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
179
papers
On emerging therapies
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].
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
179 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:
179 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:
categories:
Small molecules
small molecules
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.
2026-07-15 | 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.
2025-11-10 | Novel eRF3a degrader enhances gentamicin-induced premature termination codon readthrough in epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) and junctional epidermolysis bullosa (JEB) are severe blistering skin disorders caused by mutations in genes encoding type VII collagen (COL7A1) and laminin 332 (LAMA3, LAMB3, or LAMC2), respectively. In RDEB, 25% of patients carry nonsense mutations that result in premature termination codons (PTCs), while in JEB, the majority of mutations in LAMB3 are nonsense mutations (80%). CC-90009, an eRF3a degrader, is effective in inducing PTC readthrough in various in vitro models of diseases caused by nonsense mutations. This study evaluated CC-90009's ability, in combination with gentamicin, to suppress PTCs and promote the expression of type VII collagen (C7) in primary RDEB keratinocytes and fibroblasts, as well as laminin 332 in primary JEB keratinocytes with nonsense mutations. While CC-90009 alone demonstrated limited efficacy, its combination with low-dose gentamicin led to a dose-dependent increase in C7 and laminin β3 production, surpassing the effects of high-dose gentamicin alone. Furthermore, CC-90009/gentamicin reversed the hypermotility and poor substratum attachment characteristic of EB cells. Finally, C7 and laminin 332 induced by CC-90009/gentamicin localized to the dermal-epidermal junction in RDEB and JEB skin equivalents. Therefore, CC-90009/gentamicin may present a novel and safe treatment option for RDEB, JEB, and other inherited skin diseases arising from nonsense mutations.
2025-06-26 | Clinical and Allelic Heterogeneity in a Small Cohort of Patients with Inherited Epidermolysis Bullosa.
Inherited epidermolysis bullosa (EB) comprises a group of genetic disorders characterized by fragile skin that blisters easily. Targeted therapies for EB necessitate personalized approaches, underscoring the importance of precise diagnostics through genetic analysis and skin biopsy using transmission electron microscopy and/or immunohistochemistry. This study highlights the application of whole-exome sequencing (WES) to identify key pathogenic variants associated with EB. Most identified variants were associated with the recessive form of dystrophic EB, including four novel COL7A1 mutations: p.Leu1488ArgfsTer222, c.7759-3C>G, p.Gln1886Ter, and c.6501+6T>C, as well as recurrent variants p.Lys142Arg and p.Gly2049Glu. Additionally, variants were detected in KRT5 (c.971T>C, p.Val324Ala), associated with EB simplex, and in LAMB3 (c.2500C>T, p.Gln834Ter) in the homozygous state, associated with junctional EB. In silico splice prediction tools suggested disrupted splicing in both cases. One patient received topical gentamicin therapy targeting the nonsense mutation p.Gln1886Ter. These findings underscore the utility of WES in EB diagnostics, broaden the mutation spectrum, and contribute to the understanding of genotype-phenotype correlations in adult patients with EB.
cell therapies
2024-09-12 | Genetic Implications and Management of Epidermolysis Bullosa in the Saudi Arabian Population.
Epidermolysis bullosa (EB) is a genetic skin disorder characterized by skin fragility and blister formation. This review explores the genetic basis and management of EB in the Saudi population, emphasizing the need for genetic insights to enable precise diagnosis, targeted treatments, and effective counseling. Diagnosis in Saudi Arabia relies on clinical assessments and genetic testing. Prenatal diagnosis may be suggested in families with children affected by EB, but it is not widely used in the Middle East. Current management focuses on symptom relief, while emerging experimental approaches such as gene and stem cell therapies are under extensive research. Challenges in EB research include developing effective targeted therapies and understanding the variability in how genotypes manifest phenotypically. Continuous research is crucial to enhance diagnostic methods, therapeutic approaches, and overall patient care.
2023-01-10 | Skin-Derived ABCB5+ Mesenchymal Stem Cells for High-Medical-Need Inflammatory Diseases: From Discovery to Entering Clinical Routine.
The ATP-binding cassette superfamily member ABCB5 identifies a subset of skin-resident mesenchymal stem cells (MSCs) that exhibit potent immunomodulatory and wound healing-promoting capacities along with superior homing ability. The ABCB5+ MSCs can be easily accessed from discarded skin samples, expanded, and delivered as a highly homogenous medicinal product with standardized potency. A range of preclinical studies has suggested therapeutic efficacy of ABCB5+ MSCs in a variety of currently uncurable skin and non-skin inflammatory diseases, which has been substantiated thus far by distinct clinical trials in chronic skin wounds or recessive dystrophic epidermolysis bullosa. Therefore, skin-derived ABCB5+ MSCs have the potential to provide a breakthrough at the forefront of MSC-based therapies striving to fulfill current unmet medical needs. The most recent milestones in this regard are the approval of a phase III pivotal trial of ABCB5+ MSCs for treatment of recessive dystrophic and junctional epidermolysis bullosa by the US Food and Drug Administration, and national market access of ABCB5+ MSCs (AMESANAR®) for therapy-refractory chronic venous ulcers under the national hospital exemption pathway in Germany.
2021-12-23 | Transgenic Epidermal Cultures for Junctional Epidermolysis Bullosa - 5-Year Outcomes.
Inherited junctional epidermolysis bullosa is a severe genetic skin disease that leads to epidermal loss caused by structural and mechanical fragility of the integuments. There is no established cure for junctional epidermolysis bullosa. We previously reported that genetically corrected autologous epidermal cultures regenerated almost an entire, fully functional epidermis on a child who had a devastating form of junctional epidermolysis bullosa. We now report long-term clinical outcomes in this patient. (Funded by POR FESR 2014-2020 - Regione Emilia-Romagna and others.).
2021-08-30 | A Novel Phenotype of Junctional Epidermolysis Bullosa with Transient Skin Fragility and Predominant Ocular Involvement Responsive to Human Amniotic Membrane Eyedrops.
