ArticleMolecular therapy : the journal of the American Society of Gene Therapy2022
Paired nicking-mediated COL17A1 reframing for junctional epidermolysis bullosa.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2022. 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, 22 citations in OpenAlex.
- Developing CRISPR-Based Therapies for Epidermolysis Bullosa: A Comprehensive Review of Current Strategies.Drugs · 2026Review
- Gene therapy for genodermatoses at the crossroads of innovation and clinical translation.Frontiers in bioengineering and biotechnology · 2026Review
- Efficient Dual Cas9 Nickase Correction of a Prevalent PathogenicJID innovations : skin science from molecules to population health · 2025Article
- The Molecular Characteristics and Therapeutic Implications of O-glycan Synthesis in Pancreatic Cancer by Integrating Transcriptome and Single-cell Data.Current medicinal chemistry · 2025Article
- Treatment of Epidermolysis Bullosa and Future Directions: A Review.Dermatology and therapy · 2024Review
- The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen.International journal of molecular sciences · 2024Review
- On- and off-target effects of paired CRISPR-Cas nickase in primary human cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Emerging Gene Therapeutics for Epidermolysis Bullosa under Development.International journal of molecular sciences · 2024Review
- Extracellular matrix in skin diseases: The road to new therapies.Journal of advanced research · 2023Review
- En route towards a personalized medicine approach: Innovative therapeutic modalities for connective tissue disorders.Matrix biology : journal of the International Society for Matrix Biology · 2023Review
- A Review of CRISPR-Based Advances in Dermatological Diseases.Molecular diagnosis & therapy · 2023Review
- A Novel Fluorescence-Based Screen of Gene Editing Molecules for Junctional Epidermolysis Bullosa.International journal of molecular sciences · 2023Article
- Article
- Paired nicking-mediated COL17A1 reframing for junctional epidermolysis bullosa.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- Article
Corrections and comments
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Authors and funding
24 authors at 3 institutions in 3 countries.
Funding
Abstract
Junctional epidermolysis bullosa (JEB) is a debilitating hereditary skin disorder caused by mutations in genes encoding laminin-332, type XVII collagen (C17), and integrin-α6β4, which maintain stability between the dermis and epidermis. We designed patient-specific Cas9-nuclease- and -nickase-based targeting strategies for reframing a common homozygous deletion in exon 52 of COL17A1 associated with a lack of full-length C17 expression. Subsequent characterization of protein restoration, indel composition, and divergence of DNA and mRNA outcomes after treatment revealed auspicious efficiency, safety, and precision profiles for paired nicking-based COL17A1 editing. Almost 46% of treated primary JEB keratinocytes expressed reframed C17. Reframed COL17A1 transcripts predominantly featured 25- and 37-nt deletions, accounting for >42% of all edits and encoding C17 protein variants that localized accurately to the cell membrane. Furthermore, corrected cells showed accurate shedding of the extracellular 120-kDa C17 domain and improved adhesion capabilities to laminin-332 compared with untreated JEB cells. Three-dimensional (3D) skin equivalents demonstrated accurate and continuous deposition of C17 within the basal membrane zone between epidermis and dermis. Our findings constitute, for the first time, gene-editing-based correction of a COL17A1 mutation and demonstrate the superiority of proximal paired nicking strategies based on Cas9 D10A nickase over wild-type Cas9-based strategies for gene reframing in a clinical context.
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Registered trials
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