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
298
papers
On emerging therapies
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
298 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:
298 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:
categories:
Small molecules
small molecules
2026-09-04 | Update on Approved Therapies for Dystrophic and Junctional Epidermolysis Bullosa.
Dystrophic epidermolysis bullosa (DEB) and junctional EB (JEB) are severe, bullous genodermatoses induced by mutations of genes encoding structural skin proteins that disrupt epidermal adhesion. Until recently, treatment was limited to symptomatic care. Since 2022, three therapies - birch triterpenes gel (Filsuvez), beremagene geperpavec-svdt (B-VEC, Vyjuvek), and prademagene zamikeracel (pz-cel, Zevaskyn) - have received regulatory approval, representing the first specific interventions for epidermolysis bullosa. Herein, we provide an overview on their mechanisms of action, efficacy, safety, and clinical implications.
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.
2026-07-09 | 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.
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.
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.
2023-11-06 | A case report of jejunum transplantation in the treatment of severe cervical esophageal stricture in patients with dystrophic epidermolysis bullosa
Epidermolysis bullosa (EB) is a rare disorder caused by autosomal genetic variation. Its main clinical features include skin and mucous membrane blisters, erosion, repeated ulcers and scar formation. The lesions mostly involve the skin, oral cavity, digestive system and urinary system. Epidermolysis bullosa complicated with esophageal stenosis is a common gastrointestinal manifestation of this disorder. Currently, there is no cure for EB, and thus symptomatic treatment is usually applied. Here we describe the case of a patient with recessive dystrophic EB complicated with severe esophageal stenosis. The narrow segment of esophagus was removed and the free part of jejunum was transplanted into the esophageal defect to reconstruct the esophagus and restore the patient's normal swallowing. For patients with EB complicated with severe esophageal stenosis, surgical resection of the diseased esophagus and jejunal transplantation can be used to repair the esophageal and restore normal swallowing pathway, providing an effective treatment for this condition.
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.
2022-10-01 | Modified Non-Cultured Cell Spray Induced Epithelization in LAMB3 Mutation Epidermolysis Bullosa
Autologous non-cultured cell (ANCC) spray has been used to treat burns, chronic wounds, and vitiligo, but its use in junctional epidermolysis bullosa (JEB) has not been published previously. Chronic wounds in JEB are caused by mutations of laminin 332 (L322), whose function is to attach and act as a glue in the basal membrane. It is proposed that ANCC applications can provide keratinocytes and fibroblasts required to improve epithelization and spontaneously correct revertant keratinocytes in the wound area.To develop a modified procedure of ANCC spray and improve epithelization using silver sulfadiazine covered with plastic wrap to treat chronic wounds of JEB.Shave excision of the donor site was performed on a 19-year-old girl with JEB. The ANCC spray was prepared and applied to the chronic wound, which was then covered with silver sulfadiazine occluded with plastic wrap.Following the ANCC spray application, epithelization was successfully initiated. Unfortunately, the wounds recurred after four months of follow-up.The modified application method of ANCC spray provides a good alternative to treat chronic wounds in JEB.
2022-02-07 | Autologous skin micro-grafts and allogenic skin allograft for mitten hand deformity treatment in epidermolysis bullosa
<p><strong>Background:</strong> In the genetic skin blistering disorder dystrophic epidermolysis bullosa recurrent blisters and erosions on mechanically stressed areas, as the hands, result in subsequent scarring and development of pseudosyndactylies and contractures. In its most severe form, all fingers are constrained into a fist of scarred (“mitten-hand”-deformity). No causative therapy exists and only a surgical release of the fingers is possible. Hereby, the development of large skin defects is inevitable; the lack of healthy autologous skin for grafting remains a difficult challenge.</p><p><strong>Methods:</strong> We propose a new technique: It adopts a treatment strategy from the therapy of large extent burns and consists of a combination of autogenic and allogenic skin grafting.</p><p><strong>Results:</strong> We present a beneficial outcome in 18 mitten hand deformities treated with this technique. In all patients, the initial functional outcome was improved. Nearly all patients got a considerably widened grip span and durable skin conditions post-operatively. Mean follow-up was 3 years. Typically, recurrence of the scarring occurred from 6 months to 2 years after operation.</p><p><strong>Conclusions:</strong> This is the first report on the use of the combination of autogenous pinch skin grafts with allogenic (parental) skin overlay for skin defects in EB. It provides undisturbed wound healing under a “biological dressing”, furthermore, a temporary take of the parental skin was visible. Defects were permanently covered with skin of increased mechanical stability, hand function improved remarkably. However, long term follow-up showed beginning recurrence in most of the patients comparable to recurrence rates described in the literature.</p>
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.
