RARE DISEASE
Dystrophic epidermolysis bullosa
Dystrophic epidermolysis bullosa
Dystrophic epidermolysis bullosa
Synonyms: DEB, Dermolytic epidermolysis bullosa, Epidermolysis bullosa dystrophica
Synonyms: DEB, Dermolytic epidermolysis bullosa, Epidermolysis bullosa dystrophica
Synonyms: DEB, Dermolytic epidermolysis bullosa, Epidermolysis bullosa dystrophica
Drug discovery
11
drugs
With orphan designations
Overview
Dystrophic epidermolysis bullosa (DEB) is a rare inherited blistering disorder caused by COL7A1 mutations, disrupting type VII collagen formation and dermal-epidermal adhesion. Subtypes include autosomal dominant (DDEB) and recessive (RDEB) forms, with RDEB often presenting severe generalized blistering, scarring, and complications like malnutrition, contractures, and aggressive squamous cell carcinomas [1][2][4]. Diagnosis combines clinical evaluation with immunofluorescence mapping or genetic testing [1][6]. Management focuses on symptomatic care, wound prevention, and emerging therapies [18][9].
Burden
Clinical: Chronic wounds, scarring, pseudosyndactyly, and 70% lifetime risk of aggressive SCC in RDEB [2][4][10].
Economic: Annual U.S. medical costs range from $22,179–$48,419 per patient, driven by bandaging (up to $245,000/year) and multidisciplinary care [5][9][19].
Humanistic: Severe pain, reduced mobility, and diminished quality of life; caregivers report substantial time spent on daily wound care (1–3 hours/session) [9][19].
Therapies
Supportive care: Daily wound management with nonadherent dressings, infection control, nutrition support, and pain/itch relief [1][5][18].
Advanced therapies: Topical gene therapy (beremagene geperpavec) for wound healing in RDEB; investigational approaches include protein/cell-based therapies and COL7A1 gene correction [3][9][13].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare skin diseases
Research Papers
1,038 drug discovery papers about Dystrophic epidermolysis bullosa, with 4 first-in-class and 22 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,038 drug discovery papers about Dystrophic epidermolysis bullosa, with 4 first-in-class and 22 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-22 | A Mechanistic Map of the Phenotypic Complexity in Recessive Dystrophic Epidermolysis Bullosa Provides Basis for Therapeutic Target Discovery and Drug Repurposing
Recessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis caused by loss-of-function mutations in the COL7A1 gene, producing a complex and heterogeneous phenotype. Clinical manifestations include skin fragility, local and systemic inflammation, impaired wound healing, dysbiosis, pain, and pruritus, increasing the risk of skin cancer. This work aimed to develop an actionable model of RDEB’s molecular mechanisms to identify and prioritize therapeutic targets for drug repurposing. Transcriptomic data of skin biopsies from pediatric RDEB patients and unaffected individuals were used to build the mechanistic map of the disease. This model, combined with machine learning, made it possible to infer actionable targets from the map circuits and identify candidate drugs capable of reversing the transcriptomic alterations. The resulting map is defined by 13 altered signaling circuits and 10 effector proteins which were linked to disease hallmarks including inflammation, fibrosis, and tumor progression. Analysis of the map identified 66 actionable targets with 74 drug candidates. Among them, overrepresentation analysis showed enrichment of phosphodiesterases and antineoplastic and immunomodulating agents. Finally, 16 drugs were prioritized for their potential to revert circuit alterations without potentiating unintended effects, with bendroflumethiazide and ibutilide showing the highest impact. This mechanistic model delivers the first functional disease map of RDEB and reveals promising therapeutic candidates targeted by approved drugs.
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.
2026-08-18 | Rigosertib Reverses Hypertrophic Cardiomyopathy in Noonan Syndrome.
RASopathies constitute a group of rare genetic disorders caused by mutations in genes along the canonical RAS/mitogen-activated protein kinase (MAPK) signaling pathway, affecting cell growth and differentiation. These syndromes, which include Noonan syndrome (NS), are characterized by developmental delays, distinctive facial dysmorphia, and cardiac defects, notably hypertrophic cardiomyopathy (HCM). Despite their prevalence and impact, therapeutic options for RASopathies remain limited. Rigosertib, a novel dual RAS/MAPK and phosphatidylinositol 3-kinase (PI3K)/AKT pathway inhibitor, is currently in clinical trials for treatment of melanoma and recessive dystrophic epidermolysis bullosa. Here, we identify rigosertib as a candidate therapy for RAF1-associated HCM. We performed a drug screen of clinically relevant compounds in transgenic Drosophila models of RASopathies to identify candidate therapeutics. Cardiac-targeted Drosophila models expressing RASopathy-associated transgenes were used to evaluate the effects of rigosertib on cardiac hypertrophy and compare its efficacy with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib. Therapeutic efficacy was further assessed in a mammalian model using Raf1L613V/+ knock-in mice treated with rigosertib for 6 weeks. Cardiac structure and function were evaluated by echocardiography, histology, and molecular analyses, including assessment of cardiomyocyte size, fetal gene expression, and extracellular signal-regulated kinase/AKT signaling. Additional NS-associated phenotypes, including skeletal growth and craniofacial abnormalities, were also evaluated. Rigosertib was effective across a panel of transgenic Drosophila RASopathy models, suggesting activity against multiple disease variants. In cardiac-targeted fly models, rigosertib reduced cardiac hypertrophy and outperformed trametinib. In Raf1L613V/+ mice, 6 weeks of treatment significantly improved left ventricular chamber dimension, posterior wall thickness, heart mass, and cardiomyocyte size, resulting in reversal of cardiac hypertrophy. Rigosertib also normalized fetal gene expression and inhibited extracellular signal-regulated kinase and AKT signaling in primary cardiomyocytes. In addition to reversing cardiac pathology, rigosertib significantly improved other NS-associated features, including increased bone growth and correction of craniofacial abnormalities. Together, our findings suggest that rigosertib normalizes and reverses RASopathy-associated HCM and other NS-associated syndromic features, supporting its development as a promising treatment for RAF1-associated HCM and, potentially, other RASopathy-dependent pathologies. This study not only highlights the therapeutic potential of rigosertib but also demonstrates the utility of an integrated approach using Drosophila and mammalian models to elucidate drug effects across complex biological systems.
2026-08-07 | Impact of modified SSD soft brace on surgical outcomes and wound healing duration following hand scar contracture release in RDEB patients.
To investigate the clinical efficacy of a modified soft brace incorporating a Silver Sulfadiazine (SSD) oil-based dressing in improving wound healing and home care quality following hand scar contracture release surgery in patients with RDEB. Thirty-five RDEB patients (aged 8-21 years) who underwent hand contracture release between 2017 and 2023 were assigned to Traditional (Vaseline gauze + brace, n = 17) or Modified (SSD dressing + brace, n = 18) groups. Perioperative outcomes, wound healing duration, compliance (RHCS), and recurrence-free survival were compared. Baseline characteristics were comparable. Compared to the Traditional Group, the Modified Group had significantly fewer dressing changes (2.33 ± 0.49 vs. 4.18 ± 0.73, P < 0.001), shorter healing duration (23.33 ± 3.40 vs. 36.24 ± 5.09 days, P < 0.001), lower epithelial stripping rate (11.1% vs. 64.7%, P = 1.6E-3), and no refractory wounds. The Modified Group also showed higher RHCS total scores (84.94 ± 9.62 vs. 46.12 ± 19.12, P < 0.001) and fewer spontaneous nocturnal blisters (11.1% vs. 64.7%). Univariable Cox regression indicated the modified regimen was associated with delayed recurrence. Kaplan-Meier analysis showed delayed recurrence in the Modified Group by log-rank test (P = 0.03), and univariable Cox analysis yielded HR 0.39, 95% CI 0.16-0.95, albeit with wide confidence intervals and limited late-term power. In this retrospective cohort, the SSD-containing non-adherent dressing used with a soft brace was associated with fewer dressing changes, less dressing-related trauma, and better reported tolerance. Prospective controlled studies with validated functional and compliance outcomes are required.
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.
antibodies
2026-04-26 | Possible involvement of interleukin-31 in pruriginosa-type recessive dystrophic epidermolysis bullosa: a positive response to nemolizumab
Selective inhibition of interleukin (IL)-31 led not only to rapid relief of severe pruritus but also to dramatic improvement of inflammatory skin lesions in pruriginosa-type recessive dystrophic epidermolysis bullosa in a boy in early adolescence. While IL-31 is well recognized as a central mediator of itch, this clinical course suggests that IL-31 functions as a disease-amplifying switch linking immune activation, scratching behaviour and cutaneous damage. Interrupting this pathway appeared to collapse the itch–scratch cycle itself, resulting in sustained clinical improvement beyond symptomatic itch control.
2026-01-06 | O15 Improving skin regeneration in JEB by targeting the integrin αvβ6
Abstract Introduction and aims Epithelial integrin αvβ6 has many important roles in skin repair in particular the activation of latent transforming growth factor (TGF)β and its abnormal activity has been associated with chronic wounds. αvβ6 integrin is transiently upregulated in blistered skin; however, it becomes chronic in epidermolysis bullosa skin blistering diseases such as recessive dystrophic epidermolysis bullosa (RDEB) and junctional epidermolysis bullosa (JEB). Here we explore how pathological integrin αvβ6 upregulation in epidermolysis bullosa (EB) is driving defective wound healing, chronic inflammation and fibrosis and if its targeted inhibition improves skin EB symptoms using an inducible JEB disease mouse model. Methods A tamoxifen-inducible JEB disease model with epidermis-specific LAMA3 knockout (KO) was utilized for identifying the αvβ6 integrin signalling changes by immunofluorescent staining and flow cytometry during skin homeostasis and wound healing. To inhibit αvβ6 signalling in JEB skin in vivo a novel αvβ6-blocking antibody 264RAD was injected intraperitoneally for 2 weeks prior skin analysis. Results αvβ6 integrin expression is significantly upregulated in epidermis of JEB KO mice, especially in the blistering areas in comparison with controls. The increased expression of αvβ6 correlates with enhanced inflammatory and fibrosis markers in blistered and wounded skin, suggesting a key role in the pathological mechanisms driving skin disease. The 264RAD treatment showed a strong decrease in integrin αvβ6 expression but also a modest increase in B-cell level accompanied by a rise in mononuclear immune cell populations. Importantly, a reduction in fibrosis around skin blisters and an improvement in wound healing has been observed in JEB KO mice treated with 264RAD. Conclusions The obtained preclinical data reveals abnormal expression of αvβ6 integrin in JEB and indicates that inhibition of αvβ6 is a potential novel therapeutic target to improve skin health and regeneration in JEB and possibly other EB subtypes.
