RARE DISEASE
Late-onset junctional epidermolysis bullosa
Late-onset junctional epidermolysis bullosa
Late-onset junctional epidermolysis bullosa
Synonyms: Epidermolysis bullosa progressiva, JEB-lo, Late-onset JEB
Synonyms: Epidermolysis bullosa progressiva, JEB-lo, Late-onset JEB
Synonyms: Epidermolysis bullosa progressiva, JEB-lo, Late-onset JEB
Drug discovery
0
drugs
With orphan designations
Overview
Late-onset junctional epidermolysis bullosa (LO-JEB) is an autosomal recessive subtype characterized by childhood/young adult-onset blistering primarily affecting acral regions (hands, feet, elbows, knees) with nail dystrophy and enamel defects. Unlike severe JEB variants, LO-JEB lacks life-threatening complications but causes chronic atrophic scarring, palmoplantar hyperhidrosis, and oral soft tissue abnormalities. Genetic mutations in COL17A1 (type XVII collagen) are most common [1][7][15]. Extracutaneous involvement is typically limited [5][19].
Burden
Therapies
Supportive care: Meticulous wound management, protective padding, and infection prevention [2][16]
Emerging therapies: Phase II trials for COL17A1-targeted protein replacement and ex vivo gene-corrected keratinocyte grafts [8][13]
Symptomatic control: Opioids for pain, dental interventions for enamel defects [2][11]
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare odontological diseases, rare skin diseases
Research Papers
178 drug discovery papers about Late-onset junctional epidermolysis bullosa, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
178 drug discovery papers about Late-onset junctional epidermolysis bullosa, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-27 | A Systematic Review of Topical and Systemic Gentamicin for Wound Healing in Patients With Junctional and Dystrophic Epidermolysis Bullosa.
Epidermolysis bullosa (EB) is an inherited mechanobullous genodermatosis caused by a mutation in genes encoding proteins integral to skin integrity. Premature termination codon readthrough therapies, such as gentamicin, have promise in facilitating full-length protein expression in patients with EB. We conducted a systematic review of the effectiveness and adverse effects of gentamicin for wound healing in EB. Six databases were searched to 01 September 2025 for clinical trials investigating gentamicin for EB. Risk of bias was assessed using the ROBINS-I tool, and data were synthesised descriptively. This study was registered with PROSPERO (CRD42024496582). Five studies involving 24 patients with junctional EB or dystrophic EB were included; four were open-label and one was double-blinded. Nineteen of the 24 patients had a known nonsense mutation. Gentamicin was administered topically (two studies), intravenously (two studies) and both topically and intradermally (one study). Wound healing was heterogeneously measured across studies, with all but one showing improved outcomes. All patients demonstrated increased expression of glycoprotein or collagen in skin biopsy specimens after gentamicin treatment. No adverse events were noted. However, four of five studies were at serious risk of bias on ROBINS-I, primarily owing to lack of blinding and absence of control groups, increasing the risk of bias for subjective outcomes such as wound healing. The available evidence suggests gentamicin may improve wound healing in EB caused by nonsense mutations, but the small number of heterogeneous studies precludes high-level evidence. Larger, blinded, randomised trials are required to confirm efficacy and long-term safety.
2026-07-27 | Molecular plasticity of LAMA3 across the disease spectrum: pathogenic mechanisms and clinical translation.
The laminin α3 chain, encoded by LAMA3, constitutes a principal component of laminin-332 (LN-332), an essential extracellular matrix (ECM) glycoprotein governing cell adhesion, proliferation, and tissue homeostasis. This systematic review consolidates current evidence on the molecular features and regulatory mechanisms of LAMA3, including its roles in PI3K/Akt, epithelial-mesenchymal transition (EMT), and Hippo-YAP signaling, as well as epigenetic and post-transcriptional modulation. Its context-dependent functions across distinct pathological states are delineated. In malignancies, including colorectal and ovarian cancers, LAMA3 functions as an oncogenic determinant that enhances invasion, metastatic dissemination, and chemotherapeutic resistance. In contrast, in hereditary diseases such as junctional epidermolysis bullosa (JEB) and chronic disorders such as idiopathic pulmonary fibrosis (IPF), LAMA3 deficiency or dysfunction constitutes a structural basis of tissue pathology. From a translational standpoint, elevated LAMA3 expression has been recognized as an independent prognostic indicator in pancreatic ductal adenocarcinoma, whereas LAMA3 promoter methylation is a candidate biomarker for platinum resistance in ovarian cancer. LAMA3-directed gene therapy for JEB has progressed to clinical evaluation. Current limitations in the field are critically examined, and emerging therapeutic approaches, including proteolysis-targeting chimeras (PROTACs), are discussed. Collectively, an integrated framework that connects LAMA3 biology with clinical applications is presented to inform future investigations and precision therapeutic strategies targeting this multifunctional molecule.
