RARE DISEASE
Inherited epidermolysis bullosa
Inherited epidermolysis bullosa
Inherited epidermolysis bullosa
Synonyms: Epidermolysis bullosa hereditaria, Hereditary epidermolysis bullosa
Synonyms: Epidermolysis bullosa hereditaria, Hereditary epidermolysis bullosa
Synonyms: Epidermolysis bullosa hereditaria, Hereditary epidermolysis bullosa
Drug discovery
49
drugs
With orphan designations
Overview
Inherited epidermolysis bullosa (EB) comprises rare genetic disorders characterized by skin and mucosal fragility due to mutations in genes encoding structural proteins critical for epidermal-dermal adhesion. Classified into four main types (simplex, junctional, dystrophic, Kindler syndrome), EB severity ranges from localized blistering to life-threatening complications involving internal organs. Diagnosis relies on genetic testing, immunofluorescence mapping, and electron microscopy. Management is multidisciplinary, emphasizing wound care, infection prevention, nutritional support, and emerging therapies like gene correction.
Therapies
Supportive care: Nonadhesive dressings, pain management, and nutritional interventions [6][12].
Advanced therapies: FDA-approved beremagene geperpavec (B-VEC) gene therapy for dystrophic EB; investigational approaches include protein/cell-based therapies and drug repurposing (e.g., JAK/IL-13 inhibitors) [3][8][18].
Categories: rare genetic diseases, rare skin diseases
Research Papers
748 drug discovery papers about Inherited epidermolysis bullosa, with 2 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
748 drug discovery papers about Inherited epidermolysis bullosa, with 2 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-06-10 | Intact Fish Skin Graft in the Treatment of EB Hand: A New Weapon in This Challenge?
Background/Objectives: Epidermolysis bullosa (EB) comprises a heterogeneous group of rare inherited skin-fragility disorders in which even minimal trauma can cause blistering, chronic wounds, scarring, and functional impairment. After surgical release of EB hand deformities, wound coverage is challenging because autologous split-thickness skin grafting creates an additional donor-site wound in already fragile tissue. This preliminary case series reports our single-center pediatric experience using intact fish skin grafting (iFSG) as an adjunct after EB hand surgery. Methods: We conducted an observational case series of five pediatric patients with dystrophic EB, including eight operated hands, treated between December 2022 and December 2025. iFSG was applied after the release of contractures and/or pseudosyndactyly. Primary outcomes were time to complete re-epithelialization, need for re-application, need for autologous grafting, and early complications. Secondary outcomes included dressing-related pain assessed with an age-appropriate visual analog scale during awake dressing care, dressing burden, and early recurrence signals. Results: The iFSG application was feasible in all cases. One localized second application was required, and no patient required autologous split-thickness skin grafting. Mean dressing-related pain was 1.6 on the visual analog scale, and mean time to complete re-epithelialization was 47.6 days. No allergic reactions occurred. Healing was slower in the two most severe bilateral mitten-hand cases, and one patient developed limited dorsal disepithelialization attributed to prolonged dressing contact on extremely fragile skin. One partial recurrence of pseudosyndactyly was observed during follow-up without the need for revision surgery. Conclusions: iFSG was feasible in this small preliminary pediatric dystrophic EB hand surgery series and may provide a biologically active scaffold that supports secondary closure while avoiding autologous donor-site creation. Because of the rarity of the disease, the limited sample size, the absence of a comparator group, and the limited follow-up, these findings should be interpreted cautiously. Larger multicenter studies with standardized functional, pain, recurrence, and caregiver-reported outcomes are needed to define the role of iFSG in EB hand reconstruction. ABILHAND-Kids was also administered to patients/caregivers and suggested encouraging perceived improvement in postoperative hand use and independence in daily activities.
2026-05-13 | Amniotic Membrane Transplantation Preserves Vision in Pediatric Recessive Dystrophic Epidermolysis Bullosa: Case Series.
Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited disorder characterized by extreme epithelial fragility and progressive cicatrization, frequently leading to severe ocular surface disease and early visual impairment. Surgical interventions such as ocular surface reconstruction (OSR) in childhood are often delayed because of anesthetic risks and concerns regarding recurrence. Consequently, the effectiveness of OSR, including amniotic membrane transplantation (AMT), and its impact on visual development remain poorly documented. Methods: We report a case series of two pediatric patients (three eyes) with genetically confirmed RDEB who underwent single-step OSR using AMT. Clinical outcomes, long-term visual acuity, perioperative management, and histopathological findings were evaluated. Results: Ocular manifestations included corneal epithelial damage, symblepharon, and pseudopterygium extending over the cornea. One patient underwent symblepharon lysis, superficial keratectomy, and AMT onto the bare sclera in the right eye at age 4 and in the left eye at age 8, both under intubated general anesthesia. The other patient underwent the same procedure in the right eye at age 6. Best spectacle-corrected visual acuity improved from ≤20/300 to 20/30 in all eyes, and pupillary zone clarity was maintained during the follow-up period (up to 6 years). Histopathology confirmed pseudopterygium with squamous metaplasia, goblet cell loss, and fibrovascular stroma. Safe general anesthesia was achieved through meticulous multidisciplinary perioperative planning involving anesthesiologists, dermatologists, and pediatricians. No systemic complications related to anesthesia or perioperative management were observed. Conclusions: Single-step OSR with on-lay AMT can restore and preserve visual function in pediatric RDEB. Early surgical intervention may prevent profound amblyopia and provide durable ocular surface stability. A multidisciplinary approach enables safe general anesthesia and perioperative management.
2026-03-28 | Macrophage Extracellular Vesicles: Therapeutic Strategies for Corneal Fibrosis in Rare Diseases.
Corneal scarring (fibrosis) is a blinding condition affecting millions of sufferers worldwide. It is not only in common ocular injuries but also in genetically inherited rare diseases such as epidermolysis bullosa (EB), keratitis-ichthyosis-deafness (KID) syndrome and aniridia. In rare diseases like EB or KID syndrome, corneal fibrosis arises from chronic inflammation, structural instability and neuro-immune dysfunction driven by genetic mutations. Current therapies are not effective in addressing the needs of affected individuals due to limited efficacy nor the considerable side effects of treatment. Extracellular vesicles (EVs) from various cell types such as mesenchymal stem cells not only possess high biocompatibility but have shown promising results in limiting corneal fibrosis. Rather than targeting a single molecular signaling pathway, EVs which contain regulatory RNAs and proteins are hypothesized to target multiple pathways synergistically. Macrophage-derived EVs (Mac-EVs) with an immunomodulatory nature may offer a promising therapeutic effect for rare diseases. Various EV delivery platforms have been proposed in preclinical studies. However, not all of these delivery techniques are appropriate for the cornea in rare diseases. In this review, we delineate recent advances in understanding corneal fibrosis from a rare disease point of view, including the impact on corneal immune cells and nerves. We then provide critical considerations of therapeutic development for corneal fibrosis in rare diseases. Furthermore, we used this knowledge to comprehensively consider the various EVs, especially Mac-EVs, synthesis methods and delivery techniques. Ultimately, this review aims to enable biomolecule researchers to develop EV-based therapies that not only exert anti-fibrotic effects but also address clinical compatibility for corneal fibrosis in rare diseases.
2025-12-04 | IPSC-derived organoid-sourced skin cells enable functional 3D skin modeling of recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited skin disorder caused by mutations in COL7A1. Patient-derived induced pluripotent stem cells (iPSCs) enable the personalized study of RDEB pathogenesis and potential therapies. However, current skin cell differentiation protocols via 2D culture perform suboptimally when applied to engineered 3D skin constructs (ESC). Here, we present an approach to source fibroblasts (iFBs) and keratinocytes (iKCs) from iPSC-derived skin organoids using an optimized differentiation protocol, and utilize them to engineer ESCs modeling wild-type and RDEB phenotypes. The resulting iPSC-derived skin cells display marker expression consistent with primary counterparts and produce ESCs exhibiting significant extracellular matrix remodeling, protein deposition, and epidermal differentiation. RDEB constructs recapitulated hallmark disease features, including absence of collagen VII and reduced iFB proliferation. This work establishes a robust and scalable strategy for generating physiologically-relevant, iPSC-derived skin constructs, offering a powerful model for studying RDEB mechanisms and advancing personalized regenerative medicine.