Junctional epidermolysis bullosa (JEB) is a clinically and genetically heterogeneous skin fragility disorder frequently caused by mutations in genes encoding the epithelial laminin isoform, laminin-332. JEB patients also present mucosal involvement, including painful corneal lesions. Recurrent corneal abrasions may lead to corneal opacities and visual impairment. Current treatments are merely supportive. We report a novel JEB phenotype distinguished by the complete resolution of skin fragility in infancy and persistent ocular involvement with unremitting and painful corneal abrasions. Biallelic LAMB3 mutations c.3052-5C>G and c.3492_3493delCG were identified as the molecular basis for this phenotype, with one mutation being a hypomorphic splice variant that allows residual wild-type laminin-332 production. The reduced laminin-332 level was associated with impaired keratinocyte adhesion. Then, we also investigated the therapeutic power of a human amniotic membrane (AM) eyedrop preparation for corneal lesions. AM were isolated from placenta donors, according to a procedure preserving the AM biological characteristics as a tissue, and confirmed to contain laminin-332. We found that AM eyedrop preparation could restore keratinocyte adhesion in an in vitro assay. Of note, AM eyedrop administration to the patient resulted in long-lasting remission of her ocular manifestations. Our findings suggest that AM eyedrops could represent an effective, non-invasive, simple-to-handle treatment for corneal lesions in patients with JEB and possibly other EB forms.
2021-05-04 | Single-keratinocyte transcriptomic analyses identify different clonal types and proliferative potential mediated by FOXM1 in human epidermal stem cells
Abstract Autologous epidermal cultures restore a functional epidermis on burned patients. Transgenic epidermal grafts do so also in genetic skin diseases such as Junctional Epidermolysis Bullosa. Clinical success strictly requires an adequate number of epidermal stem cells, detected as holoclone-forming cells, which can be only partially distinguished from the other clonogenic keratinocytes and cannot be prospectively isolated. Here we report that single-cell transcriptome analysis of primary human epidermal cultures identifies categories of genes clearly distinguishing the different keratinocyte clonal types, which are hierarchically organized along a continuous, mainly linear trajectory showing that stem cells sequentially generate progenitors producing terminally differentiated cells. Holoclone-forming cells display stem cell hallmarks as genes regulating DNA repair, chromosome segregation, spindle organization and telomerase activity. Finally, we identify FOXM1 as a YAP-dependent key regulator of epidermal stem cells. These findings improve criteria for measuring stem cells in epidermal cultures, which is an essential feature of the graft.
proteins
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.
2025-01-09 | Prevalence of Crown Resorption in Amelogenesis Imperfecta due to Junctional Epidermolysis Bullosa.
Junctional epidermolysis bullosa (JEB) is a rare genetic disease manifesting with skin and mucosal blistering. As part of the JEB, patients present with syndromic amelogenesis imperfecta (AI). Reports have described external crown resorption (ECR) in the teeth of patients with JEB, but its prevalence is unknown. To determine the prevalence of ECR in patients with JEB. A longitudinal retrospective cohort study was performed at the Special Care Dentistry Clinic, University of Chile. Clinical records of patients with JEB between 2005 and 2024 were analysed. Prevalence of ECR per patient, per type of tooth and per tooth was calculated. Of the 20 patients examined, 90% presented ECR in at least one tooth, with an average of 4.8 primary and 6.8 permanent teeth affected. The most affected type of teeth were the incisors. 57.5% of primary incisors and 68% of permanent incisors had resorption. The most affected tooth was #82 in primary dentition (75%) and #32 in the permanent dentition (88.9%). The prevalence of ECR in patients with AI due to JEB caused by variants in LAMB3 was 90%. Establishing clinical and radiographic dental protocols for the early detection of ECR is essential to prevent extensive tooth destruction.
2023-05-22 | Amino Acid Substitution in the Cysteine-Rich Region of the Integrin β4 Subunit Causes Late-Onset Mild Junctional Epidermolysis Bullosa without Extracutaneous Involvement.
Integrin α6β4, encoded by ITGA6 and ITGB4, is a transmembrane component of hemidesmosomes and plays an important role in connecting keratinocytes with extracellular matrix proteins. ITGB4 or ITGA6 biallelic pathogenic variants cause junctional epidermolysis bullosa (JEB) with pyloric atresia, which is associated with high lethality. Patients who survive usually develop JEB of intermediate severity and urorenal manifestations. In this study, we report a very rare subtype of late-onset, nonsyndromic JEB associated with a recurrent amino acid substitution in the highly conserved cysteine-rich tandem repeats of the integrin β4 subunit. Literature review shows that among the patients diagnosed with ITGB4 mutations, only two had no extracutaneous manifestations, and only two patients with JEB with pyloric atresia carried missense mutations located in cysteine-rich tandem repeats. We analyzed the consequences of the novel ITGB4 variant c.1642G>A, p.Gly548Arg, on the clinical phenotype, the predicted protein structure, cellular phenotype, and gene expression pattern to show its pathogenicity. The results indicated that the p.Gly548Arg amino acid substitution affected the protein structure of integrin β4 subunits and disrupted the stability of hemidesmosomes and in turn impaired the adhesion of keratinocytes. RNA-sequencing results indicated similar changes in extracellular matrix structure organization and differentiation in keratinocytes completely devoid of integrin β4 and with the amino acid substitution p.Gly548Arg, which further supports the dysregulation of the function of the integrin β4 subunit caused by p.Gly548Arg. Our results provided evidence for a late-onset, mild JEB subtype without extracutaneous manifestations and extend the ITGB4-related genotype-phenotype correlations.
2012-12-01 | Enzymatic autoantibody glycan hydrolysis alleviates autoimmunity against type VII collagen
Autoantibody-mediated diseases comprise a heterogeneous group of disorders in which the pathogenic potential of autoantibodies has been clearly demonstrated. In general, their treatment relies on the long-term use of systemic corticosteroids and other immunosuppressants that are associated with considerable adverse reactions. EndoS, an endoglycosidase derived from Streptococcus pyogenes, specifically hydrolyzes the N-linked glycan of native IgG and has previously been shown to modulate the interaction between the Fc portion of autoantibody and Fcγ receptors on leukocytes. Here, different models of autoimmunity to type VII collagen, a structural protein of the dermal-epidermal junction (DEJ), were employed to explore the therapeutic potential of EndoS. First, pretreatment of otherwise pathogenic anti-murine type VII collagen (mCOL7) IgG with EndoS significantly reduced split formation at the DEJ in cryosections of murine skin and abrogated clinical disease in mice. Next, the effect of EndoS was also seen when the enzyme was injected into mice after pathogenic anti-mCOL7 IgG had been administered. Finally, to mimic the patient situation even closer, EndoS was applied in mice that had already developed clinical disease after immunization with mCOL7. In all EndoS-treated mice, disease progression was stopped, and in the majority of mice, clinical disease even regressed. Of note, EndoS was shown to hydrolyze already in vivo-bound pathogenic autoantibodies. In addition, EndoS treatment decreased lesional expression of activating FcγRs while increasing FcγRIIB expression.