2025-11-01 | Prime editing as a promising therapeutic strategy for junctional epidermolysis bullosa.
Gene therapies offer new possibilities for the precise correction of monogenic disorders. Here, we present the first prime editing (PE)-based gene repair strategy for pathogenic COL17A1 variants that cause junctional epidermolysis bullosa (JEB). Type XVII collagen (C17), encoded by COL17A1, plays a critical role in skin aging, regeneration, and the maintenance of epidermal stem cell integrity. Treatment of primary human JEB keratinocytes with PE mRNAs resulted in COL17A1 editing efficiencies of up to 60% in bulk-treated cells, leading to the restoration of full-length, accurately shed C17. Chromosomal aberrations analysis by single targeted linker-mediated PCR sequencing analysis of gene-edited JEB keratinocytes confirmed the absence of unintended chromosomal rearrangements at potential off-target sites and only minimal on-target aberrations. Remarkably, in a xenograft model, in which C17+ cells represented only 55.9% of the input population, COL17A1-corrected cells populated 92.2% of the basal keratinocyte layer in the resulting skin grafts after 6 weeks. These observations highlight a potential selective advantage imparted by C17 restoration, in line with its canonical role in anchoring hemidesmosomes to the basement membrane and preserving the structural integrity of the interfollicular epidermal stem cell niche. Based on our results, we envision PE as an efficient and safe option to restore gene function in EB and other genodermatoses.
2025-10-07 | Type VII Collagen Disorders Simplified.
Epidermolysis bullosa acquisita (EBA) and bullous systemic lupus erythematosus (BSLE) are autoimmune mechanobullous diseases that are caused by autoantibodies directed against type VII collagen. The functionality of type VII collagen is vital to the skin and mucous membranes because it makes up the anchoring fibrils that adhere the epithelium to the underlying connective tissue. Dystrophic epidermolysis bullosa (DEB), which bears some clinical similarities to EBA and BSLE, is caused by mutations in the type VII collagen gene (COL7A1) that may be dominant or recessive, leading to partial or total loss of the anchoring fibrils. Differentiating all 3 of these rare diagnoses variably requires thorough personal and family histories, histopathology, immunopathology, autoantibody profile, electron microscopy, and gene mutation analysis. Treatment of EBA and BSLE involves antineutrophil and immunosuppressive drugs that often give unsatisfactory responses. Rituximab has been successful in resistant cases. Until recently, the treatment of DEB and other heritable epidermolysis bullosa (EB) diseases caused by disparate mutations was limited to supportive care, prevention of trauma to skin and wound infections, regular dressing changes, and skin cancer surveillance. Three major treatment advances recently were approved for DEB and junctional EB.
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.
proteins
2026-08-23 | SINE Insertion in LAMA3 in Dogs With Junctional Epidermolysis Bullosa.