2026-01-01 | The Clinical Efficacy and Safety of Dupilumab Monotherapy in Dystrophic Epidermolysis Bullosa: A Retrospective Real‐World Study
Background Dupilumab has demonstrated promising efficacy and safety in patients with dystrophic epidermolysis bullosa (DEB). However, clinical data addressing its long‐term effectiveness and safety across diverse DEB subtypes remain limited. Objective To evaluate the long‐term effectiveness and safety of dupilumab in the treatment of various subtypes of DEB, especially severe DEB. Methods This retrospective study analyzed patients with DEB who received dupilumab therapy at Henan Provincial People’s Hospital between January 2021 and October 2023. Results Twelve patients with five subtypes of DEB (Intermediate DDEB, Severe RDEB, Intermediate RDEB, DDEB Pruriginosa, and RDEB Pruriginosa) were enrolled. Genetic analysis of COL7A1 was performed and identified 8 new mutations, including c.7720_7721insG, c.313_1834del, dsIVS15 + 1G > T, c.6082G > A, c.6191G > A, c.7697G > A, c.7087G > A, and c.8662_8677del. Eosinophil count tests were normal in all patients, and serum total IgE was elevated in 7/12 patients. The mean baseline BEBS score (23.86 ± 15.77) declined progressively to 16.35 ± 12.50, 12.34 ± 9.91, and 10.4 ± 9.09 at the 16‐week, 24‐week, and 52‐week follow‐ups, respectively. The mean baseline NRS pruritus score of all patients was 7.25 ± 0.97, and it decreased to 3.83 ± 1.47 and 1.82 ± 0.89 at the 4‐week and 52‐week follow‐ups, respectively. The mean baseline DLQI score of all patients was 19.12 ± 6.21, and it decreased to 10.36 ± 6.19, 5.82 ± 3.37, and 5.00 ± 3.00 at the 16‐week, 24‐week, and 52‐week follow‐ups, respectively. BEBS, NRS pruritus, and DLQI baseline scores were statistically significant differences from those after 52 weeks of treatment ( p < 0.01). Of the 12 DEB patients, Patient #6 had a poor treatment effect and Patient #12 had transient conjunctivitis. Notably, five patients maintained sustained treatment efficacy without significant adverse events for over two years. Conclusion Dupilumab showed long‐term effectiveness and safety in real‐world practice in 11 Chinese patients with five subtypes of DEB (Intermediate DDEB, Severe RDEB, Intermediate RDEB, DDEB Pruriginosa, and RDEB Pruriginosa).
2025-04-24 | Efficacy and Safety of Dupilumab Monotherapy in Patients With Dystrophic Epidermolysis Bullosa: A Retrospective Study of 8 Cases.
Dystrophic epidermolysis bullosa (DEB) is a genetic skin disease with limited therapeutic options for managing pruritus. This study retrospectively evaluated the efficacy and safety of Dupilumab monotherapy in patients with DEB suffering from severe pruritus. DEB patients treated with Dupilumab between June 2021 and June 2023 were reviewed. DEB severity and pruritus intensity were assessed using the Birmingham Epidermolysis Bullosa Severity (BEBS, range 0-100) scores and the Numerical Rating Scale (NRS, range 0-10), respectively. A linear mixed model was used to evaluate the changes in NRS scores of Dupilumab monotherapy over time. The Wilcoxon signed-rank test was used to compare the differences in BEBS scores between pretreatment and posttreatment. Statistical significance was defined as p < 0.05. Eight patients were included (four males and four females; aged 5-38 years). Subtypes included severe (n = 4), intermediate (n = 2), pruriginosa RDEB (n = 1), or pruriginosa DDEB (n = 1). The baseline NRS scores averaged 8.75 ± 1.04, with significant reductions of 58.51%, 60.00%, and 49.94% at 4, 8, and 12 weeks, respectively (p < 0.001). The mean BEBS score at baseline was 35.36 ± 21.47, decreased by 22.29% at 12 weeks (p = 0.049), while the mean area of damaged skin score was 19.63 ± 1.71 at baseline, decreased by 31.23% after 12 weeks (p = 0.048). The mean duration of Dupilumab treatment was 44.50 (12-130) weeks. One DDEB-Pr patient discontinued Dupilumab for planned conception, with no adverse effects reported for the pregnant woman or newborn. Dupilumab appears to be a safe and effective treatment for pruritus in patients with DEB. Preliminary findings also support its potential use in women of reproductive age. Further larger prospective studies are needed to confirm these results.
2025-04-07 | Cross-sectional analysis of wound-associated soluble factors in early, established, and chronic wounds of recessive dystrophic epidermolysis bullosa patients
Background Poorly healing wounds represent the primary health-related burden for hereditary recessive dystrophic epidermolysis bullosa (RDEB) patients. Contribution of wound-associated soluble constituents to wound progression remains not well defined. Objective To conduct cross-sectional analysis of cytokine, chemokine, and growth factor in exudates from RDEB wounds and define changes associated with wound progression. Methods Concentrations of selected cytokines, chemokines, and growth factors were evaluated by multiplex ELISA in eight blister fluids and 76 exudates from early, established, and chronic RDEB and five chronic venous ulcers. A cross-sectional analysis was performed. Results Our data demonstrated that accumulation of IL-1β, IL-17, TNF alpha as well as HGF, G-CSF, and VEGF is associated with progression of RDEB wounds to poorly healing state. The levels of these molecules were significantly higher in RDEB wounds than in venous ulcers. High levels of neutrophil-recruiting CCR2, CXCR1/2 ligands and T cell-recruiting CCR4 ligands were also detected in all RDEB wounds. Conclusion Although this study is limited to cross-sectional analysis of wound exudates, detected high levels of specific pro-inflammatory, pro-angiogenic, and neutrophil-recruiting factors, such as IL1b, CXCL8, and VEGF, define progression of RDEB wounds to chronic state and offer potential pharmacological targets to improve wound healing in the patients.
cell therapies
2026-09-24 | Trophoblast Extracellular Vesicles Rewire Immunity: A Symptom-Relief Avenue for Recessive Dystrophic Epidermolysis Bullosa.
Redirecting immune responses toward tissue repair represents a promising strategy for treating inflammatory and degenerative diseases. Extracellular vesicles (EVs), derived from allogeneic stem cells, have shown potential for modulating proinflammatory immunity. Among these, placental-derived EVs (PEVs) are emerging as candidates for immune-mediated inflammatory disorders due to their role in establishing maternal immune tolerance. However, their applicability beyond pregnancy remains limited by key translational barriers, including the lack of a standardized and scalable source system and need to demonstrate immunomodulatory activity in non-pregnancy allogeneic contexts. In this study, we identify extravillous trophoblasts (EVTs), which play critical role in early placental development, as key source of immunoregulatory PEVs. To overcome donor variability, we employed the HIPEC cell model as established surrogate for primary EVTs and assessed the effects of their derived EVs (EVT-EVs) on circulating monocytes, pivotal mediators of inflammatory responses. High-dimensional molecular profiling revealed that EVT-EVs, similar to EVs derived from first-trimester primary human trophoblast, carry a distinctive anti-inflammatory signature, including a unique miRNA repertoire enriched in immunoregulatory pathways. Integrated proteomic and lipidomic analyses demonstrated that EVT-EVs induce coordinated functional reprograming of monocytes toward an immunomodulatory, inflammation-resolving phenotype. Notably, EVT-EVs also modulated the inflammatory bias of monocytes from patients with recessive dystrophic epidermolysis bullosa (RDEB), a genetic disorder characterized by chronic inflammation, thereby promoting restoration of immune balance. Collectively, these findings identify EVT-EVs as a scalable, off-the-shelf platform with high translational potential for the treatment of chronic inflammatory diseases.
2026-09-07 | Cord Blood-Derived Platelet Gel in Wound Healing: From Biological Rationale to Clinical Application.
Chronic and complex wounds are a major burden worldwide, and a considerable number remain unresponsive to traditional therapy. Cord blood-derived platelet gel (CBPG) is a novel allogeneic wound therapy providing a fibrin-based scaffold enriched with neonatal platelet-derived growth factors, including high concentrations of VEGF, HGF and FGF, directly into the wound bed, without the need for blood collection from the patient. This narrative review provides an overview of the biological features of CBPG, discusses clinical evidence across different wound indications, and assesses ethical, regulatory, and translational issues important to its development. CBPG has been studied in clinical trials in recessive dystrophic epidermolysis bullosa, cutaneous and oral chronic graft versus host disease after allogeneic haematopoietic stem cell transplantation, partial thickness burns, neonatal pressure injuries and diabetic foot ulcers. Across these conditions, CBPG has shown a consistent safety profile and promising signals of benefit, but evidence is restricted by small sample sizes, diverse methods and short follow-up. CBPG offers a biologically rational alternative to complex wound management in fragile patient populations. To move toward validated clinical application, manufacturing standardisation, regulatory classification, multicentre randomised trials with embedded health-economic endpoints, and transparent governance of cord blood allocation are needed.
2026-08-01 | Zevaskyn (prademagene zamikeracel) for wound treatment in individuals with recessive dystrophic epidermolysis bullosa: A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG)
Collagen Type VII, Alpha-1 is encoded by the COL7A1 gene (HGNC:2214) on chromosome 3p21.31. Biallelic pathogenic variants in COL7A1 are associated with autosomal recessive dystrophic epidermolysis bullosa (RDEB), resulting from a defect of COL7A1 function in anchoring fibrils at the cell-cell or cell-matrix junctions.1 RDEB is characterized by chronic blistering and impaired wound healing starting as early as the neonatal period and is associated with debilitating pain, a high risk of infection, fibrosis at the affected areas with scarring that can result in fusion of digits, and other epidermal changes, as well as mucosal lesions that lead to sequelae including iron-deficient anemia and malnutrition.
