me AONs, paving the way for further experimentation to evaluate their benefit-toxicity profile following systemic delivery.Michaella GeorgiadouMelina ChristouKleitos SokratousJesper WengelKyriaki MichailidouKyriacos KyriacouAndrie KoutsoulidouNikolaos P. MastroyiannopoulosLeonidas A. PhylactouMDPI AGarticleDMDexon skippingantisense oligonucleotidesLNA/2′<i>O</i>MemdxMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1113, p 1113 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DMD exon skipping antisense oligonucleotides LNA/2′<i>O</i>Me mdx Medicine R Pharmacy and materia medica RS1-441
spellingShingle	DMD exon skipping antisense oligonucleotides LNA/2′<i>O</i>Me mdx Medicine R Pharmacy and materia medica RS1-441 Michaella Georgiadou Melina Christou Kleitos Sokratous Jesper Wengel Kyriaki Michailidou Kyriacos Kyriacou Andrie Koutsoulidou Nikolaos P. Mastroyiannopoulos Leonidas A. Phylactou Intramuscular Evaluation of Chimeric Locked Nucleic Acid/2′<i>O</i>Methyl-Modified Antisense Oligonucleotides for Targeted Exon 23 Skipping in Mdx Mice
description	Duchenne muscular dystrophy (DMD) is a fatal disorder characterised by progressive muscle wasting. It is caused by mutations in the dystrophin gene, which disrupt the open reading frame leading to the loss of functional dystrophin protein in muscle fibres. Antisense oligonucleotide (AON)-mediated skipping of the mutated exon, which allows production of a truncated but partially functional dystrophin protein, has been at the forefront of DMD therapeutic research for over two decades. Nonetheless, novel nucleic acid modifications and AON designs are continuously being developed to improve the clinical benefit profile of current drugs in the DMD pipeline. We herein designed a series of 15mer and 20mer AONs, consisting of 2′<i>O</i>-Methyl (2′<i>O</i>Me)- and locked nucleic acid (LNA)-modified nucleotides in different percentage compositions, and assessed their efficiency in inducing exon 23 skipping and dystrophin restoration in locally injected muscles of mdx mice. We demonstrate that LNA/2′<i>O</i>Me AONs with a 30% LNA composition were significantly more potent in inducing exon skipping and dystrophin restoration in treated mdx muscles, compared to a previously tested 2′<i>O</i>Me AON and LNA/2′<i>O</i>Me chimeras with lower or higher LNA compositions. These results underscore the therapeutic potential of LNA/2′<i>O</i>Me AONs, paving the way for further experimentation to evaluate their benefit-toxicity profile following systemic delivery.
format	article
author	Michaella Georgiadou Melina Christou Kleitos Sokratous Jesper Wengel Kyriaki Michailidou Kyriacos Kyriacou Andrie Koutsoulidou Nikolaos P. Mastroyiannopoulos Leonidas A. Phylactou
author_facet	Michaella Georgiadou Melina Christou Kleitos Sokratous Jesper Wengel Kyriaki Michailidou Kyriacos Kyriacou Andrie Koutsoulidou Nikolaos P. Mastroyiannopoulos Leonidas A. Phylactou
author_sort	Michaella Georgiadou
title	Intramuscular Evaluation of Chimeric Locked Nucleic Acid/2′<i>O</i>Methyl-Modified Antisense Oligonucleotides for Targeted Exon 23 Skipping in Mdx Mice
title_short	Intramuscular Evaluation of Chimeric Locked Nucleic Acid/2′<i>O</i>Methyl-Modified Antisense Oligonucleotides for Targeted Exon 23 Skipping in Mdx Mice
title_full	Intramuscular Evaluation of Chimeric Locked Nucleic Acid/2′<i>O</i>Methyl-Modified Antisense Oligonucleotides for Targeted Exon 23 Skipping in Mdx Mice
title_fullStr	Intramuscular Evaluation of Chimeric Locked Nucleic Acid/2′<i>O</i>Methyl-Modified Antisense Oligonucleotides for Targeted Exon 23 Skipping in Mdx Mice
title_full_unstemmed	Intramuscular Evaluation of Chimeric Locked Nucleic Acid/2′<i>O</i>Methyl-Modified Antisense Oligonucleotides for Targeted Exon 23 Skipping in Mdx Mice
title_sort	intramuscular evaluation of chimeric locked nucleic acid/2′<i>o</i>methyl-modified antisense oligonucleotides for targeted exon 23 skipping in mdx mice
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/859912fa29444673b665f4b3783ea3bc
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Intramuscular Evaluation of Chimeric Locked Nucleic Acid/2′<i>O</i>Methyl-Modified Antisense Oligonucleotides for Targeted Exon 23 Skipping in Mdx Mice

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