Junctional epidermolysis bullosa (JEB) is a hereditary skin disorder caused by defects in proteins responsible for dermal-epidermal adhesion. We investigated the genetic cause of JEB in three related mixed-breed puppies presenting with congenital skin blistering and ulceration. Whole-genome sequencing of one affected dog followed by comparison with 1538 control genomes identified a private candidate variant, XM_038543644.1:c.5690_5691ins240, in LAMA3, a known JEB-associated gene. Visual inspection of the short-read alignments and Sanger sequencing revealed a homozygous 240-bp SINE insertion in exon 45 that had initially been miscalled as a heterozygous short insertion. Fragment length analysis confirmed complete co-segregation of the variant with the disease phenotype within the available family. The SINE insertion is flanked by a 16-bp target site duplication, contains a 45-nt poly(A) tail, and is predicted to remain in-frame, introducing an additional 80 amino acids into the laminin α3 coiled-coil domain without introducing a premature stop codon. Although the molecular consequences were not functionally investigated, the insertion is expected to disrupt normal laminin-332 heterotrimer assembly and secretion. This study expands the spectrum of pathogenic LAMA3 variants associated with canine JEB and highlights the importance of visual inspection of short-read sequencing data for the detection and correct interpretation of structurally complex variants such as transposable element insertions.
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.
2026-06-10 | 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.
2024-05-17 | O10 Tuneable Caf1 protein polymers as an innovative and scalable solution for regenerative wound care
Abstract Introduction and aims Wound healing is a complex process essential for tissue restoration, where the extracellular matrix (ECM) plays a crucial role by providing structural and biochemical support to cells. Laminin 332, a key ECM component, is a promising target for protein-based therapeutics in view of its pathogenic role in junctional epidermolysis bullosa (JEB). Bioengineered capsular antigen F1 protein (Caf1) has emerged as a potential candidate molecule. We have developed the technology to enable bacteria to produce Caf1 polymers with multiple tailored bioactive motifs. Additionally, the unique properties of Caf1 minimize the potential for a host immune response. In this study, we engineered Caf1 proteins to express specific synthetic basement membrane components related to laminin 332 with the aim of restoring ECM equilibrium and achieving effective wound healing. Methods To evaluate Caf1 construct effects on human epidermal keratinocytes (HEKs) (CCD 1106) and human dermal fibroblasts (HDFs), scratch assays were performed under different treatment with Caf constructs. The Incucyte® ZOOM system (Sartorius AG, Göttingen, Germany) automated scratch wound and Live-Cell Analysis System screened constructs enhancing wound healing, capturing images every 2 h. Analysis involved quantifying the area under the curve of wound confluence (%) over 72 h to assess wound closure. Results The migration of HDFs was enhanced by 10.4% ± 0.95% (P < 0.05 Anova, n = 9 independent experiments) when there was interaction with Caf1-CTB4 (PMQKMRGDVFSP). The migration of CCDs was enhanced by 12.7% ± 1.03% when interacting with Caf1-J3 (KNSFMALYLSKGR) and by 14.4% ± 1.11% when interacting with Caf1-J4 (TALIRATYGEYSTGYI) (P < 0.05 Anova; n = 3 independent experiments). Combining Caf1-J3 and Caf1-J4 synergistically boosts CCD migration by 19.1% ± 1.42% (P < 0.05 Anova; n = 3 independent experiments), yielding better Results compared with individual treatments. Conclusions Caf1 exhibits promise as a platform for motif delivery, and the incorporation of cell migration motifs into Caf1 holds the potential to enhance wound healing.
