ArticleNucleic acids research2020
AON-induced splice-switching and DMPK pre-mRNA degradation as potential therapeutic approaches for Myotonic Dystrophy type 1.
Article in Nucleic acids research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 19 citations in OpenAlex.
- Fatty-acid-based antimiR-23b delivery in the DMSXL model: A potential therapeutic strategy for brain dysfunction in myotonic dystrophy type 1.Cell reports. Medicine · 2026Article
- Emerging therapeutic strategies in muscular dystrophy: an updated review on pathogenesis and treatment advances.Molecular biology reports · 2026Review
- Promoter-targeted small RNA duplexes increase MBNL1 transcription and mitigate myotonic dystrophy-associated spliceopathy.Nucleic acids research · 2025Article
- Multisystem Symptoms in Myotonic Dystrophy Type 1: A Management and Therapeutic Perspective.International journal of molecular sciences · 2025Review
- Expansion of Splice-Switching Therapy with Antisense Oligonucleotides.International journal of molecular sciences · 2025Review
- Differences in alternative splicing and their potential underlying factors between animals and plants.Journal of advanced research · 2024Review
- Antiviral Efficacy of RNase H-Dependent Gapmer Antisense Oligonucleotides against Japanese Encephalitis Virus.International journal of molecular sciences · 2023Article
- Promising AAV.U7snRNAs vectors targetingFrontiers in cell and developmental biology · 2023Article
- Sustainable recovery of MBNL activity in autoregulatory feedback loop in myotonic dystrophy.Molecular therapy. Nucleic acids · 2022Article
- Cyclic mismatch binding ligands interact with disease-associated CGG trinucleotide repeats in RNA and suppress their translation.Nucleic acids research · 2021Article
- Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy.JMA journal · 2021Review
- Therapeutic Modulation of RNA Splicing in Malignant and Non-Malignant Disease.Trends in molecular medicine · 2021Review
- hnRNP L is essential for myogenic differentiation and modulates myotonic dystrophy pathologies.Muscle & nerve · 2021Article
- RNA-based therapies: A cog in the wheel of lung cancer defense.Molecular cancer · 2021Review
- Brain Pathogenesis and Potential Therapeutic Strategies in Myotonic Dystrophy Type 1.Frontiers in aging neuroscience · 2021Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Expansion of an unstable CTG repeat in the 3'UTR of the DMPK gene causes Myotonic Dystrophy type 1 (DM1). CUG-expanded DMPK transcripts (CUGexp) sequester Muscleblind-like (MBNL) alternative splicing regulators in ribonuclear inclusions (foci), leading to abnormalities in RNA processing and splicing. To alleviate the burden of CUGexp, we tested therapeutic approach utilizing antisense oligonucleotides (AONs)-mediated DMPK splice-switching and degradation of mutated pre-mRNA. Experimental design involved: (i) skipping of selected constitutive exons to induce frameshifting and decay of toxic mRNAs by an RNA surveillance mechanism, and (ii) exclusion of the alternative exon 15 (e15) carrying CUGexp from DMPK mRNA. While first strategy failed to stimulate DMPK mRNA decay, exclusion of e15 enhanced DMPK nuclear export but triggered accumulation of potentially harmful spliced out pre-mRNA fragment containing CUGexp. Neutralization of this fragment with antisense gapmers complementary to intronic sequences preceding e15 failed to diminish DM1-specific spliceopathy due to AONs' chemistry-related toxicity. However, intronic gapmers alone reduced the level of DMPK mRNA and mitigated DM1-related cellular phenotypes including spliceopathy and nuclear foci. Thus, a combination of the correct chemistry and experimental approach should be carefully considered to design a safe AON-based therapeutic strategy for DM1.
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