2026-06-28 | Identification of a long-term surviving human mesenchymal stromal cell subpopulation and implications for recessive dystrophic epidermolysis bullosa treatment.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by loss-of-function pathogenic variants in COL7A1 encoding type VII collagen (C7). Patients with RDEB suffer since birth from skin and mucosal blistering and develop severe local and systemic complications resulting in poor prognosis. Mesenchymal stromal cells (MSCs) have demonstrated their potential to enhance wound healing and reduce skin inflammation in RDEB patients due to their anti-inflammatory properties and capacity to express C7. We aim to optimize in vitro conditioning of human bone marrow-derived MSCs (BM-MSCs) to improve their limited survival following local injection in a murine model. BM-MSCs from healthy human donors were transduced with a lentiviral vector encoding firefly luciferase and mCherry reporter proteins and then subjected to various culture conditions: monolayer on plastic or spheroid culture, either in hypoxia (5% O2) or in normoxia (21% O2). These cells were subsequently injected intradermally (ID) in immunodeficient mice and their survival was assessed by in vivo imaging. BM-MSCs populations were analyzed prior to injection by single-cell RNA sequencing (scRNAseq). Murine skin injected with BM-MSCs were sampled two months post-injection and the surviving subpopulations were characterized by spatial transcriptomic. scRNAseq analysis revealed marked variations between monolayer and spheroid conditions, which were significantly impacted by oxygen level. Although most injected cells gradually died within the first 2 months in all tested conditions, 1% of live bioluminescent cells persisted for 54 up to 61 weeks post-injection. Spatial transcriptomics data analysis demonstrated that all surviving cells, regardless of their in vitro preconditioning, retained the expression of the MSC markers THY1, ENG, and NT5E, shared features with fibroblasts, and exhibited enriched expression in genes related to extracellular matrix and collagen fibril organization, which are key processes in wound healing. Spatial transcriptomic and scRNAseq data integration suggested that surviving BM-MSCs were initially present in the injected population, regardless of their culture condition. Remarkably, none of the in vitro preconditioning strategies appeared to affect their survival capacity or functional properties following local injection. The identification and characterization of a BM-MSC subpopulation capable of long-term survival following ID injection hold promise for the development of improved cell therapy protocols for RDEB.
2026-06-03 | Mesenchymal stromal cell infusions of umbilical cord-derived mesenchymal stromal cells in children with Recessive Dystrophic Epidermolysis Bullosa (MissionEB): a qualitative sub study of a randomised, double-blind, placebo controlled, crossover, phase 3 trial
Abstract Background Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare genetic skin condition causing fragile skin, blistering, and scarring. It leads to chronic pain, slow wound healing, and severe limitations, profoundly impacting patient and family quality of life. Umbilical cord tissue-derived mesenchymal stromal cells (UC-MSC) have shown therapeutic promise. The Mission EB trial (ISRCTN14409785; registration date 25/03/2021) assessed UC-MSC safety and effectiveness in children with RDEB in a placebo-controlled, double-blinded, crossover study. Methods This study used a qualitative research design with semi-structured interviews and thematic analysis, to explore Mission EB trial treatment impact on the quality of life of patients and parents. Parents and patients were interviewed at two time points (approximately 3- and 12-months post-randomisation). Purposive sampling included 10 parents and 6 children; 13 individuals (8 adults, 5 children) were interviewed twice (once in each study period). Interviews were transcribed verbatim, independently coded, with overall impressions agreed upon prior to unblinding. Results RDEB significantly impacted daily life, marked by pain and itch. Participants were hopeful of the trial, willing to pursue minor improvements. UC-MSC infusions led to reduced pain/itchiness, improved wound healing, and resulted in fewer self-reported dressing changes. These benefits often translated to increased energy, improved eating, and greater daily activity participation. Benefits were more pronounced with active treatment. Negative effects were minimal, primarily venous access difficulties. Blinded participants could discern active UC-MSC from placebo based on symptom changes; 10 of 13 showed clear differences aligning with treatment. All parents interviewed expressed willingness for their child to receive treatment again. Conclusions This qualitative research provides valuable insights into perceived benefits of UC-MSC treatment for children with RDEB. Interview findings regarding symptom improvement and participants’ ability to discern active treatment shed light on its perceived benefit in RDEB, especially in milder RDEB patients. The study highlights the critical importance of qualitative methodologies in adding to quantitative trial outcomes and capturing the meaningful impact of interventions on the lives of patients and families particularly where quantitative measures may not fully reflect lived experience.
gene therapies
2026-03-01 | An evaluation of prademagene zamikeracel for the treatment of recessive dystrophic epidermolysis bullosa.
Prademagene zamikeracel is an autologous, genetically corrected epidermal graft therapy designed to address the underlying molecular defect in recessive dystrophic epidermolysis bullosa (RDEB). The product is manufactured from a patient's own keratinocytes, which are modified ex vivo to overexpress a normal copy of COL7A1, the gene coding for type VII collagen (C7), which is essential for anchoring fibril formation and stable dermal-epidermal cohesion. In individuals with biallelic COL7A1 variants, loss of C7 results in severe skin fragility, painful and widespread wounds, debilitating scarring, and a high risk of aggressive cutaneous squamous cell carcinoma. This review outlines the key scientific foundations, translational advances, and clinical trial outcomes that supported regulatory approval of prademagene zamikeracel for use in adult and pediatric patients with RDEB. The development of prademagene zamikeracel represents a significant advance in regenerative therapy for RDEB, demonstrating that durable restoration of C7 expression and long-term wound improvement can be achieved through skin grafting.
2026-01-01 | O13 Preliminary results from correcting COL7A1 (c.G>A) mutation with adenine base editor 8e (ABE8e) in primary fibroblasts from dominant dystrophic epidermolysis bullosa (DDEB) patients
Abstract Introduction and aims Dominant dystrophic epidermolysis bullosa (DDEB) is a congenital blistering skin disease caused by mutant collagen VII (C7) chains interfering with the folding of wildtype (WT) C7, which weakens dermoepidermal junctions. Base editors (BEs) offer unique advantage in precisely correcting the mutant COL7A1 allele while preserving the WT allele. While our group has previously demonstrated the use of adenine base editor 8e (ABE8e) to correct recessive dystrophic epidermolysis bullosa (RDEB), this is the first report of ABE8e being applied to DDEB. Methods Primary fibroblasts from patients with DDEB carrying the COL7A1 exon 73 c.6127G>A mutation were electroporated with ABE8e mRNA and single guide (sg)RNA. Base editing efficiency was evaluated by semiquantitative analysis of Sanger sequencing chromatographs in EditR. Protein-level correction was assessed using a C7 Western blot. In preparation for future in vivo base editing, we validated a DDEB mouse model carrying the Col7a1 exon 73 c.6085C>G mutation using Sanger sequencing. Results Sanger sequencing analysis revealed that ABE8e achieved 19–41% editing efficiency in correcting the c.6127G>A mutation, with a 2 : 1 sgRNA-to-ABE8e ratio yielding higher efficiency than a 1 : 2 ratio. However, Western blot analysis did not show consistent protein-level correction. Sanger sequencing confirmed that our DDEB mouse model is heterozygous for the Col7a1 c.6085G>C mutation. Conclusions This study demonstrated partial DNA-level correction of the COL7A1 c.6127 G>A allele in ABE8e-electroporated primary DDEB fibroblasts ex vivo. However, this editing did not result in increased C7 protein levels. Notably, Western blots assess differences in C7 quantity, but not stability – a key factor in DDEB pathology. Further replication of DNA-level correction and evaluation of C7 stability using a trypsin digestion assay will be essential. These efforts will lay the foundation for transitioning from ex vivo experiments to in vivo correction of the Col7a1 c.6085C>G mutation in our DDEB mouse model.
2026-01-01 | O14 Next-generation sequencing precision: on- and off-target analysis of gene editing in recessive dystrophic epidermolysis bullosa
Abstract Introduction and aims Base editors (BEs) and prime editors (PEs) offer distinct advantages over CRISPR-Cas9 for correcting pathogenic variants. Previously, our group achieved 94.6% efficiency in correcting the COL7A1 c.5047 C>T nonsense pathogenic variant in fibroblasts, associated with recessive dystrophic epidermolysis bullosa (RDEB), using adenine base editor 8e (ABE8e). However, the safety and cell type-specific efficiencies of these techniques remain unclear. This study aims to use a PE to correct the c.5047 C>T pathogenic variant in primary patient fibroblasts and epidermal stem cells to promote wound healing and compare the efficiency and off-target effects of BE and PE using next-generation sequencing (NGS). Methods Primary fibroblasts carrying a heterozygous COL7A1 c.5047 C>T pathogenic variant were transfected with ABE8e mRNA and the PE5bmax system using electroporation and lipid nanoparticles (LNPs). Sanger sequencing and NGS were used to confirm pathogenic variant correction and assess editing efficiencies. Whole-genome sequencing (WGS) was conducted for genome-wide off-target analysis, with pairwise variant calling performed to identify somatic variants in edited vs. unedited samples. Targeted amplicon sequencing was employed to evaluate editing accuracy at the target site. Results ABE8e delivered via LNPs corrected the c.5047 C>T pathogenic variant in fibroblasts with 84% efficiency using lipofectamine, as confirmed by Sanger sequencing and NGS. Prime Editor PE5bmax achieved 43% overall editing efficiency, with 32% variant correction confirmed by Sanger sequencing. Preliminary WGS analysis revealed increased indels and mismatches across the genome in edited samples, although further variant characterization is needed for a comprehensive safety profile. Conclusions ABE8e and PE5bmax successfully corrected the c.5047 C>T mutation in fibroblasts, with respective on-target efficiencies of 84% and 32%. These strategies are being extended to epidermal stem cells for potential wound healing therapies. Comprehensive WGS and targeted sequencing will aid in optimizing these techniques for clinical applications.
2026-01-01 | P19 Proof of concept for a variant-agnostic, permanent DNA editing cure for dystrophic epidermolysis bullosa
Abstract Introduction and aims Dystrophic epidermolysis bullosa (DEB) is an inherited blistering skin disease with over 800 causative mutations identified in the COL7A1 gene. eePASSIGE is a breakthrough DNA editing technology that pairs prime editing (PE) with serine integrase technology, allowing for targeted integration of large DNA constructs. We aim (i) to use eePASSIGE to integrate a full-length cDNA of COL7A1 into the AAVS1 safe harbour locus, and (ii) to develop lipid-based nanoparticles (LNPs) capable of delivering eePASSIGE machinery to human skin cells. Together, these two strategies form the basis for a proposed permanent ‘one-size-fits-all’ DEB cure. Methods We have used lipofection of HEK293T, N/TERT, and human fibroblast cells to provide proof of concept. For PE and eePASSIGE, lipofectamine was used to deliver plasmid DNA encoding editing constructs and pegRNAs. For PE, Sanger sequencing of target site amplicons was used to identify successful edits. For eePASSIGE, puromycin selection was used to isolate successfully edited cells. For LNP studies, fluorescent reporter mRNA was delivered to N/TERTs and fibroblasts; successful transfection was quantified with flow cytometry. Results In N/TERT cells, we achieved up to 17% PE efficiency in transfected cells, although only 1% of cells were successfully transfected. eePASSIGE was used to successfully integrate a puromycin resistance gene into HEK293T cells at the AAVS1 safe harbour locus. Lipid nanoparticles were used to successfully transfect human fibroblasts and keratinocytes in submerged culture with reporter constructs with up to 80% efficiency and with lower toxicity than lipofectamine. Conclusions Our experiments thus far have laid the groundwork for future study of eePASSIGE to integrate large coding constructs into disease-relevant cells. Our next steps are (i) to improve transfection of eePASSIGE machinery in cells of interest, and (ii) to optimize LNP formulations for use in three-dimensional culture and in vivo mouse skin.