2023-09-11 | Loss of cholesterol in Junctional Epidermolysis Bullosa skin identifies a key role for Laminin-332 in actomyosin mediated cholesterol transport
Abstract Individuals with Junctional Epidermolysis Bullosa (JEB), a rare genetic skin disease characterised by loss of function mutations in the Laminin332 (Lam332), do not survive beyond their first birthday. Here we report that loss of Lam332 leads to absence of cholesterol lipid from the epidermis in vitro and in vivo . Stable knockdown of Lam332 chains (LAMA3, LAMB3 and LAMC2) was established using shRNA and were used to develop 3D skin equivalents. Changes in lipid synthesis were assessed by western blot analysis and immunohistochemistry. Findings were confirmed in an inducible mouse model of Lamα3 ( Lama3 flox/flox /K14 CreERT ) and in anonymized, archival human tissue: JEB skin and normal age-matched controls. Further lipid analysis was explored using lipidomics in 3D skin equivalents and mouse tissue. Cholesterol biosynthesis genes were increased with loss of Lam332 in vitro , however a decrease in nile red lipid staining was observed in Lamα3 mouse (n = 6) and in JEB patient skin (n = 7). Further changes to the epidermal lipid profile with loss of Lam332 was confirmed with lipidomic analysis of Lamα3 mouse epidermis and Lam332 skin equivalents. Cholesterol transport within Lam332 KD keratinocytes was revealed to be disrupted, which in keratinocytes is dependent on the actomyosin network, which was reversed with recombinant human Lam332. In conclusion these findings suggest a role for Lam332 in lipid metabolism in the skin and a broader role in epidermal homeostasis and barrier formation. Restoration of cholesterol transport in JEB patients offers the potential to improve the skin barrier and survival.
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.
2024-07-17 | Biochemical role of FOXM1-dependent histone linker H1B in human epidermal stem cells
Abstract Epidermal stem cells orchestrate epidermal renewal and timely wound repair through a tight regulation of self-renewal, proliferation, and differentiation. In culture, human epidermal stem cells generate a clonal type referred to as holoclone, which give rise to transient amplifying progenitors (meroclone and paraclone-forming cells) eventually generating terminally differentiated cells. Leveraging single-cell transcriptomic data, we explored the FOXM1-dependent biochemical signals controlling self-renewal and differentiation in epidermal stem cells aimed at improving regenerative medicine applications. We report that the expression of H1 linker histone subtypes decrease during serial cultivation. At clonal level we observed that H1B is the most expressed isoform, particularly in epidermal stem cells, as compared to transient amplifying progenitors. Indeed, its expression decreases in primary epithelial culture where stem cells are exhausted due to FOXM1 downregulation. Conversely, H1B expression increases when the stem cells compartment is sustained by enforced FOXM1 expression, both in primary epithelial cultures derived from healthy donors and JEB patient. Moreover, we demonstrated that FOXM1 binds the promotorial region of H1B, hence regulates its expression. We also show that H1B is bound to the promotorial region of differentiation-related genes and negatively regulates their expression in epidermal stem cells. We propose a novel mechanism wherein the H1B acts downstream of FOXM1, contributing to the fine interplay between self-renewal and differentiation in human epidermal stem cells. These findings further define the networks that sustain self-renewal along the previously identified YAP-FOXM1 axis.
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.
2023-07-14 | Seven naturally variant loci serve as genetic modifiers of Lamc2jeb induced non-Herlitz junctional Epidermolysis Bullosa in mice.
Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma. While primary genetic risk of all subforms of EB adhere to Mendelian patterns of inheritance, their clinical presentations and severities can vary greatly, implying genetic modifiers. The Lamc2jeb mouse model of non-Herlitz junctional EB (JEB-nH) demonstrated that genetic modifiers can contribute substantially to the phenotypic variability of JEB and likely other forms of EB. The innocuous changes in an 'EB related gene', Col17a1, have shown it to be a dominant modifier of Lamc2jeb. This work identifies six additional Quantitative Trait Loci (QTL) that modify disease in Lamc2jeb/jeb mice. Three QTL include other known 'EB related genes', with the strongest modifier effect mapping to a region including the epidermal hemi-desmosomal structural gene dystonin (Dst-e/Bpag1-e). Three other QTL map to intervals devoid of known EB-associated genes. Of these, one contains the nuclear receptor coactivator Ppargc1a as its primary candidate and the others contain related genes Pparg and Igf1, suggesting modifier pathways. These results, demonstrating the potent disease modifying effects of normally innocuous genetic variants, greatly expand the landscape of genetic modifiers of EB and therapeutic approaches that may be applied.
small molecules
2026-09-04 | Update on Approved Therapies for Dystrophic and Junctional Epidermolysis Bullosa.