2025-11-17 | Mesenchymal stromal cell therapy in epidermolysis bullosa: current perspectives and future directions
Epidermolysis bullosa (EB) is a group of inherited mucocutaneous disorders. Mesenchymal stromal cells (MSCs) are non-hematopoietic self-renewing, multipotent cells that are a promising therapeutic avenue for EB, given their ability to home to injury, low immunogenicity, and demonstrated wound-healing, anti-fibrotic, and pro-collagen effects. This review article synthesizes the current literature and advancement on MSC therapy in EB, and highlights the potential to optimize their use, including exploring MSC-derived extracellular vesicles as a potential cell-free therapy. Innovative delivery methods can also improve the accessibility and effectiveness of MSC therapies by providing localized treatment, minimizing systemic side effects, and increasing patient comfort.
small molecules
2026-07-27 | A Systematic Review of Topical and Systemic Gentamicin for Wound Healing in Patients With Junctional and Dystrophic Epidermolysis Bullosa.
Epidermolysis bullosa (EB) is an inherited mechanobullous genodermatosis caused by a mutation in genes encoding proteins integral to skin integrity. Premature termination codon readthrough therapies, such as gentamicin, have promise in facilitating full-length protein expression in patients with EB. We conducted a systematic review of the effectiveness and adverse effects of gentamicin for wound healing in EB. Six databases were searched to 01 September 2025 for clinical trials investigating gentamicin for EB. Risk of bias was assessed using the ROBINS-I tool, and data were synthesised descriptively. This study was registered with PROSPERO (CRD42024496582). Five studies involving 24 patients with junctional EB or dystrophic EB were included; four were open-label and one was double-blinded. Nineteen of the 24 patients had a known nonsense mutation. Gentamicin was administered topically (two studies), intravenously (two studies) and both topically and intradermally (one study). Wound healing was heterogeneously measured across studies, with all but one showing improved outcomes. All patients demonstrated increased expression of glycoprotein or collagen in skin biopsy specimens after gentamicin treatment. No adverse events were noted. However, four of five studies were at serious risk of bias on ROBINS-I, primarily owing to lack of blinding and absence of control groups, increasing the risk of bias for subjective outcomes such as wound healing. The available evidence suggests gentamicin may improve wound healing in EB caused by nonsense mutations, but the small number of heterogeneous studies precludes high-level evidence. Larger, blinded, randomised trials are required to confirm efficacy and long-term safety.
2026-07-08 | Esophageal Stricture in a 5-Year-Old Child with Epidermolysis Bullosa: Case Report of a Rare Complication at a Very Young Age.
Epidermolysis bullosa (EB) represents a group of rare inherited mechanobullous disorders characterized by extreme skin and mucosal fragility. Dystrophic EB (DEB), caused by mutations in the COL7A1 gene, often leads to cycles of blistering, healing, and scarring with multisystem involvement, including the gastrointestinal tract. Esophageal strictures are not uncommon in recessive DEB (RDEB), appearing after the first decade of life (∼12.6 years). We describe a relatively early complication in a 5-year-old child. A 5-year-old girl with genetically confirmed RDEB presented with 4 months of progressive dysphagia, vomiting, and retrosternal pain, more pronounced with solids. Her disease history included severe skin fragility since birth, scarring, and autoamputation of toes. Examination showed multiple healed ulcers, mitten deformities of all limbs, dental caries, and bilateral corneal opacities. Laboratory evaluation revealed anemia (Hb 7.7 g/dL). Barium swallow demonstrated a short mid-esophageal stricture; upper gastrointestinal endoscopy confirmed focal narrowing at 14 cm from the incisors. Endoscopic balloon dilatation up to 8 mm using a controlled radial expansion was performed, and the patient was initiated on oral losartan (8 mg/day) to reduce transforming growth factors-β-mediated fibrosis and stricture recurrence. Serial dilatations were planned at 3-week intervals. This case represents one of the youngest reported presentations of esophageal stricture in RDEB. The combination of early endoscopic balloon dilatation and adjunct antifibrotic therapy with losartan may reduce recurrence and improve nutritional outcomes. Monitoring for early esophageal involvement in young patients with RDEB is essential for timely intervention.