2025-11-19 | Base edited skin equivalents with clinical potential for ex vivo correction of recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic disorder caused by bi-allelic null mutations in the COL7A1 gene. Among various therapeutic genome editing (GE) strategies, adenine base editors (ABEs) have demonstrated particular efficacy in nonsense mutations. Previous studies have predominantly focused on RDEB fibroblasts, which produce significantly less type VII collagen (C7) than keratinocytes. This study evaluates the efficacy and safety of ABE8e, via mRNA electroporation, to correct three different COL7A1 nonsense mutations (one homozygous and two heterozygous [patients 1, 2, and 3]), and a cryptic splice site mutation (patient 4) in primary cells from RDEB patients. Sanger and next-generation sequencing revealed high efficiency (>90%) at the intended mutation-causing nucleotides. Bystander effects were observed in two of the four loci analyzed. Deeper off-target study was performed in the first two patients. A safe off-target profile was observed in the homozygous patient (P1), while off-target effects were identified in the heterozygous patient (P2). The restoration of C7 expression in treated cells was consistent with genotypic correction. Additionally, functional assessments, including transplantation of skin equivalents formed by both base-edited keratinocytes and fibroblasts, demonstrated sustained in vivo skin regeneration and proper C7 deposition at the basement membrane. ABE8e-mediated base editing shows high efficacy and safety correcting COL7A1 mutations in the two cell types, broadening the scope of this GE therapeutic modality for RDEB treatment.
other
2026-09-18 | Disrupted Skin-Nerve Homeostasis in Recessive Dystrophic Epidermolysis Bullosa: a Neurocutaneous Unit Perspective on Pain.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited disorder characterised by type VII collagen impairment, leading to dermo-epidermal junction (DEJ) instability and chronic skin fragility. Pain is a near-universal and quality-of-life-limiting feature; however, explanations centred solely on tissue injury and inflammation do not fully account for its persistence or treatment resistance. Increasing evidence supports a broader framework in which disrupted skin-nerve homeostasis within the neurocutaneous unit (NCU) contributes to pain generation. This narrative, hypothesis-driven review integrates clinical, experimental and translational evidence to examine the role of the NCU, the functional interface between keratinocytes and intraepidermal sensory fibres, in RDEB pain. Chronic injury, persistent inflammation and DEJ disruption create a microenvironment that is unfavourable for sensory nerve maintenance and repair. Clinical and experimental findings support the presence of small-fibre pathology, reflected by reduced intraepidermal nerve fibre density, altered sensory thresholds and neuropathic pain descriptors. Mechanistically, repeated injury appears to impair reinnervation and contribute to progressive distal sensory fibre loss within a hostile cutaneous microenvironment. Keratinocyte dysfunction drives this process through impaired neurotrophic support and the sustained release of pro-inflammatory mediators that directly sensitise nociceptors. In parallel, dermal fibrosis and extracellular matrix remodelling may constrain axonal regeneration. Molecular studies further demonstrate a persistent inflammatory and pro-fibrotic signature in RDEB skin, including clinically non-lesional areas. These converging abnormalities suggest that disrupted skin-nerve homeostasis is an important contributor to disease-associated pain. Translational evidence suggests partial reversibility, with pain reduction observed following therapies targeting neuropathic mechanisms or restoring DEJ integrity. Together, these findings support a framework in which altered neurocutaneous interactions contribute substantially to pain in RDEB, underscoring the need for mechanism-based and potentially early neuroprotective strategies.
2026-08-14 | Fragile skin may benefit from decoration
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe hereditary blistering disorder characterized by fragility of the skin and mucous membranes due to mutations in the COL7A1 gene, which encodes type VII collagen, the principal component of anchoring fibrils1,2 (Figure 1A). Loss or dysfunction of type VII collagen leads to separation at the dermal-epidermal junction, resulting in chronic wounds, scarring, and progressive multisystem complications. RDEB is associated with substantial morbidity, including strictures in esophagus, pseudosyndactyly (fusion of fingers), nutritional impairment, and an exceptionally high lifetime risk of developing aggressive cutaneous squamous cell carcinoma (cSCC)1,2 (Figure 1A).
2026-05-18 | Systemic clinical-grade recombinant decorin reduces disease burden and fibrosis in advanced recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a skin and epithelial fragility disease that progresses with severe fibrosis. This fibrosis is debilitating and promotes the development of aggressive squamous cell carcinomas (SCCs). Effective management of fibrosis may improve quality of life in RDEB and reduce the risk of high-risk SCCs. Decorin, a small leucine-rich proteoglycan, has natural fibrosis-limiting activity. Higher expression of decorin has been linked to milder RDEB, and decorin has shown anti-fibrotic effects in multiple models of experimentally induced fibrosis. However, a short circulating half-life, manufacturing challenges, and broad target engagement have limited the development of systemic decorin therapy. Here, we describe scalable production of recombinant human decorin protein core (rh Decorin) and test repeated intravenous administration in a murine model of advanced RDEB. We show that rh Decorin accumulates in the skin and other injured sites and improves RDEB-related signs. Systemic administration enables decorin-mediated direct and indirect inhibition of TGF-β activity in peripheral tissues. Characterization of the dermal collagen matrix revealed evidence of remodeling capacity of fibrotic lesions in RDEB when cellular contractile activities are targeted, providing an explanation for the anti-fibrotic effects of rh Decorin in advanced disease. These results support further evaluation of intravenous rh Decorin for the treatment of RDEB, especially for fibrotic manifestations.
2026-05-05 | Engineered natural extracellular matrix platform for modelling skin diseases and identifying therapeutic targets.
Dysregulation of the dermal extracellular matrix (ECM) drives skin pathologies by influencing tissue mechanics, dermal-epidermal adhesion, and disease progression. However, current in vitro models often fail to replicate native ECM complexity or disease-specific alterations, limiting mechanistic studies and therapeutic target discovery. This gap is particularly critical for untreatable skin fragility disorders, where abnormal dermal ECM underlies severe clinical manifestations. This study aimed to develop and validate an engineered natural ECM (NatECM) platform that recapitulates key compositional and biomechanical features of fibroblast-derived dermal ECM. As a proof-of-concept, we applied NatECM to model clinically distinct variants of dystrophic epidermolysis bullosa (DEB), the skin fragility disorders prototype, to identify ECM-related and disease-specific alterations and to interrogate candidate therapeutic targets. Primary fibroblasts from healthy donors and DEB patients were cultured to self-assemble their ECM, generating NatECM dermal equivalents. ECM organization was evaluated by immunostaining and ultrastructural analyses, nano- and macro-scale mechanical properties were measured by atomic force microscopy and uniaxial tensile testing, and ECM composition was characterized by proteomics. Functional relevance was evaluated by keratinocyte adhesion assays and fibulin-5 supplementation experiments. NatECM reproduced intrinsic fibroblast-derived dermal ECM features and captured disease-associated mechanical and structural impairments characteristic of DEB. Across DEB variants, NatECM unveiled subtype-specific proteomic alterations that affect ECM structure and elastic fiber formation. We identified a "fragility quartet" - fibulin-5, decorin, and collagens III and V - consistently downregulated across all variants and linked to defective ECM mechanics. Fibulin-5 supplementation restored ECM elastic behavior and strengthened keratinocyte adhesion, supporting its role as a candidate ECM regulator. The NatECM platform faithfully models fibroblast-derived dermal ECM and enables the identification and functional investigation of key molecular ECM regulators in DEB. Its tunability and physiological relevance position NatECM as a robust tool for studying ECM-driven skin disorders and for accelerating the identification of candidate therapeutic targets.
2026-03-06 | Systemic inflammation in recessive dystrophic epidermolysis bullosa: a five-year longitudinal study.
Recessive dystrophic epidermolysis bullosa (RDEB) is characterized by skin fragility, extensive wounding, and systemic complications. While inflammation contributes to disease severity, its pattern, longitudinal dynamics and clinical correlates remain poorly defined. To characterize the course of systemic inflammatory markers over time in patients with RDEB and explore their associations with clinical, microbiological, and laboratory parameters. This retrospective longitudinal study analyzed clinical and laboratory data of 120 visits within 5 years from 44 patients with intermediate (N=22) and severe (N=22) RDEB. Acute-phase proteins (CRP, IL-6, SAA), neutrophil to lymphocyte ratio (NLR), leukocytes, thrombocytes and ferritin were examined in relation to wound body surface area, mucosal involvement, collagen VII (C7) protein expression levels, squamous cell carcinoma (SCC) presence, nutritional status, anemia markers, wound microbiology and immunoglobulins. Severe RDEB showed an early and sustained systemic inflammatory profile, with CRP, IL-6, and SAA elevated >3.5-fold from early childhood, plateauing in mid-adulthood. Intermediate RDEB maintained low inflammatory activity throughout life. Acute phase proteins and NLR were significantly elevated in the presence of SCC (CRP: p<0.001; IL-6: p=0.002; SAA: p=0.011; NLR: p=0.004), collagen VII absence (CRP: p=0.002), and colonization by Pseudomonas (CRP, IL-6: p<0.001) or fungi (CRP: p=0.006). CRP and age were the most robust independent predictors of SCC risk. Streptococcus, Pseudomonas, fungi, or polymicrobial colonization were associated with a broader systemic inflammatory response, when compared to infections with Staphylococcus. Hypoalbuminemia and elevated immunoglobulins correlated with inflammatory markers and anemia of chronic disease was reflected by declining iron and increased ferritin levels. In multivariable models, reduced C7 expression, wound burden and SCC were the strongest independent predictors of acute phase inflammation. This study reveals that severe RDEB involves early-onset, progressive systemic inflammation that peaks in mid-adulthood and then plateaus, suggesting a critical window for therapeutic intervention. In contrast, intermediate RDEB shows minimal systemic inflammation. The findings support a three-tiered treatment approach-wound burden reduction through curative/corrective interventions, antimicrobial strategies and anti-inflammatory therapy -aligned with standard of care and nutritional supplementation.