Dystrophic epidermolysis bullosa (DEB) and junctional EB (JEB) are severe, bullous genodermatoses induced by mutations of genes encoding structural skin proteins that disrupt epidermal adhesion. Until recently, treatment was limited to symptomatic care. Since 2022, three therapies - birch triterpenes gel (Filsuvez), beremagene geperpavec-svdt (B-VEC, Vyjuvek), and prademagene zamikeracel (pz-cel, Zevaskyn) - have received regulatory approval, representing the first specific interventions for epidermolysis bullosa. Herein, we provide an overview on their mechanisms of action, efficacy, safety, and clinical implications.
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.
2026-07-09 | 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.
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.
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.
2023-11-06 | A case report of jejunum transplantation in the treatment of severe cervical esophageal stricture in patients with dystrophic epidermolysis bullosa
Epidermolysis bullosa (EB) is a rare disorder caused by autosomal genetic variation. Its main clinical features include skin and mucous membrane blisters, erosion, repeated ulcers and scar formation. The lesions mostly involve the skin, oral cavity, digestive system and urinary system. Epidermolysis bullosa complicated with esophageal stenosis is a common gastrointestinal manifestation of this disorder. Currently, there is no cure for EB, and thus symptomatic treatment is usually applied. Here we describe the case of a patient with recessive dystrophic EB complicated with severe esophageal stenosis. The narrow segment of esophagus was removed and the free part of jejunum was transplanted into the esophageal defect to reconstruct the esophagus and restore the patient's normal swallowing. For patients with EB complicated with severe esophageal stenosis, surgical resection of the diseased esophagus and jejunal transplantation can be used to repair the esophageal and restore normal swallowing pathway, providing an effective treatment for this condition.
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.
2022-10-01 | Modified Non-Cultured Cell Spray Induced Epithelization in LAMB3 Mutation Epidermolysis Bullosa
Autologous non-cultured cell (ANCC) spray has been used to treat burns, chronic wounds, and vitiligo, but its use in junctional epidermolysis bullosa (JEB) has not been published previously. Chronic wounds in JEB are caused by mutations of laminin 332 (L322), whose function is to attach and act as a glue in the basal membrane. It is proposed that ANCC applications can provide keratinocytes and fibroblasts required to improve epithelization and spontaneously correct revertant keratinocytes in the wound area.To develop a modified procedure of ANCC spray and improve epithelization using silver sulfadiazine covered with plastic wrap to treat chronic wounds of JEB.Shave excision of the donor site was performed on a 19-year-old girl with JEB. The ANCC spray was prepared and applied to the chronic wound, which was then covered with silver sulfadiazine occluded with plastic wrap.Following the ANCC spray application, epithelization was successfully initiated. Unfortunately, the wounds recurred after four months of follow-up.The modified application method of ANCC spray provides a good alternative to treat chronic wounds in JEB.
2022-02-07 | Autologous skin micro-grafts and allogenic skin allograft for mitten hand deformity treatment in epidermolysis bullosa
<p><strong>Background:</strong> In the genetic skin blistering disorder dystrophic epidermolysis bullosa recurrent blisters and erosions on mechanically stressed areas, as the hands, result in subsequent scarring and development of pseudosyndactylies and contractures. In its most severe form, all fingers are constrained into a fist of scarred (“mitten-hand”-deformity). No causative therapy exists and only a surgical release of the fingers is possible. Hereby, the development of large skin defects is inevitable; the lack of healthy autologous skin for grafting remains a difficult challenge.</p><p><strong>Methods:</strong> We propose a new technique: It adopts a treatment strategy from the therapy of large extent burns and consists of a combination of autogenic and allogenic skin grafting.</p><p><strong>Results:</strong> We present a beneficial outcome in 18 mitten hand deformities treated with this technique. In all patients, the initial functional outcome was improved. Nearly all patients got a considerably widened grip span and durable skin conditions post-operatively. Mean follow-up was 3 years. Typically, recurrence of the scarring occurred from 6 months to 2 years after operation.</p><p><strong>Conclusions:</strong> This is the first report on the use of the combination of autogenous pinch skin grafts with allogenic (parental) skin overlay for skin defects in EB. It provides undisturbed wound healing under a “biological dressing”, furthermore, a temporary take of the parental skin was visible. Defects were permanently covered with skin of increased mechanical stability, hand function improved remarkably. However, long term follow-up showed beginning recurrence in most of the patients comparable to recurrence rates described in the literature.</p>
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.