2008-06-24 | Protein therapeutics for junctional epidermolysis bullosa: incorporation of recombinant beta3 chain into laminin 332 in beta3-/- keratinocytes in vitro.
Junctional epidermolysis bullosa (JEB) is an inherited mechanobullous disease characterized by reduced adherence of the epidermal keratinocytes to the underlying dermis, and is often caused by the absence of functional laminin 332 due to the lack or dysfunction of its beta3 chain. As there are no specific therapies for JEB, we tested whether a protein replacement strategy could be applicable for the restoration of the laminin 332 assembly and reversion of the JEB phenotype in human keratinocytes that lack beta3 subunit. Here, we developed the protocol for production and purification of the biologically active recombinant beta3 chain. Next, we demonstrated that delivery of recombinant beta3 polypeptide into the endoplasmic reticulum of the immortalized beta3-null keratinocytes led to the restoration of the laminin 332 assembly, secretion, and deposition into the basement membrane zone, as confirmed by Western blot analysis, confocal immunofluorescent microscopy in vitro, and on cultured organotypic human JEB skin reconstructs. Although the amount of laminin 332 produced by protein-treated beta3-null keratinocytes is lower than that in normal human keratinocytes, our results demonstrate the applicability of the recombinant proteins for JEB treatment and open new perspectives for the development of novel therapeutics for this inherited, currently intractable, skin disorder.
gene therapies
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.
2026-06-10 | So Much More Than Just Structural Support: Laminin-332 and Its Multifaceted Functions in Skin Homeostasis and Disease.
The extracellular matrix (ECM) is increasingly recognised as a dynamic regulator of tissue function beyond its traditional structural role. In the skin, the ECM supports tissue integrity while also controlling processes such as stem cell maintenance, wound healing and disease progression. This review focuses on laminin-332, a key component of the epidermal-dermal junction. Its essential role in maintaining epidermal cohesion is illustrated by junctional epidermolysis bullosa, a severe inherited blistering disorder and recent advances in laminin-332-targeted genetic therapies are discussed. Beyond structural support, laminin-332 also mediates signalling through integrins and syndecans, thereby influencing epidermal homeostasis, migration, repair and the development of cutaneous squamous cell carcinoma. Its role in epidermal stem cell maintenance further links laminin-332 to skin ageing. The review also examines its functions in hair follicle biology, melanocyte behaviour, skin immunity and emerging evidence implicating laminin-332 in epidermal metabolism-an exciting area for future investigation. Finally, the structure and functions of other cutaneous laminins are compared with laminin-332 to help explain its specialised roles.
2025-06-13 | Skin microbiome analysis of a junctional epidermolysis bullosa patient treated with genetically modified stem cells.
Junctional epidermolysis bullosa (JEB) is a subtype of epidermolysis bullosa caused by mutations in the LAMB3 gene. We treated a patient with JEB using genetically corrected autologous epidermal cultures retrovirally transduced with the functional LAMB3 gene sequence. The objective of this study was to analyze the skin microbiome of this patient, with a particular focus on transgenic skin, and to compare the findings to the skin microbiome of healthy controls and patients with atopic dermatitis and well-documented microbial dysbiosis. Skin microbiome analysis was performed on a JEB patient 72 months after combined gene and stem cell therapy. Skin swabs from age-matched healthy controls and atopic dermatitis patients were included from the ProRaD study of CK-CARE. The transgenic skin had comparably high relative and absolute Staphylococcus (S.) aureus abundance to blistering and non-blistering skin of the JEB patient, while the total bacterial load was lower. In blistering skin of the JEB patient, higher bacterial load was driven by S. aureus. Our investigation confirms a unique microbiome composition in JEB, characterized by S. aureus driven bacterial overgrowth. The dysbiosis was not reversed in transgenic, non-blistering skin areas. However, the transgenic skin demonstrates stability in an environment of bacterial dysbiosis.
2025-02-13 | Efficient Dual Cas9 Nickase Correction of a Prevalent Pathogenic LAMB 3 Variant for Junctional Epidermolysis Bullosa.
Gene editing facilitated by homology-directed repair represents a promising strategy for precisely correcting pathogenic variants underlying monogenic disorders, including the life-threatening skin blistering condition junctional epidermolysis bullosa (JEB). Frequent reports of unintended off-target genotoxicity associated with conventional Cas9 nuclease editing have increasingly led to the adoption of dual-Cas9 nickases (dual-Cas9n) owing to their improved safety profile. However, rates of precise repair obtained with such strategies remain low. In this study, we establish a dual-Cas9n approach targeting LAMB3, using electroporation to deliver Cas9-nickase ribonucleoproteins and modified single-stranded oligodeoxynucleotide repair templates into primary JEB keratinocytes. Targeting a hotspot pathogenic variant (c.1903C>T, p.R635∗), we report perfect correction efficiencies of up to 54% based on standard next-generation sequencing. Using a high-fidelity Cas9 nuclease, we also report perfect repair of up to 74% when using a small-molecule modulator of DNA repair. Dual-Cas9n-corrected JEB keratinocytes demonstrated restored laminin-332 expression and secretion in vitro, leading to improved cellular adhesion and accurate laminin-332 localization in engineered skin equivalents. This protocol represents a significant improvement in precision gene repair using Cas9 nickases for epidermolysis bullosa, with the potential to be applied to a large cohort of patients harboring this prevalent pathogenic variant.
2024-08-02 | Treatment of Epidermolysis Bullosa and Future Directions: A Review.
Epidermolysis bullosa (EB) comprises rare genetic disorders characterized by skin and mucosal membrane blistering induced by mechanical trauma. Molecularly, pathogenic variants affect genes encoding proteins crucial for epidermal-dermal adhesion and stability. Management of severe EB is multidisciplinary, focusing on wound healing support, ensuring that patients thrive, and complication treatment. Despite extensive research over 30 years, novel therapeutic approaches face challenges. Gene therapy and protein therapy struggle with efficacy, while regenerative cell-based therapies show limited effects. Drug repurposing to target various pathogenic mechanisms has gained attention, as has in vivo gene therapy with drugs for dystrophic and junctional EB that were recently approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). However, their high cost limits global accessibility. This review examines therapeutic advancements made over the past 5 years, exploiting a systematic literature review and clinical trial data.
other
2026-09-04 | Updates in the Treatment of Pain and Pruritus in Epidermolysis Bullosa.
