ArticleThe British journal of dermatology2019
An ex vivo RNA trans-splicing strategy to correct human generalized severe epidermolysis bullosa simplex.
Article in The British journal of dermatology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
- Basal pharmacokinetic parameters of topically applied diacerein in pediatric patients with generalized severe epidermolysis bullosa simplex.Orphanet journal of rare diseases · 2018Trial
- Treatment Landscape for Epidermolysis Bullosa Simplex: A Review of Established and Emerging Therapies.Pediatric dermatology · 2026Review
- Gene therapy for genodermatoses at the crossroads of innovation and clinical translation.Frontiers in bioengineering and biotechnology · 2026Review
- Gene-edited cells: novel allogeneic gene/cell therapy for epidermolysis bullosa.Journal of applied genetics · 2024Review
- RNA exon editing: Splicing the way to treat human diseases.Molecular therapy. Nucleic acids · 2024Review
- Pathological Mechanisms Involved in Epidermolysis Bullosa Simplex: Current Knowledge and Therapeutic Perspectives.International journal of molecular sciences · 2024Review
- Stairways to Advanced Therapies for Epidermolysis Bullosa.Cold Spring Harbor perspectives in biology · 2023Review
- Article
- 5'RNAInternational journal of molecular sciences · 2022Article
- Evaluating a Targeted Cancer Therapy Approach Mediated by RNAInternational journal of molecular sciences · 2022Article
- Integrated Management Strategies for Epidermolysis Bullosa: Current Insights.International journal of general medicine · 2022Review
- Investigational Treatments for Epidermolysis Bullosa.American journal of clinical dermatology · 2021Review
- Personalized Development of Antisense Oligonucleotides for Exon Skipping Restores Type XVII Collagen Expression in Junctional Epidermolysis Bullosa.International journal of molecular sciences · 2021Article
- A Novel Mutation p.L461P inAnnals of dermatology · 2021Article
- Therapeutic applications of trans-splicing.British medical bulletin · 2020Article
- Molecular Therapeutics in Development for Epidermolysis Bullosa: Update 2020.Molecular diagnosis & therapy · 2020Review
- A cancer stem cell-like phenotype is associated with miR-10b expression in aggressive squamous cell carcinomas.Cell communication and signaling : CCS · 2020Article
- Skin Fragility: Perspectives on Evidence-based Therapies.Acta dermato-venereologica · 2020Review
- Epidermolysis bullosa: Advances in research and treatment.Experimental dermatology · 2019Review
- Therapies for epidermolysis bullosa: delivery is key.The British journal of dermatology · 2019Article
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
backgroundGeneralized severe epidermolysis bullosa simplex (EBS-gen sev) is a genetic blistering skin disease in which autosomal dominant mutations in either the keratin KRT5 or KRT14 genes lead to impaired function of the intermediate filament cytoskeleton in the basal epidermis. Here we present an ex vivo RNA trans-splicing-based therapeutic approach to correct the phenotype.
objectivesTo correct a mutation within exon 1 of the KRT14 gene, using a 5'-trans-splicing approach, where any mutation within the first seven exons could be replaced by a single therapeutic molecule.
methodsA therapeutic RNA trans-splicing molecule containing wild-type exons 1-7 was stably transduced into an EBS patient-derived keratinocyte line. Trans-splicing was confirmed via reverse-transcriptase polymerase chain reaction, Western blotting and immunofluorescence microscopy. Skin equivalents generated from corrected keratinocytes were grafted onto nude mice and analysed about 8 weeks post-transplantation for regular epidermal stratification, trans-splicing-induced green fluorescent protein expression and blistering.
resultsTransplanted skin equivalents generated from trans-splicing-corrected patient keratinocytes showed a stable and blister-free epidermis. KRT14 correction disrupted EBS-gen sev-associated proinflammatory signalling, as shown at the mRNA and protein levels. Disruption of the pathogenic feedback loop in addition to overall downregulation of KRT14 expression highlighted the effect of KRT14 correction on the EBS pathomechanism.
conclusionsOur data demonstrate that trans-splicing-mediated mRNA therapy is an effective method for the correction of dominantly inherited KRT14 mutations at the transcriptional level. This results in the rescue of the EBS-gen sev phenotype and stabilization of the epidermis in a xenograft mouse model.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.