2026-07-15 | Wound-Healing Effects of Birch Bark and Propolis Extracts on Epidermolysis Bullosa Keratinocytes.
Epidermolysis bullosa (EB) is a group of genetic diseases characterized by skin fragility. Although therapeutic options aim to accelerate wound-healing, improvement is needed; therefore, birch bark and propolis were investigated due to their beneficial biological properties. A representative ethanolic extract was analyzed by reversed-phase high-performance liquid chromatography with diode array detection (RP-HPLC-DAD) for chemical profiling of the raw materials. A hydrophobic natural deep eutectic solvent (HNaDES) for birch bark extraction, as well as a hydrogel and a bigel enriched with propolis and birch bark extract, were prepared and characterized by Fourier transform infrared (FT-IR) spectroscopy. Cytotoxicity and wound-healing potential were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and scratch assays in six human keratinocyte cell lines: two from healthy individuals, two from recessive dystrophic ΕΒ patients (RDEB), and two from laminin-332-deficient junctional EB patients (JEB). RP-HPLC-DAD revealed the presence of phenolic compounds (e.g., chrysin, pinocembrin, pinobanksin) and pentacyclic triterpenes (e.g., betulin and betulinic acid), characteristic of propolis and birch bark, respectively. FT-IR confirmed HNaDES formation and indicated physical interactions within the gels. All systems exhibited no cytotoxicity at 1 μg/mL and increased cell vitality. Moreover, in keratinocytes derived from JEB patients, hydrogel improved wound- healing significantly at 24 h, whereas bigel showed significant improvement at 8 h. The developed systems could be promising topical treatments.
2026-07-09 | Dermal papillary fibroblasts promote persistent granulation tissue formation in junctional epidermolysis bullosa.
The skin is composed of multiple fibroblast subpopulations with different functions in homeostasis and repair, but their role in skin diseases is largely unknown. Junctional epidermolysis bullosa (JEB) is a hereditary skin disorder characterised by severe skin fragility and aberrant granulation tissue formation, caused by loss-of-function variants in basement membrane proteins, including laminin-332. We developed JEB-like organotypic (OT) cultures with distinct fibroblast subpopulations and explored their role in an inducible JEB in vivo disease model, mimicking key features of the human disease. Mechanistically, papillary fibroblasts are highly increased in the granulation tissue of blistered JEB skin, promoting pathological αvβ6 integrin and TGFβ signalling in JEB keratinocytes. Treatment with the TGFβ receptor inhibitor RepSox not only normalised aberrant cell proliferation, differentiation, and cytokine signalling in JEB OTs but also reduced aberrant granulation tissue formation and skin blistering in laminin-332-depleted mice. Collectively, our study reveals that papillary fibroblasts promote JEB pathogenesis through increasing αvβ6 integrin and TGFβ signalling and disruption of these pathological signalling interactions significantly improved skin health and regeneration in JEB.
2026-06-10 | Engineered Caf1 Constructs Encoding Laminin-332 Motifs: A Novel Approach for Enhanced Cutaneous Wound Healing.
Laminin-332 is a key extracellular matrix (ECM) protein that supports keratinocyte adhesion, migration, and re-epithelialisation during wound healing. Its loss, as in Junctional Epidermolysis Bullosa (JEB) disrupts re-epithelialization, which highlights its therapeutic relevance. However, direct application of full-length laminin or its fragments is limited by poor stability and high production costs. As an alternative, biomaterial scaffolds are being developed. The Capsular Antigen F1 (Caf1) is one such scaffold, offering a stable, customisable platform for presenting bioactive motifs in a more practical format. To develop stable Caf1 scaffolds displaying laminin-332 motifs and evaluate their therapeutic potential in promoting epithelial repair under both normal and laminin-deficient conditions, with the goal of enabling clinically translatable wound-healing strategies. Laminin-332-derived peptide motifs were identified through a systematic literature review and ranked using a scoring system. Leading candidates were engineered into Caf1 and expressed in Escherichia coli. Keratinocyte migration, motility, adhesion and pSMAD2 signalling were assessed in vitro using normal human epidermal keratinocytes and LAMA3-knockdown cells cultured on Caf1-coated plates. An ex vivo human skin wound model was used to assess translational relevance: wounded skin explants were treated with Caf1 constructs and cultured at the air-liquid interface for 7 days. Re-epithelialization and epithelial thickness were evaluated by haematoxylin and eosin staining. Caf1 proteins displaying laminin-332-derived motifs were expressed in E. coli and purified. Among the engineered constructs, Caf1-J3 and Caf1-J4 significantly enhanced keratinocyte migration and single-cell motility in vitro. Combined application further accelerated wound closure, suggesting complementary effects. In LAMA3-deficient keratinocytes, these coatings restored adhesion, promoted actin cytoskeletal organisation, and reduced nuclear pSMAD2 levels. In ex vivo wounded human skin, they also promoted re-epithelialisation and supported homogeneous neo-epidermis formation. These findings show that short laminin-332-derived motifs, when presented on the Caf1 scaffold, can mimic and partially recover key basement membrane functions in epithelial repair. Caf1-J3 and Caf1-J4 function as minimal bioactive units that restore keratinocyte cell adhesion and modulate key signalling pathways involved in wound healing. This modular protein platform offers a clinically relevant strategy for chronic wounds and ECM-deficient skin, and provides a foundation for next-generation regenerative therapies.