Pruritus and pain are pervasive, often debilitating symptoms in epidermolysis bullosa (EB), arising from complex immune, neural, and barrier dysfunction. Pruritus, especially in dystrophic and junctional EB subtypes, results from Th2/Th17-mediated inflammation, neuropeptide signaling, and neuropathic changes. Management includes antihistamines, topical agents, gabapentinoids, and emerging systemic therapies, such as dupilumab, JAK inhibitors, and neurokinin-1 inhibitors. Pain in EB is multifactorial, combining nociceptive and neuropathic mechanisms due to chronic wound, fibrosis, and nerve sensitization, requiring multimodal treatment strategies, including psychosocial therapies, analgesics, neuropathic agents, anti-inflammatory medications, and opioids. This review summarizes practical approaches to managing EB-associated pruritus and pain in the context of advancing insights into underlying pathophysiologic pathways.
2023-12-20 | METTL14-mediated N6-methyladenosine modification of Col17a1/Itgα6/Itgβ4 governs epidermal homeostasis.
N6-methyladenosine (m6A) is the most abundant and reversible modification occurring in eukaryotic mRNAs, however, its functions in mammalian epidermal development are still not fully elucidated. To explore the role of METTL14 (Methyltransferase like 14), one of the m6A methyltransferases, in maintaining epidermal homeostasis. We constructed mice with Mettl14-inactivation in the epidermal basal cells. The phenotype was explored by H&E staining and immunofluorescence staining. To explore the underlying mechanisms, we performed RNA-seq, Ribosome profiling and MeRIP-seq on wild-type and Mettl14-inactivation epidermal keratinocytes. Moreover, HaCaT cells were used for in vitro validation. Inactivation of Mettl14 in murine epidermis led to transient thicker epidermis and exhaustion of the epidermal stem cell pool. Interestingly, we found that the mRNA of type XVII collagen (Col17a1), integrin β4 (Itgβ4) and α6 (Itgα6) had m6A modifications, and the proteins expression were decreased in Mettl14-inactivated epidermis. Furthermore, in epidermis-specific Mettl4-inactivated mice, the epidermis was detached from the dermis and presented a phenotype similar to junctional epidermolysis bullosa (JEB), which may result from hemidesmosomes damage (decrease of COL17A1, ITGB4 and ITGA6). Knockdown of Mettl14 in HaCaT cells impaired the self-renewal and decreased the protein level of COL17A1, ITGB4 and ITGA6 and Itgβ4 knockdown inhibited colony formation. Our study highlighted the role of METTL14 in the maintenance of epidermal homeostasis and identified its critical role through m6A-mediated translational inhibition of Col17a1, Itgβ4 and Itgα6. Our study suggested that METTL14 may be a potential therapeutic target for the treatment of hemidesmosomes-deficient diseases, such as JEB.
2023-11-17 | A case of junctional epidermolysis bullosa intermediate with collagen XVII deficiency treated with dupilumab.
Inherited epidermolysis bullosa is a heterogeneous group of hereditary skin diseases characterized by skin (mucosa) fragility, which leads to blistering. Junctional epidermolysis bullosa is associated with mutations in genes expressing proteins of the dermo-epidermal junction. Dupilumab, an antibody that directly targets interleukin (IL)-4 receptor alpha, may be an effective treatment for dystrophic epidermolysis bullosa. We describe a case of junctional epidermolysis bullosa that improved with dupilumab.
2023-05-01 | Interleukin-17A immune pattern across genetic acantholytic and blistering disorders.
There is a high therapeutic need in acantholytic and blistering genodermatoses. Cutaneous inflammation is a reasonable therapeutic target, although the patterns are not yet fully elucidated. Here we investigated by immunohistochemistry whether interleukin (IL)-17A is expressed in the inflammatory infiltrate in 34 patients with Hailey-Hailey disease, Darier disease, and junctional and dystrophic epidermolysis bullosa. There was a 5-7-fold increase in the number of IL-17A-positive cells in all patients' samples as compared with normal skin. IL-17A cells were present in epidermal acantholytic areas and dermal inflammatory infiltrates in Hailey-Hailey and Darier disease. In epidermolysis bullosa samples, positive cells were present at the dermoepidermal junction zone. The IL-17A inflammatory pattern was validated by observing upregulation of downstream genes/proteins, S100A7, S100A8 and S100A9 (S100 calcium-binding proteins). These results suggest that IL-17A contributes to skin inflammation and could be a therapeutic target during inflammatory flares in these disorders.
2021-05-14 | Aberrant splicing as potential modifier of the phenotype of junctional epidermolysis bullosa.
A lack or dysfunction of the anchoring protein laminin-332 in the basement membrane leads to the skin blistering disorder junctional epidermolysis bullosa (JEB). The mutation c.628G>A in the gene LAMB3 encoding the laminin β3-chain is associated with generalized intermediate JEB; it may introduce an amino acid substitution (p.Glu210Lys) or disrupt splicing. This retrospective study aimed at determining the effects of aberrant splicing on the JEB phenotype. LAMB3 transcription was analysed in two siblings compound heterozygous for the LAMB3 mutations p.Glu210Lys and p.Arg635* with a diverging JEB phenotype from late childhood on. Laminin-332 levels in skin sections and in cultured keratinocytes were investigated by immunofluorescence staining. Real-time PCR was used to quantify LAMB3 expression in keratinocytes. RNA splice variants were identified by subcloning of a LAMB3 cDNA fraction and subsequent DNA sequencing. Structural models of laminin-332 helped to assess the impact of certain mutations on laminin-332 folding. Both siblings showed diminished LAMB3 expression. Laminin-332 was equally reduced in skin sections obtained during infancy but differed in keratinocytes isolated during adolescence. Although aberrant LAMB3 splicing with 26 variants was detected in both patients, splicing differed significantly: the full-length LAMB3 transcript harbouring the p.Glu210Lys mutation was found more often in the patient affected less severely (14/108 vs. 5/106 clones; P = 0.03). Structural modelling predicted that several deletions in LAMB3, but not the point mutation p.Glu210Lys, have an effect on laminin-332 folding and secretion. Differential LAMB3 mRNA splicing in the patients may explain the disparate JEB phenotype. By elucidating the regulation of laminin-332 gene expression, these findings may contribute to the development of therapeutic strategies for JEB and might help to understand phenotype modification by splice-site mutations in other hereditary diseases.
small molecules
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.