2025-11-01 | Prime editing as a promising therapeutic strategy for junctional epidermolysis bullosa.
Gene therapies offer new possibilities for the precise correction of monogenic disorders. Here, we present the first prime editing (PE)-based gene repair strategy for pathogenic COL17A1 variants that cause junctional epidermolysis bullosa (JEB). Type XVII collagen (C17), encoded by COL17A1, plays a critical role in skin aging, regeneration, and the maintenance of epidermal stem cell integrity. Treatment of primary human JEB keratinocytes with PE mRNAs resulted in COL17A1 editing efficiencies of up to 60% in bulk-treated cells, leading to the restoration of full-length, accurately shed C17. Chromosomal aberrations analysis by single targeted linker-mediated PCR sequencing analysis of gene-edited JEB keratinocytes confirmed the absence of unintended chromosomal rearrangements at potential off-target sites and only minimal on-target aberrations. Remarkably, in a xenograft model, in which C17+ cells represented only 55.9% of the input population, COL17A1-corrected cells populated 92.2% of the basal keratinocyte layer in the resulting skin grafts after 6 weeks. These observations highlight a potential selective advantage imparted by C17 restoration, in line with its canonical role in anchoring hemidesmosomes to the basement membrane and preserving the structural integrity of the interfollicular epidermal stem cell niche. Based on our results, we envision PE as an efficient and safe option to restore gene function in EB and other genodermatoses.
2025-10-07 | Type VII Collagen Disorders Simplified.
Epidermolysis bullosa acquisita (EBA) and bullous systemic lupus erythematosus (BSLE) are autoimmune mechanobullous diseases that are caused by autoantibodies directed against type VII collagen. The functionality of type VII collagen is vital to the skin and mucous membranes because it makes up the anchoring fibrils that adhere the epithelium to the underlying connective tissue. Dystrophic epidermolysis bullosa (DEB), which bears some clinical similarities to EBA and BSLE, is caused by mutations in the type VII collagen gene (COL7A1) that may be dominant or recessive, leading to partial or total loss of the anchoring fibrils. Differentiating all 3 of these rare diagnoses variably requires thorough personal and family histories, histopathology, immunopathology, autoantibody profile, electron microscopy, and gene mutation analysis. Treatment of EBA and BSLE involves antineutrophil and immunosuppressive drugs that often give unsatisfactory responses. Rituximab has been successful in resistant cases. Until recently, the treatment of DEB and other heritable epidermolysis bullosa (EB) diseases caused by disparate mutations was limited to supportive care, prevention of trauma to skin and wound infections, regular dressing changes, and skin cancer surveillance. Three major treatment advances recently were approved for DEB and junctional EB.
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.
proteins
2026-08-23 | SINE Insertion in LAMA3 in Dogs With Junctional Epidermolysis Bullosa.
