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Splice-Switching Antisense Oligonucleotides: 30 Years after Advocating Exon-Skipping Therapy for Duchenne Muscular Dystrophy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 February 2025) | Viewed by 1925

Special Issue Editor

Prof. Dr. Masafumi Matsuo

E-Mail Website
Guest Editor
Graduate School of Science, Technology and Innovation, Kobe University, Kobe 651-2180, Hyogo, Japan
Interests: duchenne muscular dystrophy; neuroimuscular diseasese; molecular genetics; splicing; antisense oligonucleotides

Special Issue Information

Dear Colleagues,

The year 2025 marks 30 years since we proposed a treatment for Duchenne muscular dystrophy (D MD) using antisense oligonucleotides (ASOs) to induce exon skipping, and consequently, dystrophin expression. When we proposed this treatment in 1995, we were afraid it would fizzle out, like a match lit in a cold sky. However, the development of splice-switching ASO-based therapies has spread like wildfire over the past 30 years. Today, four ASOs that induce exon skipping, as DMD therapies, offer great hope for patients worldwide. In addition, one ASO that promotes exon incorporation into mRNA has produced a treatment for spinal muscular atrophy. Recently, an ASO that treats only one patient has presented us with the ultimate personalized medicine. In addition, ASOs that carry out splice switching have been applied to redirect gene function for the effective treatment of diseases. At the same time, studies on the chemical modification or delivery of nucleic acids for improving the efficacy of ASOs are also making great progress. This Special Issue highlights studies on splice-switching ASOs in these various areas, which we hope will serve as a cornerstone for the future of ASO drugs. We welcome submissions from the many researchers involved in ASO studies.

Prof. Dr. Masafumi Matsuo
Guest Editor

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Keywords

  • antisense oligonucleotides
  • modified nucleic acid
  • splicing
  • splicing switch
  • exon skipping
  • pseudoexon
  • N-of-1
  • precision medicine

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Published Papers (3 papers)

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13 pages, 1187 KiB  
Article
Sequence-Specific Free Energy Changes in DNA/RNA Induced by a Single LNA-T Modification in Antisense Oligonucleotides
by Elisa Tomita-Sudo, Tomoka Akita, Nae Sakimoto, Saori Tahara-Takamine and Junji Kawakami
Int. J. Mol. Sci. 2024, 25(24), 13240; https://doi.org/10.3390/ijms252413240 - 10 Dec 2024
Viewed by 636
Abstract
2′,4′-methylene bridged nucleic acid/locked nucleic acid (2′,4′-BNA/LNA; LNA) is a modified nucleic acid that improves the function of antisense oligonucleotide therapeutics. In particular, LNA in the DNA strand increases its binding affinity for the target RNA. Predicting the binding affinities of LNA-containing antisense [...] Read more.
2′,4′-methylene bridged nucleic acid/locked nucleic acid (2′,4′-BNA/LNA; LNA) is a modified nucleic acid that improves the function of antisense oligonucleotide therapeutics. In particular, LNA in the DNA strand increases its binding affinity for the target RNA. Predicting the binding affinities of LNA-containing antisense oligonucleotides and RNA duplexes is useful for designing antisense oligonucleotides. The nearest neighbor parameters may be useful for binding affinity prediction, similar to those for natural nucleic acids. However, the sequence dependence of the thermodynamic stability of DNA/RNA duplexes containing LNA remains unexplored. Therefore, in this study, we evaluated the thermodynamic stabilities of DNA/RNA duplexes containing a single LNA modification in the DNA strand. We found that LNA-stabilized DNA/RNA duplexes averaged −1.5 kcal mol−1. Our findings suggest that the thermodynamic stabilization effect of LNA is sequence-specific. Full article
(This article belongs to the Special Issue Splice-Switching Antisense Oligonucleotides: 30 Years after Advocating Exon-Skipping Therapy for Duchenne Muscular Dystrophy)
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Review

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14 pages, 280 KiB  
Review
Expansion of Splice-Switching Therapy with Antisense Oligonucleotides
by Yasuhiro Takeshima
Int. J. Mol. Sci. 2025, 26(5), 2270; https://doi.org/10.3390/ijms26052270 - 4 Mar 2025
Viewed by 83
Abstract
Since 2016, splice-switching therapy, in which splicing is controlled by antisense oligonucleotides, has been applied in clinical practice for spinal muscular atrophy and Duchenne muscular dystrophy. In the former disease, this therapy induces exon inclusion, while, in the latter, it induces exon skipping, [...] Read more.
Since 2016, splice-switching therapy, in which splicing is controlled by antisense oligonucleotides, has been applied in clinical practice for spinal muscular atrophy and Duchenne muscular dystrophy. In the former disease, this therapy induces exon inclusion, while, in the latter, it induces exon skipping, leading expression of functional proteins. Basic and clinical studies of splice-switching therapy for many monogenic diseases have now been conducted. The molecular mechanisms of splice-switching therapy include not only the induction of exon inclusion and skipping, but also the induction of pseudoexon skipping and suppression of splicing sites generated by mutations. In addition, therapies that alter protein function by regulating splicing are being investigated not only for monogenic diseases but also for non-monogenic ones such as cancer and immune-related disorders. It is expected that many of these basic studies will be translated into clinical applications. This review describes the current status of basic research and clinical applications of splice-switching therapy to promote the development of treatments for noncurable diseases. Full article
(This article belongs to the Special Issue Splice-Switching Antisense Oligonucleotides: 30 Years after Advocating Exon-Skipping Therapy for Duchenne Muscular Dystrophy)
15 pages, 3625 KiB  
Review
30 Years Since the Proposal of Exon Skipping Therapy for Duchenne Muscular Dystrophy and the Future of Pseudoexon Skipping
by Masafumi Matsuo
Int. J. Mol. Sci. 2025, 26(3), 1303; https://doi.org/10.3390/ijms26031303 - 3 Feb 2025
Viewed by 773
Abstract
Thirty years ago, in 1995, I proposed a fundamental treatment for Duchenne Muscular Dystrophy (DMD) using antisense oligonucleotides (ASOs) to induce exon skipping and restore dystrophin expression. DMD is a progressive and fatal muscular dystrophy, and the establishment of an effective therapy has [...] Read more.
Thirty years ago, in 1995, I proposed a fundamental treatment for Duchenne Muscular Dystrophy (DMD) using antisense oligonucleotides (ASOs) to induce exon skipping and restore dystrophin expression. DMD is a progressive and fatal muscular dystrophy, and the establishment of an effective therapy has been a pressing demand among patients worldwide. Exon-skipping therapy utilizing ASOs has garnered significant attention as one of the most promising treatments for DMD, stimulating global research and development efforts in ASO technology. Two decades later, in 2016, one ASO was conditionally approved by the U.S. FDA as the first DMD treatment. This review summarizes the current status and challenges of ASO-based exon-skipping therapies for DMD and explores the prospects of pseudoexon skipping using ASOs, which holds the potential for achieving a complete cure for DMD. Full article
(This article belongs to the Special Issue Splice-Switching Antisense Oligonucleotides: 30 Years after Advocating Exon-Skipping Therapy for Duchenne Muscular Dystrophy)
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