2026-07-15 | 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.
2025-11-10 | Novel eRF3a degrader enhances gentamicin-induced premature termination codon readthrough in epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) and junctional epidermolysis bullosa (JEB) are severe blistering skin disorders caused by mutations in genes encoding type VII collagen (COL7A1) and laminin 332 (LAMA3, LAMB3, or LAMC2), respectively. In RDEB, 25% of patients carry nonsense mutations that result in premature termination codons (PTCs), while in JEB, the majority of mutations in LAMB3 are nonsense mutations (80%). CC-90009, an eRF3a degrader, is effective in inducing PTC readthrough in various in vitro models of diseases caused by nonsense mutations. This study evaluated CC-90009's ability, in combination with gentamicin, to suppress PTCs and promote the expression of type VII collagen (C7) in primary RDEB keratinocytes and fibroblasts, as well as laminin 332 in primary JEB keratinocytes with nonsense mutations. While CC-90009 alone demonstrated limited efficacy, its combination with low-dose gentamicin led to a dose-dependent increase in C7 and laminin β3 production, surpassing the effects of high-dose gentamicin alone. Furthermore, CC-90009/gentamicin reversed the hypermotility and poor substratum attachment characteristic of EB cells. Finally, C7 and laminin 332 induced by CC-90009/gentamicin localized to the dermal-epidermal junction in RDEB and JEB skin equivalents. Therefore, CC-90009/gentamicin may present a novel and safe treatment option for RDEB, JEB, and other inherited skin diseases arising from nonsense mutations.
2025-06-26 | Clinical and Allelic Heterogeneity in a Small Cohort of Patients with Inherited Epidermolysis Bullosa.
Inherited epidermolysis bullosa (EB) comprises a group of genetic disorders characterized by fragile skin that blisters easily. Targeted therapies for EB necessitate personalized approaches, underscoring the importance of precise diagnostics through genetic analysis and skin biopsy using transmission electron microscopy and/or immunohistochemistry. This study highlights the application of whole-exome sequencing (WES) to identify key pathogenic variants associated with EB. Most identified variants were associated with the recessive form of dystrophic EB, including four novel COL7A1 mutations: p.Leu1488ArgfsTer222, c.7759-3C>G, p.Gln1886Ter, and c.6501+6T>C, as well as recurrent variants p.Lys142Arg and p.Gly2049Glu. Additionally, variants were detected in KRT5 (c.971T>C, p.Val324Ala), associated with EB simplex, and in LAMB3 (c.2500C>T, p.Gln834Ter) in the homozygous state, associated with junctional EB. In silico splice prediction tools suggested disrupted splicing in both cases. One patient received topical gentamicin therapy targeting the nonsense mutation p.Gln1886Ter. These findings underscore the utility of WES in EB diagnostics, broaden the mutation spectrum, and contribute to the understanding of genotype-phenotype correlations in adult patients with EB.
cell therapies
2024-09-12 | Genetic Implications and Management of Epidermolysis Bullosa in the Saudi Arabian Population.
Epidermolysis bullosa (EB) is a genetic skin disorder characterized by skin fragility and blister formation. This review explores the genetic basis and management of EB in the Saudi population, emphasizing the need for genetic insights to enable precise diagnosis, targeted treatments, and effective counseling. Diagnosis in Saudi Arabia relies on clinical assessments and genetic testing. Prenatal diagnosis may be suggested in families with children affected by EB, but it is not widely used in the Middle East. Current management focuses on symptom relief, while emerging experimental approaches such as gene and stem cell therapies are under extensive research. Challenges in EB research include developing effective targeted therapies and understanding the variability in how genotypes manifest phenotypically. Continuous research is crucial to enhance diagnostic methods, therapeutic approaches, and overall patient care.
2023-01-10 | Skin-Derived ABCB5+ Mesenchymal Stem Cells for High-Medical-Need Inflammatory Diseases: From Discovery to Entering Clinical Routine.
The ATP-binding cassette superfamily member ABCB5 identifies a subset of skin-resident mesenchymal stem cells (MSCs) that exhibit potent immunomodulatory and wound healing-promoting capacities along with superior homing ability. The ABCB5+ MSCs can be easily accessed from discarded skin samples, expanded, and delivered as a highly homogenous medicinal product with standardized potency. A range of preclinical studies has suggested therapeutic efficacy of ABCB5+ MSCs in a variety of currently uncurable skin and non-skin inflammatory diseases, which has been substantiated thus far by distinct clinical trials in chronic skin wounds or recessive dystrophic epidermolysis bullosa. Therefore, skin-derived ABCB5+ MSCs have the potential to provide a breakthrough at the forefront of MSC-based therapies striving to fulfill current unmet medical needs. The most recent milestones in this regard are the approval of a phase III pivotal trial of ABCB5+ MSCs for treatment of recessive dystrophic and junctional epidermolysis bullosa by the US Food and Drug Administration, and national market access of ABCB5+ MSCs (AMESANAR®) for therapy-refractory chronic venous ulcers under the national hospital exemption pathway in Germany.
2021-12-23 | Transgenic Epidermal Cultures for Junctional Epidermolysis Bullosa - 5-Year Outcomes.
Inherited junctional epidermolysis bullosa is a severe genetic skin disease that leads to epidermal loss caused by structural and mechanical fragility of the integuments. There is no established cure for junctional epidermolysis bullosa. We previously reported that genetically corrected autologous epidermal cultures regenerated almost an entire, fully functional epidermis on a child who had a devastating form of junctional epidermolysis bullosa. We now report long-term clinical outcomes in this patient. (Funded by POR FESR 2014-2020 - Regione Emilia-Romagna and others.).
2021-08-30 | A Novel Phenotype of Junctional Epidermolysis Bullosa with Transient Skin Fragility and Predominant Ocular Involvement Responsive to Human Amniotic Membrane Eyedrops.