small molecules
2026-09-22 | A Mechanistic Map of the Phenotypic Complexity in Recessive Dystrophic Epidermolysis Bullosa Provides Basis for Therapeutic Target Discovery and Drug Repurposing
Recessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis caused by loss-of-function mutations in the COL7A1 gene, producing a complex and heterogeneous phenotype. Clinical manifestations include skin fragility, local and systemic inflammation, impaired wound healing, dysbiosis, pain, and pruritus, increasing the risk of skin cancer. This work aimed to develop an actionable model of RDEB’s molecular mechanisms to identify and prioritize therapeutic targets for drug repurposing. Transcriptomic data of skin biopsies from pediatric RDEB patients and unaffected individuals were used to build the mechanistic map of the disease. This model, combined with machine learning, made it possible to infer actionable targets from the map circuits and identify candidate drugs capable of reversing the transcriptomic alterations. The resulting map is defined by 13 altered signaling circuits and 10 effector proteins which were linked to disease hallmarks including inflammation, fibrosis, and tumor progression. Analysis of the map identified 66 actionable targets with 74 drug candidates. Among them, overrepresentation analysis showed enrichment of phosphodiesterases and antineoplastic and immunomodulating agents. Finally, 16 drugs were prioritized for their potential to revert circuit alterations without potentiating unintended effects, with bendroflumethiazide and ibutilide showing the highest impact. This mechanistic model delivers the first functional disease map of RDEB and reveals promising therapeutic candidates targeted by approved drugs.
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.
2026-08-18 | Rigosertib Reverses Hypertrophic Cardiomyopathy in Noonan Syndrome.
RASopathies constitute a group of rare genetic disorders caused by mutations in genes along the canonical RAS/mitogen-activated protein kinase (MAPK) signaling pathway, affecting cell growth and differentiation. These syndromes, which include Noonan syndrome (NS), are characterized by developmental delays, distinctive facial dysmorphia, and cardiac defects, notably hypertrophic cardiomyopathy (HCM). Despite their prevalence and impact, therapeutic options for RASopathies remain limited. Rigosertib, a novel dual RAS/MAPK and phosphatidylinositol 3-kinase (PI3K)/AKT pathway inhibitor, is currently in clinical trials for treatment of melanoma and recessive dystrophic epidermolysis bullosa. Here, we identify rigosertib as a candidate therapy for RAF1-associated HCM. We performed a drug screen of clinically relevant compounds in transgenic Drosophila models of RASopathies to identify candidate therapeutics. Cardiac-targeted Drosophila models expressing RASopathy-associated transgenes were used to evaluate the effects of rigosertib on cardiac hypertrophy and compare its efficacy with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib. Therapeutic efficacy was further assessed in a mammalian model using Raf1L613V/+ knock-in mice treated with rigosertib for 6 weeks. Cardiac structure and function were evaluated by echocardiography, histology, and molecular analyses, including assessment of cardiomyocyte size, fetal gene expression, and extracellular signal-regulated kinase/AKT signaling. Additional NS-associated phenotypes, including skeletal growth and craniofacial abnormalities, were also evaluated. Rigosertib was effective across a panel of transgenic Drosophila RASopathy models, suggesting activity against multiple disease variants. In cardiac-targeted fly models, rigosertib reduced cardiac hypertrophy and outperformed trametinib. In Raf1L613V/+ mice, 6 weeks of treatment significantly improved left ventricular chamber dimension, posterior wall thickness, heart mass, and cardiomyocyte size, resulting in reversal of cardiac hypertrophy. Rigosertib also normalized fetal gene expression and inhibited extracellular signal-regulated kinase and AKT signaling in primary cardiomyocytes. In addition to reversing cardiac pathology, rigosertib significantly improved other NS-associated features, including increased bone growth and correction of craniofacial abnormalities. Together, our findings suggest that rigosertib normalizes and reverses RASopathy-associated HCM and other NS-associated syndromic features, supporting its development as a promising treatment for RAF1-associated HCM and, potentially, other RASopathy-dependent pathologies. This study not only highlights the therapeutic potential of rigosertib but also demonstrates the utility of an integrated approach using Drosophila and mammalian models to elucidate drug effects across complex biological systems.
2026-08-07 | Impact of modified SSD soft brace on surgical outcomes and wound healing duration following hand scar contracture release in RDEB patients.
To investigate the clinical efficacy of a modified soft brace incorporating a Silver Sulfadiazine (SSD) oil-based dressing in improving wound healing and home care quality following hand scar contracture release surgery in patients with RDEB. Thirty-five RDEB patients (aged 8-21 years) who underwent hand contracture release between 2017 and 2023 were assigned to Traditional (Vaseline gauze + brace, n = 17) or Modified (SSD dressing + brace, n = 18) groups. Perioperative outcomes, wound healing duration, compliance (RHCS), and recurrence-free survival were compared. Baseline characteristics were comparable. Compared to the Traditional Group, the Modified Group had significantly fewer dressing changes (2.33 ± 0.49 vs. 4.18 ± 0.73, P < 0.001), shorter healing duration (23.33 ± 3.40 vs. 36.24 ± 5.09 days, P < 0.001), lower epithelial stripping rate (11.1% vs. 64.7%, P = 1.6E-3), and no refractory wounds. The Modified Group also showed higher RHCS total scores (84.94 ± 9.62 vs. 46.12 ± 19.12, P < 0.001) and fewer spontaneous nocturnal blisters (11.1% vs. 64.7%). Univariable Cox regression indicated the modified regimen was associated with delayed recurrence. Kaplan-Meier analysis showed delayed recurrence in the Modified Group by log-rank test (P = 0.03), and univariable Cox analysis yielded HR 0.39, 95% CI 0.16-0.95, albeit with wide confidence intervals and limited late-term power. In this retrospective cohort, the SSD-containing non-adherent dressing used with a soft brace was associated with fewer dressing changes, less dressing-related trauma, and better reported tolerance. Prospective controlled studies with validated functional and compliance outcomes are required.
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.
antibodies
2026-04-26 | Possible involvement of interleukin-31 in pruriginosa-type recessive dystrophic epidermolysis bullosa: a positive response to nemolizumab
Selective inhibition of interleukin (IL)-31 led not only to rapid relief of severe pruritus but also to dramatic improvement of inflammatory skin lesions in pruriginosa-type recessive dystrophic epidermolysis bullosa in a boy in early adolescence. While IL-31 is well recognized as a central mediator of itch, this clinical course suggests that IL-31 functions as a disease-amplifying switch linking immune activation, scratching behaviour and cutaneous damage. Interrupting this pathway appeared to collapse the itch–scratch cycle itself, resulting in sustained clinical improvement beyond symptomatic itch control.
2026-01-06 | O15 Improving skin regeneration in JEB by targeting the integrin αvβ6
Abstract Introduction and aims Epithelial integrin αvβ6 has many important roles in skin repair in particular the activation of latent transforming growth factor (TGF)β and its abnormal activity has been associated with chronic wounds. αvβ6 integrin is transiently upregulated in blistered skin; however, it becomes chronic in epidermolysis bullosa skin blistering diseases such as recessive dystrophic epidermolysis bullosa (RDEB) and junctional epidermolysis bullosa (JEB). Here we explore how pathological integrin αvβ6 upregulation in epidermolysis bullosa (EB) is driving defective wound healing, chronic inflammation and fibrosis and if its targeted inhibition improves skin EB symptoms using an inducible JEB disease mouse model. Methods A tamoxifen-inducible JEB disease model with epidermis-specific LAMA3 knockout (KO) was utilized for identifying the αvβ6 integrin signalling changes by immunofluorescent staining and flow cytometry during skin homeostasis and wound healing. To inhibit αvβ6 signalling in JEB skin in vivo a novel αvβ6-blocking antibody 264RAD was injected intraperitoneally for 2 weeks prior skin analysis. Results αvβ6 integrin expression is significantly upregulated in epidermis of JEB KO mice, especially in the blistering areas in comparison with controls. The increased expression of αvβ6 correlates with enhanced inflammatory and fibrosis markers in blistered and wounded skin, suggesting a key role in the pathological mechanisms driving skin disease. The 264RAD treatment showed a strong decrease in integrin αvβ6 expression but also a modest increase in B-cell level accompanied by a rise in mononuclear immune cell populations. Importantly, a reduction in fibrosis around skin blisters and an improvement in wound healing has been observed in JEB KO mice treated with 264RAD. Conclusions The obtained preclinical data reveals abnormal expression of αvβ6 integrin in JEB and indicates that inhibition of αvβ6 is a potential novel therapeutic target to improve skin health and regeneration in JEB and possibly other EB subtypes.
2026-01-01 | The Clinical Efficacy and Safety of Dupilumab Monotherapy in Dystrophic Epidermolysis Bullosa: A Retrospective Real‐World Study
Background Dupilumab has demonstrated promising efficacy and safety in patients with dystrophic epidermolysis bullosa (DEB). However, clinical data addressing its long‐term effectiveness and safety across diverse DEB subtypes remain limited. Objective To evaluate the long‐term effectiveness and safety of dupilumab in the treatment of various subtypes of DEB, especially severe DEB. Methods This retrospective study analyzed patients with DEB who received dupilumab therapy at Henan Provincial People’s Hospital between January 2021 and October 2023. Results Twelve patients with five subtypes of DEB (Intermediate DDEB, Severe RDEB, Intermediate RDEB, DDEB Pruriginosa, and RDEB Pruriginosa) were enrolled. Genetic analysis of COL7A1 was performed and identified 8 new mutations, including c.7720_7721insG, c.313_1834del, dsIVS15 + 1G > T, c.6082G > A, c.6191G > A, c.7697G > A, c.7087G > A, and c.8662_8677del. Eosinophil count tests were normal in all patients, and serum total IgE was elevated in 7/12 patients. The mean baseline BEBS score (23.86 ± 15.77) declined progressively to 16.35 ± 12.50, 12.34 ± 9.91, and 10.4 ± 9.09 at the 16‐week, 24‐week, and 52‐week follow‐ups, respectively. The mean baseline NRS pruritus score of all patients was 7.25 ± 0.97, and it decreased to 3.83 ± 1.47 and 1.82 ± 0.89 at the 4‐week and 52‐week follow‐ups, respectively. The mean baseline DLQI score of all patients was 19.12 ± 6.21, and it decreased to 10.36 ± 6.19, 5.82 ± 3.37, and 5.00 ± 3.00 at the 16‐week, 24‐week, and 52‐week follow‐ups, respectively. BEBS, NRS pruritus, and DLQI baseline scores were statistically significant differences from those after 52 weeks of treatment ( p < 0.01). Of the 12 DEB patients, Patient #6 had a poor treatment effect and Patient #12 had transient conjunctivitis. Notably, five patients maintained sustained treatment efficacy without significant adverse events for over two years. Conclusion Dupilumab showed long‐term effectiveness and safety in real‐world practice in 11 Chinese patients with five subtypes of DEB (Intermediate DDEB, Severe RDEB, Intermediate RDEB, DDEB Pruriginosa, and RDEB Pruriginosa).
