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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| Format: | Article |
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MDPI AG
2021-10-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/11/1113 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T05:10:04Z |
| format | Article |
| id | doaj.art-859912fa29444673b665f4b3783ea3bc |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T05:10:04Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-859912fa29444673b665f4b3783ea3bc2023-11-23T00:55:27ZengMDPI AGPharmaceuticals1424-82472021-10-011411111310.3390/ph14111113Intramuscular Evaluation of Chimeric Locked Nucleic Acid/2′<i>O</i>Methyl-Modified Antisense Oligonucleotides for Targeted Exon 23 Skipping in Mdx MiceMichaella Georgiadou0Melina Christou1Kleitos Sokratous2Jesper Wengel3Kyriaki Michailidou4Kyriacos Kyriacou5Andrie Koutsoulidou6Nikolaos P. Mastroyiannopoulos7Leonidas A. Phylactou8Molecular Genetics, Function & Therapy Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, CyprusMolecular Genetics, Function & Therapy Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, CyprusBioinformatics Group, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, CyprusDepartment of Physics, Chemistry and Pharmacy, University of Southern Denmark, DK-5230 Odense, DenmarkBiostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, CyprusCancer Genetics, Therapeutics & Ultrastructural Pathology Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, CyprusMolecular Genetics, Function & Therapy Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, CyprusMolecular Genetics, Function & Therapy Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, CyprusMolecular Genetics, Function & Therapy Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, CyprusDuchenne 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.https://www.mdpi.com/1424-8247/14/11/1113DMDexon skippingantisense oligonucleotidesLNA/2′<i>O</i>Memdx |
| spellingShingle | 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 Pharmaceuticals DMD exon skipping antisense oligonucleotides LNA/2′<i>O</i>Me mdx |
| 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_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_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_sort | intramuscular evaluation of chimeric locked nucleic acid 2 i o i methyl modified antisense oligonucleotides for targeted exon 23 skipping in mdx mice |
| topic | DMD exon skipping antisense oligonucleotides LNA/2′<i>O</i>Me mdx |
| url | https://www.mdpi.com/1424-8247/14/11/1113 |
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