Junctional epidermolysis bullosa (JEB) is a clinically and genetically heterogeneous skin fragility disorder frequently caused by mutations in genes encoding the epithelial laminin isoform, laminin-332. JEB patients also present mucosal involvement, including painful corneal lesions. Recurrent corneal abrasions may lead to corneal opacities and visual impairment. Current treatments are merely supportive. We report a novel JEB phenotype distinguished by the complete resolution of skin fragility in infancy and persistent ocular involvement with unremitting and painful corneal abrasions. Biallelic LAMB3 mutations c.3052-5C>G and c.3492_3493delCG were identified as the molecular basis for this phenotype, with one mutation being a hypomorphic splice variant that allows residual wild-type laminin-332 production. The reduced laminin-332 level was associated with impaired keratinocyte adhesion. Then, we also investigated the therapeutic power of a human amniotic membrane (AM) eyedrop preparation for corneal lesions. AM were isolated from placenta donors, according to a procedure preserving the AM biological characteristics as a tissue, and confirmed to contain laminin-332. We found that AM eyedrop preparation could restore keratinocyte adhesion in an in vitro assay. Of note, AM eyedrop administration to the patient resulted in long-lasting remission of her ocular manifestations. Our findings suggest that AM eyedrops could represent an effective, non-invasive, simple-to-handle treatment for corneal lesions in patients with JEB and possibly other EB forms.
2021-05-04 | Single-keratinocyte transcriptomic analyses identify different clonal types and proliferative potential mediated by FOXM1 in human epidermal stem cells
Abstract Autologous epidermal cultures restore a functional epidermis on burned patients. Transgenic epidermal grafts do so also in genetic skin diseases such as Junctional Epidermolysis Bullosa. Clinical success strictly requires an adequate number of epidermal stem cells, detected as holoclone-forming cells, which can be only partially distinguished from the other clonogenic keratinocytes and cannot be prospectively isolated. Here we report that single-cell transcriptome analysis of primary human epidermal cultures identifies categories of genes clearly distinguishing the different keratinocyte clonal types, which are hierarchically organized along a continuous, mainly linear trajectory showing that stem cells sequentially generate progenitors producing terminally differentiated cells. Holoclone-forming cells display stem cell hallmarks as genes regulating DNA repair, chromosome segregation, spindle organization and telomerase activity. Finally, we identify FOXM1 as a YAP-dependent key regulator of epidermal stem cells. These findings improve criteria for measuring stem cells in epidermal cultures, which is an essential feature of the graft.
proteins
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.
2025-01-09 | Prevalence of Crown Resorption in Amelogenesis Imperfecta due to Junctional Epidermolysis Bullosa.
Junctional epidermolysis bullosa (JEB) is a rare genetic disease manifesting with skin and mucosal blistering. As part of the JEB, patients present with syndromic amelogenesis imperfecta (AI). Reports have described external crown resorption (ECR) in the teeth of patients with JEB, but its prevalence is unknown. To determine the prevalence of ECR in patients with JEB. A longitudinal retrospective cohort study was performed at the Special Care Dentistry Clinic, University of Chile. Clinical records of patients with JEB between 2005 and 2024 were analysed. Prevalence of ECR per patient, per type of tooth and per tooth was calculated. Of the 20 patients examined, 90% presented ECR in at least one tooth, with an average of 4.8 primary and 6.8 permanent teeth affected. The most affected type of teeth were the incisors. 57.5% of primary incisors and 68% of permanent incisors had resorption. The most affected tooth was #82 in primary dentition (75%) and #32 in the permanent dentition (88.9%). The prevalence of ECR in patients with AI due to JEB caused by variants in LAMB3 was 90%. Establishing clinical and radiographic dental protocols for the early detection of ECR is essential to prevent extensive tooth destruction.
2023-05-22 | Amino Acid Substitution in the Cysteine-Rich Region of the Integrin β4 Subunit Causes Late-Onset Mild Junctional Epidermolysis Bullosa without Extracutaneous Involvement.
Integrin α6β4, encoded by ITGA6 and ITGB4, is a transmembrane component of hemidesmosomes and plays an important role in connecting keratinocytes with extracellular matrix proteins. ITGB4 or ITGA6 biallelic pathogenic variants cause junctional epidermolysis bullosa (JEB) with pyloric atresia, which is associated with high lethality. Patients who survive usually develop JEB of intermediate severity and urorenal manifestations. In this study, we report a very rare subtype of late-onset, nonsyndromic JEB associated with a recurrent amino acid substitution in the highly conserved cysteine-rich tandem repeats of the integrin β4 subunit. Literature review shows that among the patients diagnosed with ITGB4 mutations, only two had no extracutaneous manifestations, and only two patients with JEB with pyloric atresia carried missense mutations located in cysteine-rich tandem repeats. We analyzed the consequences of the novel ITGB4 variant c.1642G>A, p.Gly548Arg, on the clinical phenotype, the predicted protein structure, cellular phenotype, and gene expression pattern to show its pathogenicity. The results indicated that the p.Gly548Arg amino acid substitution affected the protein structure of integrin β4 subunits and disrupted the stability of hemidesmosomes and in turn impaired the adhesion of keratinocytes. RNA-sequencing results indicated similar changes in extracellular matrix structure organization and differentiation in keratinocytes completely devoid of integrin β4 and with the amino acid substitution p.Gly548Arg, which further supports the dysregulation of the function of the integrin β4 subunit caused by p.Gly548Arg. Our results provided evidence for a late-onset, mild JEB subtype without extracutaneous manifestations and extend the ITGB4-related genotype-phenotype correlations.
2012-12-01 | Enzymatic autoantibody glycan hydrolysis alleviates autoimmunity against type VII collagen
Autoantibody-mediated diseases comprise a heterogeneous group of disorders in which the pathogenic potential of autoantibodies has been clearly demonstrated. In general, their treatment relies on the long-term use of systemic corticosteroids and other immunosuppressants that are associated with considerable adverse reactions. EndoS, an endoglycosidase derived from Streptococcus pyogenes, specifically hydrolyzes the N-linked glycan of native IgG and has previously been shown to modulate the interaction between the Fc portion of autoantibody and Fcγ receptors on leukocytes. Here, different models of autoimmunity to type VII collagen, a structural protein of the dermal-epidermal junction (DEJ), were employed to explore the therapeutic potential of EndoS. First, pretreatment of otherwise pathogenic anti-murine type VII collagen (mCOL7) IgG with EndoS significantly reduced split formation at the DEJ in cryosections of murine skin and abrogated clinical disease in mice. Next, the effect of EndoS was also seen when the enzyme was injected into mice after pathogenic anti-mCOL7 IgG had been administered. Finally, to mimic the patient situation even closer, EndoS was applied in mice that had already developed clinical disease after immunization with mCOL7. In all EndoS-treated mice, disease progression was stopped, and in the majority of mice, clinical disease even regressed. Of note, EndoS was shown to hydrolyze already in vivo-bound pathogenic autoantibodies. In addition, EndoS treatment decreased lesional expression of activating FcγRs while increasing FcγRIIB expression.