2025-04-24 | Efficacy and Safety of Dupilumab Monotherapy in Patients With Dystrophic Epidermolysis Bullosa: A Retrospective Study of 8 Cases.
Dystrophic epidermolysis bullosa (DEB) is a genetic skin disease with limited therapeutic options for managing pruritus. This study retrospectively evaluated the efficacy and safety of Dupilumab monotherapy in patients with DEB suffering from severe pruritus. DEB patients treated with Dupilumab between June 2021 and June 2023 were reviewed. DEB severity and pruritus intensity were assessed using the Birmingham Epidermolysis Bullosa Severity (BEBS, range 0-100) scores and the Numerical Rating Scale (NRS, range 0-10), respectively. A linear mixed model was used to evaluate the changes in NRS scores of Dupilumab monotherapy over time. The Wilcoxon signed-rank test was used to compare the differences in BEBS scores between pretreatment and posttreatment. Statistical significance was defined as p < 0.05. Eight patients were included (four males and four females; aged 5-38 years). Subtypes included severe (n = 4), intermediate (n = 2), pruriginosa RDEB (n = 1), or pruriginosa DDEB (n = 1). The baseline NRS scores averaged 8.75 ± 1.04, with significant reductions of 58.51%, 60.00%, and 49.94% at 4, 8, and 12 weeks, respectively (p < 0.001). The mean BEBS score at baseline was 35.36 ± 21.47, decreased by 22.29% at 12 weeks (p = 0.049), while the mean area of damaged skin score was 19.63 ± 1.71 at baseline, decreased by 31.23% after 12 weeks (p = 0.048). The mean duration of Dupilumab treatment was 44.50 (12-130) weeks. One DDEB-Pr patient discontinued Dupilumab for planned conception, with no adverse effects reported for the pregnant woman or newborn. Dupilumab appears to be a safe and effective treatment for pruritus in patients with DEB. Preliminary findings also support its potential use in women of reproductive age. Further larger prospective studies are needed to confirm these results.
2025-04-07 | Cross-sectional analysis of wound-associated soluble factors in early, established, and chronic wounds of recessive dystrophic epidermolysis bullosa patients
Background Poorly healing wounds represent the primary health-related burden for hereditary recessive dystrophic epidermolysis bullosa (RDEB) patients. Contribution of wound-associated soluble constituents to wound progression remains not well defined. Objective To conduct cross-sectional analysis of cytokine, chemokine, and growth factor in exudates from RDEB wounds and define changes associated with wound progression. Methods Concentrations of selected cytokines, chemokines, and growth factors were evaluated by multiplex ELISA in eight blister fluids and 76 exudates from early, established, and chronic RDEB and five chronic venous ulcers. A cross-sectional analysis was performed. Results Our data demonstrated that accumulation of IL-1β, IL-17, TNF alpha as well as HGF, G-CSF, and VEGF is associated with progression of RDEB wounds to poorly healing state. The levels of these molecules were significantly higher in RDEB wounds than in venous ulcers. High levels of neutrophil-recruiting CCR2, CXCR1/2 ligands and T cell-recruiting CCR4 ligands were also detected in all RDEB wounds. Conclusion Although this study is limited to cross-sectional analysis of wound exudates, detected high levels of specific pro-inflammatory, pro-angiogenic, and neutrophil-recruiting factors, such as IL1b, CXCL8, and VEGF, define progression of RDEB wounds to chronic state and offer potential pharmacological targets to improve wound healing in the patients.
cell therapies
2026-09-24 | Trophoblast Extracellular Vesicles Rewire Immunity: A Symptom-Relief Avenue for Recessive Dystrophic Epidermolysis Bullosa.
Redirecting immune responses toward tissue repair represents a promising strategy for treating inflammatory and degenerative diseases. Extracellular vesicles (EVs), derived from allogeneic stem cells, have shown potential for modulating proinflammatory immunity. Among these, placental-derived EVs (PEVs) are emerging as candidates for immune-mediated inflammatory disorders due to their role in establishing maternal immune tolerance. However, their applicability beyond pregnancy remains limited by key translational barriers, including the lack of a standardized and scalable source system and need to demonstrate immunomodulatory activity in non-pregnancy allogeneic contexts. In this study, we identify extravillous trophoblasts (EVTs), which play critical role in early placental development, as key source of immunoregulatory PEVs. To overcome donor variability, we employed the HIPEC cell model as established surrogate for primary EVTs and assessed the effects of their derived EVs (EVT-EVs) on circulating monocytes, pivotal mediators of inflammatory responses. High-dimensional molecular profiling revealed that EVT-EVs, similar to EVs derived from first-trimester primary human trophoblast, carry a distinctive anti-inflammatory signature, including a unique miRNA repertoire enriched in immunoregulatory pathways. Integrated proteomic and lipidomic analyses demonstrated that EVT-EVs induce coordinated functional reprograming of monocytes toward an immunomodulatory, inflammation-resolving phenotype. Notably, EVT-EVs also modulated the inflammatory bias of monocytes from patients with recessive dystrophic epidermolysis bullosa (RDEB), a genetic disorder characterized by chronic inflammation, thereby promoting restoration of immune balance. Collectively, these findings identify EVT-EVs as a scalable, off-the-shelf platform with high translational potential for the treatment of chronic inflammatory diseases.
2026-09-07 | Cord Blood-Derived Platelet Gel in Wound Healing: From Biological Rationale to Clinical Application.
Chronic and complex wounds are a major burden worldwide, and a considerable number remain unresponsive to traditional therapy. Cord blood-derived platelet gel (CBPG) is a novel allogeneic wound therapy providing a fibrin-based scaffold enriched with neonatal platelet-derived growth factors, including high concentrations of VEGF, HGF and FGF, directly into the wound bed, without the need for blood collection from the patient. This narrative review provides an overview of the biological features of CBPG, discusses clinical evidence across different wound indications, and assesses ethical, regulatory, and translational issues important to its development. CBPG has been studied in clinical trials in recessive dystrophic epidermolysis bullosa, cutaneous and oral chronic graft versus host disease after allogeneic haematopoietic stem cell transplantation, partial thickness burns, neonatal pressure injuries and diabetic foot ulcers. Across these conditions, CBPG has shown a consistent safety profile and promising signals of benefit, but evidence is restricted by small sample sizes, diverse methods and short follow-up. CBPG offers a biologically rational alternative to complex wound management in fragile patient populations. To move toward validated clinical application, manufacturing standardisation, regulatory classification, multicentre randomised trials with embedded health-economic endpoints, and transparent governance of cord blood allocation are needed.
2026-08-01 | Zevaskyn (prademagene zamikeracel) for wound treatment in individuals with recessive dystrophic epidermolysis bullosa: A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG)
Collagen Type VII, Alpha-1 is encoded by the COL7A1 gene (HGNC:2214) on chromosome 3p21.31. Biallelic pathogenic variants in COL7A1 are associated with autosomal recessive dystrophic epidermolysis bullosa (RDEB), resulting from a defect of COL7A1 function in anchoring fibrils at the cell-cell or cell-matrix junctions.1 RDEB is characterized by chronic blistering and impaired wound healing starting as early as the neonatal period and is associated with debilitating pain, a high risk of infection, fibrosis at the affected areas with scarring that can result in fusion of digits, and other epidermal changes, as well as mucosal lesions that lead to sequelae including iron-deficient anemia and malnutrition.
2026-06-28 | Identification of a long-term surviving human mesenchymal stromal cell subpopulation and implications for recessive dystrophic epidermolysis bullosa treatment.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by loss-of-function pathogenic variants in COL7A1 encoding type VII collagen (C7). Patients with RDEB suffer since birth from skin and mucosal blistering and develop severe local and systemic complications resulting in poor prognosis. Mesenchymal stromal cells (MSCs) have demonstrated their potential to enhance wound healing and reduce skin inflammation in RDEB patients due to their anti-inflammatory properties and capacity to express C7. We aim to optimize in vitro conditioning of human bone marrow-derived MSCs (BM-MSCs) to improve their limited survival following local injection in a murine model. BM-MSCs from healthy human donors were transduced with a lentiviral vector encoding firefly luciferase and mCherry reporter proteins and then subjected to various culture conditions: monolayer on plastic or spheroid culture, either in hypoxia (5% O2) or in normoxia (21% O2). These cells were subsequently injected intradermally (ID) in immunodeficient mice and their survival was assessed by in vivo imaging. BM-MSCs populations were analyzed prior to injection by single-cell RNA sequencing (scRNAseq). Murine skin injected with BM-MSCs were sampled two months post-injection and the surviving subpopulations were characterized by spatial transcriptomic. scRNAseq analysis revealed marked variations between monolayer and spheroid conditions, which were significantly impacted by oxygen level. Although most injected cells gradually died within the first 2 months in all tested conditions, 1% of live bioluminescent cells persisted for 54 up to 61 weeks post-injection. Spatial transcriptomics data analysis demonstrated that all surviving cells, regardless of their in vitro preconditioning, retained the expression of the MSC markers THY1, ENG, and NT5E, shared features with fibroblasts, and exhibited enriched expression in genes related to extracellular matrix and collagen fibril organization, which are key processes in wound healing. Spatial transcriptomic and scRNAseq data integration suggested that surviving BM-MSCs were initially present in the injected population, regardless of their culture condition. Remarkably, none of the in vitro preconditioning strategies appeared to affect their survival capacity or functional properties following local injection. The identification and characterization of a BM-MSC subpopulation capable of long-term survival following ID injection hold promise for the development of improved cell therapy protocols for RDEB.
