ArticleGene therapy2015
Ameliorating pathogenesis by removing an exon containing a missense mutation: a potential exon-skipping therapy for laminopathies.
Article in Gene therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 42 citations in OpenAlex.
- An Unbiased Drug Screen in a Drosophila Model ofInternational journal of molecular sciences · 2026Article
- CRISPR-mediated targeting of theMolecular therapy. Advances · 2026Article
- Clinical applications of exon-skipping antisense oligonucleotides in neuromuscular diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Use of polyadenosine tail mimetics to enhance mRNA expression from genes associated with haploinsufficiency disorders.Molecular therapy. Nucleic acids · 2025Article
- Expansion of Splice-Switching Therapy with Antisense Oligonucleotides.International journal of molecular sciences · 2025Review
- Recent Advances in RNA Therapy and Its Carriers to Treat the Single-Gene Neurological Disorders.Biomedicines · 2022Review
- Preclinical Advances of Therapies for Laminopathies.Journal of clinical medicine · 2021Review
- Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy.JMA journal · 2021Review
- Clinical Applications of Single-Stranded Oligonucleotides: Current Landscape of Approved and In-Development Therapeutics.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Review
- Emerging Oligonucleotide Therapeutics for Rare Neuromuscular Diseases.Journal of neuromuscular diseases · 2021Review
- Consequences ofCells · 2020Article
- Update on Muscular Dystrophies with Focus on Novel Treatments and Biomarkers.Current neurology and neuroscience reports · 2020Review
- Emery-Dreifuss muscular dystrophy.Muscle & nerve · 2020Review
- Hybridization-mediated off-target effects of splice-switching antisense oligonucleotides.Nucleic acids research · 2020Article
- New Therapeutics Options for Pediatric Neuromuscular Disorders.Frontiers in pediatrics · 2020Review
- Delivery of GalNAc-Conjugated Splice-Switching ASOs to Non-hepatic Cells through Ectopic Expression of Asialoglycoprotein Receptor.Molecular therapy. Nucleic acids · 2019Article
- Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering.Cell reports · 2018Article
- Treating pediatric neuromuscular disorders: The future is now.American journal of medical genetics. Part A · 2018Review
- Gene Editing and Gene-Based Therapeutics for Cardiomyopathies.Heart failure clinics · 2018Review
- A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation.The Journal of clinical endocrinology and metabolism · 2018Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Exon skipping, as a therapy to restore a reading frame or switch protein isoforms, is under clinical trial. We hypothesised that removing an in-frame exon containing a mutation could also improve pathogenic phenotypes. Our model is laminopathies: incurable tissue-specific degenerative diseases associated with LMNA mutations. LMNA encodes A-type lamins, that together with B-type lamins, form the nuclear lamina. Lamins contain an alpha-helical central rod domain composed of multiple heptad repeats. Eliminating LMNA exon 3 or 5 removes six heptad repeats, so shortens, but should not otherwise significantly alter, the alpha-helix. Human Lamin A or Lamin C with a deletion corresponding to amino acids encoded by exon 5 (Lamin A/C-Δ5) localised normally in murine lmna-null cells, rescuing both nuclear shape and endogenous Lamin B1/emerin distribution. However, Lamin A carrying pathogenic mutations in exon 3 or 5, or Lamin A/C-Δ3, did not. Furthermore, Lamin A/C-Δ5 was not deleterious to wild-type cells, unlike the other Lamin A mutants including Lamin A/C-Δ3. Thus Lamin A/C-Δ5 function as effectively as wild-type Lamin A/C and better than mutant versions. Antisense oligonucleotides skipped LMNA exon 5 in human cells, demonstrating the possibility of treating certain laminopathies with this approach. This proof-of-concept is the first to report the therapeutic potential of exon skipping for diseases arising from missense mutations.
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