2008-06-24 | Protein therapeutics for junctional epidermolysis bullosa: incorporation of recombinant beta3 chain into laminin 332 in beta3-/- keratinocytes in vitro.
Junctional epidermolysis bullosa (JEB) is an inherited mechanobullous disease characterized by reduced adherence of the epidermal keratinocytes to the underlying dermis, and is often caused by the absence of functional laminin 332 due to the lack or dysfunction of its beta3 chain. As there are no specific therapies for JEB, we tested whether a protein replacement strategy could be applicable for the restoration of the laminin 332 assembly and reversion of the JEB phenotype in human keratinocytes that lack beta3 subunit. Here, we developed the protocol for production and purification of the biologically active recombinant beta3 chain. Next, we demonstrated that delivery of recombinant beta3 polypeptide into the endoplasmic reticulum of the immortalized beta3-null keratinocytes led to the restoration of the laminin 332 assembly, secretion, and deposition into the basement membrane zone, as confirmed by Western blot analysis, confocal immunofluorescent microscopy in vitro, and on cultured organotypic human JEB skin reconstructs. Although the amount of laminin 332 produced by protein-treated beta3-null keratinocytes is lower than that in normal human keratinocytes, our results demonstrate the applicability of the recombinant proteins for JEB treatment and open new perspectives for the development of novel therapeutics for this inherited, currently intractable, skin disorder.
gene therapies
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.
2026-06-10 | So Much More Than Just Structural Support: Laminin-332 and Its Multifaceted Functions in Skin Homeostasis and Disease.
The extracellular matrix (ECM) is increasingly recognised as a dynamic regulator of tissue function beyond its traditional structural role. In the skin, the ECM supports tissue integrity while also controlling processes such as stem cell maintenance, wound healing and disease progression. This review focuses on laminin-332, a key component of the epidermal-dermal junction. Its essential role in maintaining epidermal cohesion is illustrated by junctional epidermolysis bullosa, a severe inherited blistering disorder and recent advances in laminin-332-targeted genetic therapies are discussed. Beyond structural support, laminin-332 also mediates signalling through integrins and syndecans, thereby influencing epidermal homeostasis, migration, repair and the development of cutaneous squamous cell carcinoma. Its role in epidermal stem cell maintenance further links laminin-332 to skin ageing. The review also examines its functions in hair follicle biology, melanocyte behaviour, skin immunity and emerging evidence implicating laminin-332 in epidermal metabolism-an exciting area for future investigation. Finally, the structure and functions of other cutaneous laminins are compared with laminin-332 to help explain its specialised roles.
2025-06-13 | Skin microbiome analysis of a junctional epidermolysis bullosa patient treated with genetically modified stem cells.
Junctional epidermolysis bullosa (JEB) is a subtype of epidermolysis bullosa caused by mutations in the LAMB3 gene. We treated a patient with JEB using genetically corrected autologous epidermal cultures retrovirally transduced with the functional LAMB3 gene sequence. The objective of this study was to analyze the skin microbiome of this patient, with a particular focus on transgenic skin, and to compare the findings to the skin microbiome of healthy controls and patients with atopic dermatitis and well-documented microbial dysbiosis. Skin microbiome analysis was performed on a JEB patient 72 months after combined gene and stem cell therapy. Skin swabs from age-matched healthy controls and atopic dermatitis patients were included from the ProRaD study of CK-CARE. The transgenic skin had comparably high relative and absolute Staphylococcus (S.) aureus abundance to blistering and non-blistering skin of the JEB patient, while the total bacterial load was lower. In blistering skin of the JEB patient, higher bacterial load was driven by S. aureus. Our investigation confirms a unique microbiome composition in JEB, characterized by S. aureus driven bacterial overgrowth. The dysbiosis was not reversed in transgenic, non-blistering skin areas. However, the transgenic skin demonstrates stability in an environment of bacterial dysbiosis.
2025-02-13 | Efficient Dual Cas9 Nickase Correction of a Prevalent Pathogenic LAMB 3 Variant for Junctional Epidermolysis Bullosa.
Gene editing facilitated by homology-directed repair represents a promising strategy for precisely correcting pathogenic variants underlying monogenic disorders, including the life-threatening skin blistering condition junctional epidermolysis bullosa (JEB). Frequent reports of unintended off-target genotoxicity associated with conventional Cas9 nuclease editing have increasingly led to the adoption of dual-Cas9 nickases (dual-Cas9n) owing to their improved safety profile. However, rates of precise repair obtained with such strategies remain low. In this study, we establish a dual-Cas9n approach targeting LAMB3, using electroporation to deliver Cas9-nickase ribonucleoproteins and modified single-stranded oligodeoxynucleotide repair templates into primary JEB keratinocytes. Targeting a hotspot pathogenic variant (c.1903C>T, p.R635∗), we report perfect correction efficiencies of up to 54% based on standard next-generation sequencing. Using a high-fidelity Cas9 nuclease, we also report perfect repair of up to 74% when using a small-molecule modulator of DNA repair. Dual-Cas9n-corrected JEB keratinocytes demonstrated restored laminin-332 expression and secretion in vitro, leading to improved cellular adhesion and accurate laminin-332 localization in engineered skin equivalents. This protocol represents a significant improvement in precision gene repair using Cas9 nickases for epidermolysis bullosa, with the potential to be applied to a large cohort of patients harboring this prevalent pathogenic variant.
2024-08-02 | Treatment of Epidermolysis Bullosa and Future Directions: A Review.
Epidermolysis bullosa (EB) comprises rare genetic disorders characterized by skin and mucosal membrane blistering induced by mechanical trauma. Molecularly, pathogenic variants affect genes encoding proteins crucial for epidermal-dermal adhesion and stability. Management of severe EB is multidisciplinary, focusing on wound healing support, ensuring that patients thrive, and complication treatment. Despite extensive research over 30 years, novel therapeutic approaches face challenges. Gene therapy and protein therapy struggle with efficacy, while regenerative cell-based therapies show limited effects. Drug repurposing to target various pathogenic mechanisms has gained attention, as has in vivo gene therapy with drugs for dystrophic and junctional EB that were recently approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). However, their high cost limits global accessibility. This review examines therapeutic advancements made over the past 5 years, exploiting a systematic literature review and clinical trial data.
other
2026-09-04 | Updates in the Treatment of Pain and Pruritus in Epidermolysis Bullosa.