2026-06-03 | Mesenchymal stromal cell infusions of umbilical cord-derived mesenchymal stromal cells in children with Recessive Dystrophic Epidermolysis Bullosa (MissionEB): a qualitative sub study of a randomised, double-blind, placebo controlled, crossover, phase 3 trial
Abstract Background Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare genetic skin condition causing fragile skin, blistering, and scarring. It leads to chronic pain, slow wound healing, and severe limitations, profoundly impacting patient and family quality of life. Umbilical cord tissue-derived mesenchymal stromal cells (UC-MSC) have shown therapeutic promise. The Mission EB trial (ISRCTN14409785; registration date 25/03/2021) assessed UC-MSC safety and effectiveness in children with RDEB in a placebo-controlled, double-blinded, crossover study. Methods This study used a qualitative research design with semi-structured interviews and thematic analysis, to explore Mission EB trial treatment impact on the quality of life of patients and parents. Parents and patients were interviewed at two time points (approximately 3- and 12-months post-randomisation). Purposive sampling included 10 parents and 6 children; 13 individuals (8 adults, 5 children) were interviewed twice (once in each study period). Interviews were transcribed verbatim, independently coded, with overall impressions agreed upon prior to unblinding. Results RDEB significantly impacted daily life, marked by pain and itch. Participants were hopeful of the trial, willing to pursue minor improvements. UC-MSC infusions led to reduced pain/itchiness, improved wound healing, and resulted in fewer self-reported dressing changes. These benefits often translated to increased energy, improved eating, and greater daily activity participation. Benefits were more pronounced with active treatment. Negative effects were minimal, primarily venous access difficulties. Blinded participants could discern active UC-MSC from placebo based on symptom changes; 10 of 13 showed clear differences aligning with treatment. All parents interviewed expressed willingness for their child to receive treatment again. Conclusions This qualitative research provides valuable insights into perceived benefits of UC-MSC treatment for children with RDEB. Interview findings regarding symptom improvement and participants’ ability to discern active treatment shed light on its perceived benefit in RDEB, especially in milder RDEB patients. The study highlights the critical importance of qualitative methodologies in adding to quantitative trial outcomes and capturing the meaningful impact of interventions on the lives of patients and families particularly where quantitative measures may not fully reflect lived experience.
gene therapies
2026-03-01 | An evaluation of prademagene zamikeracel for the treatment of recessive dystrophic epidermolysis bullosa.
Prademagene zamikeracel is an autologous, genetically corrected epidermal graft therapy designed to address the underlying molecular defect in recessive dystrophic epidermolysis bullosa (RDEB). The product is manufactured from a patient's own keratinocytes, which are modified ex vivo to overexpress a normal copy of COL7A1, the gene coding for type VII collagen (C7), which is essential for anchoring fibril formation and stable dermal-epidermal cohesion. In individuals with biallelic COL7A1 variants, loss of C7 results in severe skin fragility, painful and widespread wounds, debilitating scarring, and a high risk of aggressive cutaneous squamous cell carcinoma. This review outlines the key scientific foundations, translational advances, and clinical trial outcomes that supported regulatory approval of prademagene zamikeracel for use in adult and pediatric patients with RDEB. The development of prademagene zamikeracel represents a significant advance in regenerative therapy for RDEB, demonstrating that durable restoration of C7 expression and long-term wound improvement can be achieved through skin grafting.
2026-01-01 | O13 Preliminary results from correcting COL7A1 (c.G>A) mutation with adenine base editor 8e (ABE8e) in primary fibroblasts from dominant dystrophic epidermolysis bullosa (DDEB) patients
Abstract Introduction and aims Dominant dystrophic epidermolysis bullosa (DDEB) is a congenital blistering skin disease caused by mutant collagen VII (C7) chains interfering with the folding of wildtype (WT) C7, which weakens dermoepidermal junctions. Base editors (BEs) offer unique advantage in precisely correcting the mutant COL7A1 allele while preserving the WT allele. While our group has previously demonstrated the use of adenine base editor 8e (ABE8e) to correct recessive dystrophic epidermolysis bullosa (RDEB), this is the first report of ABE8e being applied to DDEB. Methods Primary fibroblasts from patients with DDEB carrying the COL7A1 exon 73 c.6127G>A mutation were electroporated with ABE8e mRNA and single guide (sg)RNA. Base editing efficiency was evaluated by semiquantitative analysis of Sanger sequencing chromatographs in EditR. Protein-level correction was assessed using a C7 Western blot. In preparation for future in vivo base editing, we validated a DDEB mouse model carrying the Col7a1 exon 73 c.6085C>G mutation using Sanger sequencing. Results Sanger sequencing analysis revealed that ABE8e achieved 19–41% editing efficiency in correcting the c.6127G>A mutation, with a 2 : 1 sgRNA-to-ABE8e ratio yielding higher efficiency than a 1 : 2 ratio. However, Western blot analysis did not show consistent protein-level correction. Sanger sequencing confirmed that our DDEB mouse model is heterozygous for the Col7a1 c.6085G>C mutation. Conclusions This study demonstrated partial DNA-level correction of the COL7A1 c.6127 G>A allele in ABE8e-electroporated primary DDEB fibroblasts ex vivo. However, this editing did not result in increased C7 protein levels. Notably, Western blots assess differences in C7 quantity, but not stability – a key factor in DDEB pathology. Further replication of DNA-level correction and evaluation of C7 stability using a trypsin digestion assay will be essential. These efforts will lay the foundation for transitioning from ex vivo experiments to in vivo correction of the Col7a1 c.6085C>G mutation in our DDEB mouse model.
2026-01-01 | O14 Next-generation sequencing precision: on- and off-target analysis of gene editing in recessive dystrophic epidermolysis bullosa
Abstract Introduction and aims Base editors (BEs) and prime editors (PEs) offer distinct advantages over CRISPR-Cas9 for correcting pathogenic variants. Previously, our group achieved 94.6% efficiency in correcting the COL7A1 c.5047 C>T nonsense pathogenic variant in fibroblasts, associated with recessive dystrophic epidermolysis bullosa (RDEB), using adenine base editor 8e (ABE8e). However, the safety and cell type-specific efficiencies of these techniques remain unclear. This study aims to use a PE to correct the c.5047 C>T pathogenic variant in primary patient fibroblasts and epidermal stem cells to promote wound healing and compare the efficiency and off-target effects of BE and PE using next-generation sequencing (NGS). Methods Primary fibroblasts carrying a heterozygous COL7A1 c.5047 C>T pathogenic variant were transfected with ABE8e mRNA and the PE5bmax system using electroporation and lipid nanoparticles (LNPs). Sanger sequencing and NGS were used to confirm pathogenic variant correction and assess editing efficiencies. Whole-genome sequencing (WGS) was conducted for genome-wide off-target analysis, with pairwise variant calling performed to identify somatic variants in edited vs. unedited samples. Targeted amplicon sequencing was employed to evaluate editing accuracy at the target site. Results ABE8e delivered via LNPs corrected the c.5047 C>T pathogenic variant in fibroblasts with 84% efficiency using lipofectamine, as confirmed by Sanger sequencing and NGS. Prime Editor PE5bmax achieved 43% overall editing efficiency, with 32% variant correction confirmed by Sanger sequencing. Preliminary WGS analysis revealed increased indels and mismatches across the genome in edited samples, although further variant characterization is needed for a comprehensive safety profile. Conclusions ABE8e and PE5bmax successfully corrected the c.5047 C>T mutation in fibroblasts, with respective on-target efficiencies of 84% and 32%. These strategies are being extended to epidermal stem cells for potential wound healing therapies. Comprehensive WGS and targeted sequencing will aid in optimizing these techniques for clinical applications.
2026-01-01 | P19 Proof of concept for a variant-agnostic, permanent DNA editing cure for dystrophic epidermolysis bullosa
Abstract Introduction and aims Dystrophic epidermolysis bullosa (DEB) is an inherited blistering skin disease with over 800 causative mutations identified in the COL7A1 gene. eePASSIGE is a breakthrough DNA editing technology that pairs prime editing (PE) with serine integrase technology, allowing for targeted integration of large DNA constructs. We aim (i) to use eePASSIGE to integrate a full-length cDNA of COL7A1 into the AAVS1 safe harbour locus, and (ii) to develop lipid-based nanoparticles (LNPs) capable of delivering eePASSIGE machinery to human skin cells. Together, these two strategies form the basis for a proposed permanent ‘one-size-fits-all’ DEB cure. Methods We have used lipofection of HEK293T, N/TERT, and human fibroblast cells to provide proof of concept. For PE and eePASSIGE, lipofectamine was used to deliver plasmid DNA encoding editing constructs and pegRNAs. For PE, Sanger sequencing of target site amplicons was used to identify successful edits. For eePASSIGE, puromycin selection was used to isolate successfully edited cells. For LNP studies, fluorescent reporter mRNA was delivered to N/TERTs and fibroblasts; successful transfection was quantified with flow cytometry. Results In N/TERT cells, we achieved up to 17% PE efficiency in transfected cells, although only 1% of cells were successfully transfected. eePASSIGE was used to successfully integrate a puromycin resistance gene into HEK293T cells at the AAVS1 safe harbour locus. Lipid nanoparticles were used to successfully transfect human fibroblasts and keratinocytes in submerged culture with reporter constructs with up to 80% efficiency and with lower toxicity than lipofectamine. Conclusions Our experiments thus far have laid the groundwork for future study of eePASSIGE to integrate large coding constructs into disease-relevant cells. Our next steps are (i) to improve transfection of eePASSIGE machinery in cells of interest, and (ii) to optimize LNP formulations for use in three-dimensional culture and in vivo mouse skin.
