RARE DISEASE
Severe generalized junctional epidermolysis bullosa
Severe generalized junctional epidermolysis bullosa
Severe generalized junctional epidermolysis bullosa
Synonyms: Epidermolysis bullosa letalis, JEB-H, Junctional epidermolysis bullosa generalisata gravis, Junctional epidermolysis bullosa, Herlitz type, Junctional epidermolysis bullosa, Herlitz-Pearson type, Severe generalized JEB
Synonyms: Epidermolysis bullosa letalis, JEB-H, Junctional epidermolysis bullosa generalisata gravis, Junctional epidermolysis bullosa, Herlitz type, Junctional epidermolysis bullosa, Herlitz-Pearson type, Severe generalized JEB
Synonyms: Epidermolysis bullosa letalis, JEB-H, Junctional epidermolysis bullosa generalisata gravis, Junctional epidermolysis bullosa, Herlitz type, Junctional epidermolysis bullosa, Herlitz-Pearson type, Severe generalized JEB
Drug discovery
0
drugs
With orphan designations
Overview
Severe generalized junctional epidermolysis bullosa (JEB) is a lethal autosomal recessive disorder characterized by profound skin and mucosal fragility, causing widespread blistering, chronic erosions, and exuberant granulation tissue. Key features include respiratory epithelial involvement, failure to thrive, and susceptibility to sepsis. Mortality exceeds 80% in infancy due to airway obstruction, malnutrition, or infection [1][10][14]. Caused by null mutations in LAMA3, LAMB3, or LAMC2 genes encoding laminin-332 [1][10].
Therapies
Wound care: Non-adhesive dressings (e.g., PolyMem®), antiseptics, and steroid creams for granulation tissue [12][18]
Systemic support: Nutritional supplementation (feeding tubes), IV antibiotics for sepsis, and airway management [3][12]
Emerging therapies: Phase III trials for ex vivo gene-corrected keratinocyte grafts and recombinant laminin-332 protein therapy [3][8]
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare odontological diseases, rare ophthalmic disorders, rare skin diseases
Research Papers
295 drug discovery papers about Severe generalized junctional epidermolysis bullosa, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
295 drug discovery papers about Severe generalized junctional epidermolysis bullosa, with 4 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.
2026-07-09 | 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.
2026-06-25 | 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.
2026-06-23 | FP14 Recombinant protein therapy for the treatment of junctional epidermolysis bullosa
Abstract Introduction and aims Junctional epidermolysis bullosa (JEB) is a rare genetic skin disorder leading to severe skin fragility from birth. It is caused by mutations in genes encoding the skin basement membrane proteins, Laminin 332, type XVII collagen or the basement membrane binding integrin α6β4, which anchor the epidermis to the dermis. JEB is characterized by widespread blistering of the skin and mucous membranes. The most severe form, JEB generalized severe, is caused by loss-of-function mutations in one of the chains of the trimeric protein Laminin 332. Babies diagnosed with this form of JEB generally do not survive beyond their first birthday. Patients suffer from failure to thrive, poor wound healing, anaemia, respiratory complications, and infections. The aim of this project is to explore the possibility of delivering recombinant laminin 332 (rLM332) to JEB skin to improve skin function. Methods We used a tamoxifen inducible mouse model of JEB (Lama3flox/floxK14CreERT), in which the Lama3 gene is specifically deleted in K14 expressing cells. JEB mice develop progressive blistering of skin and mucosa and exhibit reduced weight gain, mirroring the human disease. We examined the potential of rLM332 to treat JEB, exploring topical and subcutaneous injection and the impact on wound healing and disease severity biomarkers. Results We found both subcutaneous injection and topical application of rLM332 results in localization of the protein to the basement membrane. We observed improved wound healing, reduced blistering, improved basement membrane type VII collagen localization, and changes to the immune environment with rLM332 treatment. These changes persist at least 10 days following the final application. Conclusions Recombinant protein therapy presents a promising avenue for the treatment of JEB in patients, with topical application a potential noninvasive method of delivery in babies with extremely fragile skin. Murine experiments indicate durable improvements in skin health and accelerated wound healing.
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.
2026-07-09 | 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.
2026-06-25 | 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.
2026-06-23 | FP14 Recombinant protein therapy for the treatment of junctional epidermolysis bullosa
Abstract Introduction and aims Junctional epidermolysis bullosa (JEB) is a rare genetic skin disorder leading to severe skin fragility from birth. It is caused by mutations in genes encoding the skin basement membrane proteins, Laminin 332, type XVII collagen or the basement membrane binding integrin α6β4, which anchor the epidermis to the dermis. JEB is characterized by widespread blistering of the skin and mucous membranes. The most severe form, JEB generalized severe, is caused by loss-of-function mutations in one of the chains of the trimeric protein Laminin 332. Babies diagnosed with this form of JEB generally do not survive beyond their first birthday. Patients suffer from failure to thrive, poor wound healing, anaemia, respiratory complications, and infections. The aim of this project is to explore the possibility of delivering recombinant laminin 332 (rLM332) to JEB skin to improve skin function. Methods We used a tamoxifen inducible mouse model of JEB (Lama3flox/floxK14CreERT), in which the Lama3 gene is specifically deleted in K14 expressing cells. JEB mice develop progressive blistering of skin and mucosa and exhibit reduced weight gain, mirroring the human disease. We examined the potential of rLM332 to treat JEB, exploring topical and subcutaneous injection and the impact on wound healing and disease severity biomarkers. Results We found both subcutaneous injection and topical application of rLM332 results in localization of the protein to the basement membrane. We observed improved wound healing, reduced blistering, improved basement membrane type VII collagen localization, and changes to the immune environment with rLM332 treatment. These changes persist at least 10 days following the final application. Conclusions Recombinant protein therapy presents a promising avenue for the treatment of JEB in patients, with topical application a potential noninvasive method of delivery in babies with extremely fragile skin. Murine experiments indicate durable improvements in skin health and accelerated wound healing.
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