Pruritus and pain are pervasive, often debilitating symptoms in epidermolysis bullosa (EB), arising from complex immune, neural, and barrier dysfunction. Pruritus, especially in dystrophic and junctional EB subtypes, results from Th2/Th17-mediated inflammation, neuropeptide signaling, and neuropathic changes. Management includes antihistamines, topical agents, gabapentinoids, and emerging systemic therapies, such as dupilumab, JAK inhibitors, and neurokinin-1 inhibitors. Pain in EB is multifactorial, combining nociceptive and neuropathic mechanisms due to chronic wound, fibrosis, and nerve sensitization, requiring multimodal treatment strategies, including psychosocial therapies, analgesics, neuropathic agents, anti-inflammatory medications, and opioids. This review summarizes practical approaches to managing EB-associated pruritus and pain in the context of advancing insights into underlying pathophysiologic pathways.
2023-12-20 | METTL14-mediated N6-methyladenosine modification of Col17a1/Itgα6/Itgβ4 governs epidermal homeostasis.
N6-methyladenosine (m6A) is the most abundant and reversible modification occurring in eukaryotic mRNAs, however, its functions in mammalian epidermal development are still not fully elucidated. To explore the role of METTL14 (Methyltransferase like 14), one of the m6A methyltransferases, in maintaining epidermal homeostasis. We constructed mice with Mettl14-inactivation in the epidermal basal cells. The phenotype was explored by H&E staining and immunofluorescence staining. To explore the underlying mechanisms, we performed RNA-seq, Ribosome profiling and MeRIP-seq on wild-type and Mettl14-inactivation epidermal keratinocytes. Moreover, HaCaT cells were used for in vitro validation. Inactivation of Mettl14 in murine epidermis led to transient thicker epidermis and exhaustion of the epidermal stem cell pool. Interestingly, we found that the mRNA of type XVII collagen (Col17a1), integrin β4 (Itgβ4) and α6 (Itgα6) had m6A modifications, and the proteins expression were decreased in Mettl14-inactivated epidermis. Furthermore, in epidermis-specific Mettl4-inactivated mice, the epidermis was detached from the dermis and presented a phenotype similar to junctional epidermolysis bullosa (JEB), which may result from hemidesmosomes damage (decrease of COL17A1, ITGB4 and ITGA6). Knockdown of Mettl14 in HaCaT cells impaired the self-renewal and decreased the protein level of COL17A1, ITGB4 and ITGA6 and Itgβ4 knockdown inhibited colony formation. Our study highlighted the role of METTL14 in the maintenance of epidermal homeostasis and identified its critical role through m6A-mediated translational inhibition of Col17a1, Itgβ4 and Itgα6. Our study suggested that METTL14 may be a potential therapeutic target for the treatment of hemidesmosomes-deficient diseases, such as JEB.
2023-11-17 | A case of junctional epidermolysis bullosa intermediate with collagen XVII deficiency treated with dupilumab.
Inherited epidermolysis bullosa is a heterogeneous group of hereditary skin diseases characterized by skin (mucosa) fragility, which leads to blistering. Junctional epidermolysis bullosa is associated with mutations in genes expressing proteins of the dermo-epidermal junction. Dupilumab, an antibody that directly targets interleukin (IL)-4 receptor alpha, may be an effective treatment for dystrophic epidermolysis bullosa. We describe a case of junctional epidermolysis bullosa that improved with dupilumab.
2023-05-01 | Interleukin-17A immune pattern across genetic acantholytic and blistering disorders.
There is a high therapeutic need in acantholytic and blistering genodermatoses. Cutaneous inflammation is a reasonable therapeutic target, although the patterns are not yet fully elucidated. Here we investigated by immunohistochemistry whether interleukin (IL)-17A is expressed in the inflammatory infiltrate in 34 patients with Hailey-Hailey disease, Darier disease, and junctional and dystrophic epidermolysis bullosa. There was a 5-7-fold increase in the number of IL-17A-positive cells in all patients' samples as compared with normal skin. IL-17A cells were present in epidermal acantholytic areas and dermal inflammatory infiltrates in Hailey-Hailey and Darier disease. In epidermolysis bullosa samples, positive cells were present at the dermoepidermal junction zone. The IL-17A inflammatory pattern was validated by observing upregulation of downstream genes/proteins, S100A7, S100A8 and S100A9 (S100 calcium-binding proteins). These results suggest that IL-17A contributes to skin inflammation and could be a therapeutic target during inflammatory flares in these disorders.
2021-05-14 | Aberrant splicing as potential modifier of the phenotype of junctional epidermolysis bullosa.
A lack or dysfunction of the anchoring protein laminin-332 in the basement membrane leads to the skin blistering disorder junctional epidermolysis bullosa (JEB). The mutation c.628G>A in the gene LAMB3 encoding the laminin β3-chain is associated with generalized intermediate JEB; it may introduce an amino acid substitution (p.Glu210Lys) or disrupt splicing. This retrospective study aimed at determining the effects of aberrant splicing on the JEB phenotype. LAMB3 transcription was analysed in two siblings compound heterozygous for the LAMB3 mutations p.Glu210Lys and p.Arg635* with a diverging JEB phenotype from late childhood on. Laminin-332 levels in skin sections and in cultured keratinocytes were investigated by immunofluorescence staining. Real-time PCR was used to quantify LAMB3 expression in keratinocytes. RNA splice variants were identified by subcloning of a LAMB3 cDNA fraction and subsequent DNA sequencing. Structural models of laminin-332 helped to assess the impact of certain mutations on laminin-332 folding. Both siblings showed diminished LAMB3 expression. Laminin-332 was equally reduced in skin sections obtained during infancy but differed in keratinocytes isolated during adolescence. Although aberrant LAMB3 splicing with 26 variants was detected in both patients, splicing differed significantly: the full-length LAMB3 transcript harbouring the p.Glu210Lys mutation was found more often in the patient affected less severely (14/108 vs. 5/106 clones; P = 0.03). Structural modelling predicted that several deletions in LAMB3, but not the point mutation p.Glu210Lys, have an effect on laminin-332 folding and secretion. Differential LAMB3 mRNA splicing in the patients may explain the disparate JEB phenotype. By elucidating the regulation of laminin-332 gene expression, these findings may contribute to the development of therapeutic strategies for JEB and might help to understand phenotype modification by splice-site mutations in other hereditary diseases.
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