2025-11-19 | Base edited skin equivalents with clinical potential for ex vivo correction of recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic disorder caused by bi-allelic null mutations in the COL7A1 gene. Among various therapeutic genome editing (GE) strategies, adenine base editors (ABEs) have demonstrated particular efficacy in nonsense mutations. Previous studies have predominantly focused on RDEB fibroblasts, which produce significantly less type VII collagen (C7) than keratinocytes. This study evaluates the efficacy and safety of ABE8e, via mRNA electroporation, to correct three different COL7A1 nonsense mutations (one homozygous and two heterozygous [patients 1, 2, and 3]), and a cryptic splice site mutation (patient 4) in primary cells from RDEB patients. Sanger and next-generation sequencing revealed high efficiency (>90%) at the intended mutation-causing nucleotides. Bystander effects were observed in two of the four loci analyzed. Deeper off-target study was performed in the first two patients. A safe off-target profile was observed in the homozygous patient (P1), while off-target effects were identified in the heterozygous patient (P2). The restoration of C7 expression in treated cells was consistent with genotypic correction. Additionally, functional assessments, including transplantation of skin equivalents formed by both base-edited keratinocytes and fibroblasts, demonstrated sustained in vivo skin regeneration and proper C7 deposition at the basement membrane. ABE8e-mediated base editing shows high efficacy and safety correcting COL7A1 mutations in the two cell types, broadening the scope of this GE therapeutic modality for RDEB treatment.
other
2026-09-18 | Disrupted Skin-Nerve Homeostasis in Recessive Dystrophic Epidermolysis Bullosa: a Neurocutaneous Unit Perspective on Pain.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited disorder characterised by type VII collagen impairment, leading to dermo-epidermal junction (DEJ) instability and chronic skin fragility. Pain is a near-universal and quality-of-life-limiting feature; however, explanations centred solely on tissue injury and inflammation do not fully account for its persistence or treatment resistance. Increasing evidence supports a broader framework in which disrupted skin-nerve homeostasis within the neurocutaneous unit (NCU) contributes to pain generation. This narrative, hypothesis-driven review integrates clinical, experimental and translational evidence to examine the role of the NCU, the functional interface between keratinocytes and intraepidermal sensory fibres, in RDEB pain. Chronic injury, persistent inflammation and DEJ disruption create a microenvironment that is unfavourable for sensory nerve maintenance and repair. Clinical and experimental findings support the presence of small-fibre pathology, reflected by reduced intraepidermal nerve fibre density, altered sensory thresholds and neuropathic pain descriptors. Mechanistically, repeated injury appears to impair reinnervation and contribute to progressive distal sensory fibre loss within a hostile cutaneous microenvironment. Keratinocyte dysfunction drives this process through impaired neurotrophic support and the sustained release of pro-inflammatory mediators that directly sensitise nociceptors. In parallel, dermal fibrosis and extracellular matrix remodelling may constrain axonal regeneration. Molecular studies further demonstrate a persistent inflammatory and pro-fibrotic signature in RDEB skin, including clinically non-lesional areas. These converging abnormalities suggest that disrupted skin-nerve homeostasis is an important contributor to disease-associated pain. Translational evidence suggests partial reversibility, with pain reduction observed following therapies targeting neuropathic mechanisms or restoring DEJ integrity. Together, these findings support a framework in which altered neurocutaneous interactions contribute substantially to pain in RDEB, underscoring the need for mechanism-based and potentially early neuroprotective strategies.
2026-08-14 | Fragile skin may benefit from decoration
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe hereditary blistering disorder characterized by fragility of the skin and mucous membranes due to mutations in the COL7A1 gene, which encodes type VII collagen, the principal component of anchoring fibrils1,2 (Figure 1A). Loss or dysfunction of type VII collagen leads to separation at the dermal-epidermal junction, resulting in chronic wounds, scarring, and progressive multisystem complications. RDEB is associated with substantial morbidity, including strictures in esophagus, pseudosyndactyly (fusion of fingers), nutritional impairment, and an exceptionally high lifetime risk of developing aggressive cutaneous squamous cell carcinoma (cSCC)1,2 (Figure 1A).
2026-05-18 | Systemic clinical-grade recombinant decorin reduces disease burden and fibrosis in advanced recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a skin and epithelial fragility disease that progresses with severe fibrosis. This fibrosis is debilitating and promotes the development of aggressive squamous cell carcinomas (SCCs). Effective management of fibrosis may improve quality of life in RDEB and reduce the risk of high-risk SCCs. Decorin, a small leucine-rich proteoglycan, has natural fibrosis-limiting activity. Higher expression of decorin has been linked to milder RDEB, and decorin has shown anti-fibrotic effects in multiple models of experimentally induced fibrosis. However, a short circulating half-life, manufacturing challenges, and broad target engagement have limited the development of systemic decorin therapy. Here, we describe scalable production of recombinant human decorin protein core (rh Decorin) and test repeated intravenous administration in a murine model of advanced RDEB. We show that rh Decorin accumulates in the skin and other injured sites and improves RDEB-related signs. Systemic administration enables decorin-mediated direct and indirect inhibition of TGF-β activity in peripheral tissues. Characterization of the dermal collagen matrix revealed evidence of remodeling capacity of fibrotic lesions in RDEB when cellular contractile activities are targeted, providing an explanation for the anti-fibrotic effects of rh Decorin in advanced disease. These results support further evaluation of intravenous rh Decorin for the treatment of RDEB, especially for fibrotic manifestations.
2026-05-05 | Engineered natural extracellular matrix platform for modelling skin diseases and identifying therapeutic targets.
Dysregulation of the dermal extracellular matrix (ECM) drives skin pathologies by influencing tissue mechanics, dermal-epidermal adhesion, and disease progression. However, current in vitro models often fail to replicate native ECM complexity or disease-specific alterations, limiting mechanistic studies and therapeutic target discovery. This gap is particularly critical for untreatable skin fragility disorders, where abnormal dermal ECM underlies severe clinical manifestations. This study aimed to develop and validate an engineered natural ECM (NatECM) platform that recapitulates key compositional and biomechanical features of fibroblast-derived dermal ECM. As a proof-of-concept, we applied NatECM to model clinically distinct variants of dystrophic epidermolysis bullosa (DEB), the skin fragility disorders prototype, to identify ECM-related and disease-specific alterations and to interrogate candidate therapeutic targets. Primary fibroblasts from healthy donors and DEB patients were cultured to self-assemble their ECM, generating NatECM dermal equivalents. ECM organization was evaluated by immunostaining and ultrastructural analyses, nano- and macro-scale mechanical properties were measured by atomic force microscopy and uniaxial tensile testing, and ECM composition was characterized by proteomics. Functional relevance was evaluated by keratinocyte adhesion assays and fibulin-5 supplementation experiments. NatECM reproduced intrinsic fibroblast-derived dermal ECM features and captured disease-associated mechanical and structural impairments characteristic of DEB. Across DEB variants, NatECM unveiled subtype-specific proteomic alterations that affect ECM structure and elastic fiber formation. We identified a "fragility quartet" - fibulin-5, decorin, and collagens III and V - consistently downregulated across all variants and linked to defective ECM mechanics. Fibulin-5 supplementation restored ECM elastic behavior and strengthened keratinocyte adhesion, supporting its role as a candidate ECM regulator. The NatECM platform faithfully models fibroblast-derived dermal ECM and enables the identification and functional investigation of key molecular ECM regulators in DEB. Its tunability and physiological relevance position NatECM as a robust tool for studying ECM-driven skin disorders and for accelerating the identification of candidate therapeutic targets.
2026-03-06 | Systemic inflammation in recessive dystrophic epidermolysis bullosa: a five-year longitudinal study.
Recessive dystrophic epidermolysis bullosa (RDEB) is characterized by skin fragility, extensive wounding, and systemic complications. While inflammation contributes to disease severity, its pattern, longitudinal dynamics and clinical correlates remain poorly defined. To characterize the course of systemic inflammatory markers over time in patients with RDEB and explore their associations with clinical, microbiological, and laboratory parameters. This retrospective longitudinal study analyzed clinical and laboratory data of 120 visits within 5 years from 44 patients with intermediate (N=22) and severe (N=22) RDEB. Acute-phase proteins (CRP, IL-6, SAA), neutrophil to lymphocyte ratio (NLR), leukocytes, thrombocytes and ferritin were examined in relation to wound body surface area, mucosal involvement, collagen VII (C7) protein expression levels, squamous cell carcinoma (SCC) presence, nutritional status, anemia markers, wound microbiology and immunoglobulins. Severe RDEB showed an early and sustained systemic inflammatory profile, with CRP, IL-6, and SAA elevated >3.5-fold from early childhood, plateauing in mid-adulthood. Intermediate RDEB maintained low inflammatory activity throughout life. Acute phase proteins and NLR were significantly elevated in the presence of SCC (CRP: p<0.001; IL-6: p=0.002; SAA: p=0.011; NLR: p=0.004), collagen VII absence (CRP: p=0.002), and colonization by Pseudomonas (CRP, IL-6: p<0.001) or fungi (CRP: p=0.006). CRP and age were the most robust independent predictors of SCC risk. Streptococcus, Pseudomonas, fungi, or polymicrobial colonization were associated with a broader systemic inflammatory response, when compared to infections with Staphylococcus. Hypoalbuminemia and elevated immunoglobulins correlated with inflammatory markers and anemia of chronic disease was reflected by declining iron and increased ferritin levels. In multivariable models, reduced C7 expression, wound burden and SCC were the strongest independent predictors of acute phase inflammation. This study reveals that severe RDEB involves early-onset, progressive systemic inflammation that peaks in mid-adulthood and then plateaus, suggesting a critical window for therapeutic intervention. In contrast, intermediate RDEB shows minimal systemic inflammation. The findings support a three-tiered treatment approach-wound burden reduction through curative/corrective interventions, antimicrobial strategies and anti-inflammatory therapy -aligned with standard of care and nutritional supplementation.
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Drug Discovery Landscape
11 orphan drug designations for Dystrophic epidermolysis bullosa, including 2 approved therapies.
11 orphan drug designations for Dystrophic epidermolysis bullosa, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
recombinant human type VII pro-collagen | proteins | FDA | — | Nova Anchora, LLC |
Highly branched poly(beta-amino ester) complexed with a nanoplasmid containing the human COL7A1 gene | gene therapies | FDA | — | Amryt Genetics Limited |
beremagene geperpavec-svdt [Vyjuvek] | gene therapies | FDA | Approved | Krystal Biotech, Inc. |
antisense oligonucleotide targeting exon 73 in the COL7A1 gene | oligonucleotides | FDA | Phoenicis Therapeutics, Inc. | |
prademagene zamikeracel [Zevaskyn] | gene therapies | FDA | Approved | Abeona Therapeutics, Inc. |
autologous genetically modified human dermal fibroblasts | cell therapies | FDA | Castle Creek Biosciences, LLC | |
recombinant human collagen alpha-1 (VII) chain homo-trimer (rC7) | proteins | FDA | Phoenix Tissue Repair | |
expanded allogeneic human dermal fibroblasts in hypothermosol(r)-FRS | cell therapies | FDA | — | Intercytex Ltd. |
Skin equivalent graft genetically corrected with a COL7A1-encoding SIN retroviral vector | gene therapies | EMA | Prof. Alain Hovnanian | |
recombinant human type VII collagen | proteins | FDA | — | David T. Woodley, MD and Mei Chen, MD |
Sucralfate suspension | small molecules | FDA | — | Darby Pharmaceuticals, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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