2026-07-27 | A Systematic Review of Topical and Systemic Gentamicin for Wound Healing in Patients With Junctional and Dystrophic Epidermolysis Bullosa.
Epidermolysis bullosa (EB) is an inherited mechanobullous genodermatosis caused by a mutation in genes encoding proteins integral to skin integrity. Premature termination codon readthrough therapies, such as gentamicin, have promise in facilitating full-length protein expression in patients with EB. We conducted a systematic review of the effectiveness and adverse effects of gentamicin for wound healing in EB. Six databases were searched to 01 September 2025 for clinical trials investigating gentamicin for EB. Risk of bias was assessed using the ROBINS-I tool, and data were synthesised descriptively. This study was registered with PROSPERO (CRD42024496582). Five studies involving 24 patients with junctional EB or dystrophic EB were included; four were open-label and one was double-blinded. Nineteen of the 24 patients had a known nonsense mutation. Gentamicin was administered topically (two studies), intravenously (two studies) and both topically and intradermally (one study). Wound healing was heterogeneously measured across studies, with all but one showing improved outcomes. All patients demonstrated increased expression of glycoprotein or collagen in skin biopsy specimens after gentamicin treatment. No adverse events were noted. However, four of five studies were at serious risk of bias on ROBINS-I, primarily owing to lack of blinding and absence of control groups, increasing the risk of bias for subjective outcomes such as wound healing. The available evidence suggests gentamicin may improve wound healing in EB caused by nonsense mutations, but the small number of heterogeneous studies precludes high-level evidence. Larger, blinded, randomised trials are required to confirm efficacy and long-term safety.
2026-07-27 | Molecular plasticity of LAMA3 across the disease spectrum: pathogenic mechanisms and clinical translation.
The laminin α3 chain, encoded by LAMA3, constitutes a principal component of laminin-332 (LN-332), an essential extracellular matrix (ECM) glycoprotein governing cell adhesion, proliferation, and tissue homeostasis. This systematic review consolidates current evidence on the molecular features and regulatory mechanisms of LAMA3, including its roles in PI3K/Akt, epithelial-mesenchymal transition (EMT), and Hippo-YAP signaling, as well as epigenetic and post-transcriptional modulation. Its context-dependent functions across distinct pathological states are delineated. In malignancies, including colorectal and ovarian cancers, LAMA3 functions as an oncogenic determinant that enhances invasion, metastatic dissemination, and chemotherapeutic resistance. In contrast, in hereditary diseases such as junctional epidermolysis bullosa (JEB) and chronic disorders such as idiopathic pulmonary fibrosis (IPF), LAMA3 deficiency or dysfunction constitutes a structural basis of tissue pathology. From a translational standpoint, elevated LAMA3 expression has been recognized as an independent prognostic indicator in pancreatic ductal adenocarcinoma, whereas LAMA3 promoter methylation is a candidate biomarker for platinum resistance in ovarian cancer. LAMA3-directed gene therapy for JEB has progressed to clinical evaluation. Current limitations in the field are critically examined, and emerging therapeutic approaches, including proteolysis-targeting chimeras (PROTACs), are discussed. Collectively, an integrated framework that connects LAMA3 biology with clinical applications is presented to inform future investigations and precision therapeutic strategies targeting this multifunctional molecule.
2026-07-15 | Wound-Healing Effects of Birch Bark and Propolis Extracts on Epidermolysis Bullosa Keratinocytes.