Junctional epidermolysis bullosa (JEB) is a hereditary skin disorder caused by defects in proteins responsible for dermal-epidermal adhesion. We investigated the genetic cause of JEB in three related mixed-breed puppies presenting with congenital skin blistering and ulceration. Whole-genome sequencing of one affected dog followed by comparison with 1538 control genomes identified a private candidate variant, XM_038543644.1:c.5690_5691ins240, in LAMA3, a known JEB-associated gene. Visual inspection of the short-read alignments and Sanger sequencing revealed a homozygous 240-bp SINE insertion in exon 45 that had initially been miscalled as a heterozygous short insertion. Fragment length analysis confirmed complete co-segregation of the variant with the disease phenotype within the available family. The SINE insertion is flanked by a 16-bp target site duplication, contains a 45-nt poly(A) tail, and is predicted to remain in-frame, introducing an additional 80 amino acids into the laminin α3 coiled-coil domain without introducing a premature stop codon. Although the molecular consequences were not functionally investigated, the insertion is expected to disrupt normal laminin-332 heterotrimer assembly and secretion. This study expands the spectrum of pathogenic LAMA3 variants associated with canine JEB and highlights the importance of visual inspection of short-read sequencing data for the detection and correct interpretation of structurally complex variants such as transposable element insertions.
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.
2026-06-10 | 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.
2024-05-17 | O10 Tuneable Caf1 protein polymers as an innovative and scalable solution for regenerative wound care
Abstract Introduction and aims Wound healing is a complex process essential for tissue restoration, where the extracellular matrix (ECM) plays a crucial role by providing structural and biochemical support to cells. Laminin 332, a key ECM component, is a promising target for protein-based therapeutics in view of its pathogenic role in junctional epidermolysis bullosa (JEB). Bioengineered capsular antigen F1 protein (Caf1) has emerged as a potential candidate molecule. We have developed the technology to enable bacteria to produce Caf1 polymers with multiple tailored bioactive motifs. Additionally, the unique properties of Caf1 minimize the potential for a host immune response. In this study, we engineered Caf1 proteins to express specific synthetic basement membrane components related to laminin 332 with the aim of restoring ECM equilibrium and achieving effective wound healing. Methods To evaluate Caf1 construct effects on human epidermal keratinocytes (HEKs) (CCD 1106) and human dermal fibroblasts (HDFs), scratch assays were performed under different treatment with Caf constructs. The Incucyte® ZOOM system (Sartorius AG, Göttingen, Germany) automated scratch wound and Live-Cell Analysis System screened constructs enhancing wound healing, capturing images every 2 h. Analysis involved quantifying the area under the curve of wound confluence (%) over 72 h to assess wound closure. Results The migration of HDFs was enhanced by 10.4% ± 0.95% (P < 0.05 Anova, n = 9 independent experiments) when there was interaction with Caf1-CTB4 (PMQKMRGDVFSP). The migration of CCDs was enhanced by 12.7% ± 1.03% when interacting with Caf1-J3 (KNSFMALYLSKGR) and by 14.4% ± 1.11% when interacting with Caf1-J4 (TALIRATYGEYSTGYI) (P < 0.05 Anova; n = 3 independent experiments). Combining Caf1-J3 and Caf1-J4 synergistically boosts CCD migration by 19.1% ± 1.42% (P < 0.05 Anova; n = 3 independent experiments), yielding better Results compared with individual treatments. Conclusions Caf1 exhibits promise as a platform for motif delivery, and the incorporation of cell migration motifs into Caf1 holds the potential to enhance wound healing.