Epidermolysis bullosa (EB) is a group of genetic diseases characterized by skin fragility. Although therapeutic options aim to accelerate wound-healing, improvement is needed; therefore, birch bark and propolis were investigated due to their beneficial biological properties. A representative ethanolic extract was analyzed by reversed-phase high-performance liquid chromatography with diode array detection (RP-HPLC-DAD) for chemical profiling of the raw materials. A hydrophobic natural deep eutectic solvent (HNaDES) for birch bark extraction, as well as a hydrogel and a bigel enriched with propolis and birch bark extract, were prepared and characterized by Fourier transform infrared (FT-IR) spectroscopy. Cytotoxicity and wound-healing potential were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and scratch assays in six human keratinocyte cell lines: two from healthy individuals, two from recessive dystrophic ΕΒ patients (RDEB), and two from laminin-332-deficient junctional EB patients (JEB). RP-HPLC-DAD revealed the presence of phenolic compounds (e.g., chrysin, pinocembrin, pinobanksin) and pentacyclic triterpenes (e.g., betulin and betulinic acid), characteristic of propolis and birch bark, respectively. FT-IR confirmed HNaDES formation and indicated physical interactions within the gels. All systems exhibited no cytotoxicity at 1 μg/mL and increased cell vitality. Moreover, in keratinocytes derived from JEB patients, hydrogel improved wound- healing significantly at 24 h, whereas bigel showed significant improvement at 8 h. The developed systems could be promising topical treatments.
2026-07-09 | Dermal papillary fibroblasts promote persistent granulation tissue formation in junctional epidermolysis bullosa.
The skin is composed of multiple fibroblast subpopulations with different functions in homeostasis and repair, but their role in skin diseases is largely unknown. Junctional epidermolysis bullosa (JEB) is a hereditary skin disorder characterised by severe skin fragility and aberrant granulation tissue formation, caused by loss-of-function variants in basement membrane proteins, including laminin-332. We developed JEB-like organotypic (OT) cultures with distinct fibroblast subpopulations and explored their role in an inducible JEB in vivo disease model, mimicking key features of the human disease. Mechanistically, papillary fibroblasts are highly increased in the granulation tissue of blistered JEB skin, promoting pathological αvβ6 integrin and TGFβ signalling in JEB keratinocytes. Treatment with the TGFβ receptor inhibitor RepSox not only normalised aberrant cell proliferation, differentiation, and cytokine signalling in JEB OTs but also reduced aberrant granulation tissue formation and skin blistering in laminin-332-depleted mice. Collectively, our study reveals that papillary fibroblasts promote JEB pathogenesis through increasing αvβ6 integrin and TGFβ signalling and disruption of these pathological signalling interactions significantly improved skin health and regeneration in JEB.
2026-06-10 | Engineered Caf1 Constructs Encoding Laminin-332 Motifs: A Novel Approach for Enhanced Cutaneous Wound Healing.
Laminin-332 is a key extracellular matrix (ECM) protein that supports keratinocyte adhesion, migration, and re-epithelialisation during wound healing. Its loss, as in Junctional Epidermolysis Bullosa (JEB) disrupts re-epithelialization, which highlights its therapeutic relevance. However, direct application of full-length laminin or its fragments is limited by poor stability and high production costs. As an alternative, biomaterial scaffolds are being developed. The Capsular Antigen F1 (Caf1) is one such scaffold, offering a stable, customisable platform for presenting bioactive motifs in a more practical format. To develop stable Caf1 scaffolds displaying laminin-332 motifs and evaluate their therapeutic potential in promoting epithelial repair under both normal and laminin-deficient conditions, with the goal of enabling clinically translatable wound-healing strategies. Laminin-332-derived peptide motifs were identified through a systematic literature review and ranked using a scoring system. Leading candidates were engineered into Caf1 and expressed in Escherichia coli. Keratinocyte migration, motility, adhesion and pSMAD2 signalling were assessed in vitro using normal human epidermal keratinocytes and LAMA3-knockdown cells cultured on Caf1-coated plates. An ex vivo human skin wound model was used to assess translational relevance: wounded skin explants were treated with Caf1 constructs and cultured at the air-liquid interface for 7 days. Re-epithelialization and epithelial thickness were evaluated by haematoxylin and eosin staining. Caf1 proteins displaying laminin-332-derived motifs were expressed in E. coli and purified. Among the engineered constructs, Caf1-J3 and Caf1-J4 significantly enhanced keratinocyte migration and single-cell motility in vitro. Combined application further accelerated wound closure, suggesting complementary effects. In LAMA3-deficient keratinocytes, these coatings restored adhesion, promoted actin cytoskeletal organisation, and reduced nuclear pSMAD2 levels. In ex vivo wounded human skin, they also promoted re-epithelialisation and supported homogeneous neo-epidermis formation. These findings show that short laminin-332-derived motifs, when presented on the Caf1 scaffold, can mimic and partially recover key basement membrane functions in epithelial repair. Caf1-J3 and Caf1-J4 function as minimal bioactive units that restore keratinocyte cell adhesion and modulate key signalling pathways involved in wound healing. This modular protein platform offers a clinically relevant strategy for chronic wounds and ECM-deficient skin, and provides a foundation for next-generation regenerative therapies.
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