2023-09-11 | Loss of cholesterol in Junctional Epidermolysis Bullosa skin identifies a key role for Laminin-332 in actomyosin mediated cholesterol transport
Abstract Individuals with Junctional Epidermolysis Bullosa (JEB), a rare genetic skin disease characterised by loss of function mutations in the Laminin332 (Lam332), do not survive beyond their first birthday. Here we report that loss of Lam332 leads to absence of cholesterol lipid from the epidermis in vitro and in vivo . Stable knockdown of Lam332 chains (LAMA3, LAMB3 and LAMC2) was established using shRNA and were used to develop 3D skin equivalents. Changes in lipid synthesis were assessed by western blot analysis and immunohistochemistry. Findings were confirmed in an inducible mouse model of Lamα3 ( Lama3 flox/flox /K14 CreERT ) and in anonymized, archival human tissue: JEB skin and normal age-matched controls. Further lipid analysis was explored using lipidomics in 3D skin equivalents and mouse tissue. Cholesterol biosynthesis genes were increased with loss of Lam332 in vitro , however a decrease in nile red lipid staining was observed in Lamα3 mouse (n = 6) and in JEB patient skin (n = 7). Further changes to the epidermal lipid profile with loss of Lam332 was confirmed with lipidomic analysis of Lamα3 mouse epidermis and Lam332 skin equivalents. Cholesterol transport within Lam332 KD keratinocytes was revealed to be disrupted, which in keratinocytes is dependent on the actomyosin network, which was reversed with recombinant human Lam332. In conclusion these findings suggest a role for Lam332 in lipid metabolism in the skin and a broader role in epidermal homeostasis and barrier formation. Restoration of cholesterol transport in JEB patients offers the potential to improve the skin barrier and survival.
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.
2024-07-17 | Biochemical role of FOXM1-dependent histone linker H1B in human epidermal stem cells
Abstract Epidermal stem cells orchestrate epidermal renewal and timely wound repair through a tight regulation of self-renewal, proliferation, and differentiation. In culture, human epidermal stem cells generate a clonal type referred to as holoclone, which give rise to transient amplifying progenitors (meroclone and paraclone-forming cells) eventually generating terminally differentiated cells. Leveraging single-cell transcriptomic data, we explored the FOXM1-dependent biochemical signals controlling self-renewal and differentiation in epidermal stem cells aimed at improving regenerative medicine applications. We report that the expression of H1 linker histone subtypes decrease during serial cultivation. At clonal level we observed that H1B is the most expressed isoform, particularly in epidermal stem cells, as compared to transient amplifying progenitors. Indeed, its expression decreases in primary epithelial culture where stem cells are exhausted due to FOXM1 downregulation. Conversely, H1B expression increases when the stem cells compartment is sustained by enforced FOXM1 expression, both in primary epithelial cultures derived from healthy donors and JEB patient. Moreover, we demonstrated that FOXM1 binds the promotorial region of H1B, hence regulates its expression. We also show that H1B is bound to the promotorial region of differentiation-related genes and negatively regulates their expression in epidermal stem cells. We propose a novel mechanism wherein the H1B acts downstream of FOXM1, contributing to the fine interplay between self-renewal and differentiation in human epidermal stem cells. These findings further define the networks that sustain self-renewal along the previously identified YAP-FOXM1 axis.
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.
2023-07-14 | Seven naturally variant loci serve as genetic modifiers of Lamc2jeb induced non-Herlitz junctional Epidermolysis Bullosa in mice.
Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma. While primary genetic risk of all subforms of EB adhere to Mendelian patterns of inheritance, their clinical presentations and severities can vary greatly, implying genetic modifiers. The Lamc2jeb mouse model of non-Herlitz junctional EB (JEB-nH) demonstrated that genetic modifiers can contribute substantially to the phenotypic variability of JEB and likely other forms of EB. The innocuous changes in an 'EB related gene', Col17a1, have shown it to be a dominant modifier of Lamc2jeb. This work identifies six additional Quantitative Trait Loci (QTL) that modify disease in Lamc2jeb/jeb mice. Three QTL include other known 'EB related genes', with the strongest modifier effect mapping to a region including the epidermal hemi-desmosomal structural gene dystonin (Dst-e/Bpag1-e). Three other QTL map to intervals devoid of known EB-associated genes. Of these, one contains the nuclear receptor coactivator Ppargc1a as its primary candidate and the others contain related genes Pparg and Igf1, suggesting modifier pathways. These results, demonstrating the potent disease modifying effects of normally innocuous genetic variants, greatly expand the landscape of genetic modifiers of EB and therapeutic approaches that may be applied.
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