2026-06-26 | Use of Tramadol in Pain Management of Neonates with Epidermolysis Bullosa: A Single-Center Experience.
Background: Inherited Epidermolysis Bullosa (EB) is a wide group of rare genetic disorders characterized by mucocutaneous fragility and blister formation. In neonates with EB, pain control is particularly complex because painful skin lesions coexist with developmental vulnerability, repeated handling, and the need for frequent wound care. Traditional opioid use carries a risk of adverse effects such as respiratory depression. Tramadol, a centrally acting weak opioid with a dual mechanism of action, may offer a safer alternative. Methods: This retrospective observational study analyzed neonates with different EB subtypes admitted to our tertiary neonatal care center between January 2020 and October 2022. Genetic diagnosis was confirmed via next-generation sequencing. Pain was assessed using the Neonatal Infant Pain Scale (NIPS). Tramadol was administered intravenously (1-2 mg/kg bolus or 0.1-0.2 mg/kg/h infusion) before daily wound dressings, then transitioned to oral dosing when appropriate. Pain scores before and after tramadol administration were compared. Results: Six neonates with various EB subtypes were included. All patients received tramadol for procedural pain control. No significant differences in NIPS scores were observed before and after tramadol administration (p = 0.997), indicating adequate pain control, although baseline pain scores were low, limiting interpretation of analgesic efficacy. No immediate adverse events were observed during hospitalization or reported during follow-up. Conclusions: Scheduled tramadol administration appears to be a safe and effective option for pain management in neonates with EB, with no observed hemodynamic or respiratory complications. Given the scarcity of data in this population, our findings highlight the need for multicenter studies to establish standardized analgesia protocols for EB neonates.
2026-06-23 | O2 Innate immune dysregulation drives recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma
Abstract Introduction and aims Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited, immunologically active, skin disorder, characterized by skin fragility and chronic inflammation, predisposing patients to aggressive early-onset squamous cell carcinoma (cSCC). Despite this, immunopathogenic mechanisms driving tumour progression remain poorly understood, while current treatments fail to address cancer initiation. This study aimed to characterize the RDEB-cSCC innate immune landscape to identify targetable pathways for therapeutic intervention. Methods We performed an integrated immune analysis using bulk RNA sequencing of matched nonlesional, perilesional and lesional biopsies as a strategy to model disease progression. This was complemented by peripheral blood immunophenotyping of healthy donors, patients with RDEB and patients with RDEB-cSCC to identify innate immune alterations associated with disease severity. To validate therapeutic targets, a patient-derived three-dimensional immunocompetent spheroid model was established, designed to recapitulate key tumour-promoting immune features, observed in patients with RDEB-cSCC. Results Transcriptomic profiling revealed a severity-dependent macrophage enrichment and activation of the immunoregulatory pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT)3, previously identified as a promising target in RDEB-cSCC. Lesional tissue and patient plasma exhibited concurrent upregulation of both pro- and anti-inflammatory cytokine signatures, indicating a dysregulated immune response. Peripheral immune profiling further revealed a significant shift towards alternatively activated monocytes, expressing CD163 and Tim4, suggesting a prepriming of precursor tumour-associated macrophages, linked to aggressive disease progression. Uniform manifold approximation and projection analysis identified unique monocyte clusters specific to RDEB-cSCC, associated with aggressive tumour behaviour. To functionally validate these tumour-promoting immune features, an immunocompetent spheroid model was developed recapitulating protumour macrophage differentiation and cytokines release associated with JAK/STAT3 activation. Targeting the model with the clinically approved JAK1/2 inhibitor, ruxolitinib, resulted in reduced spheroid growth, increase necrosis and a significant shift in monocyte polarization towards antitumour phenotype. Conclusions These findings highlight the innate immune dysregulation as a central driver of RDEB-cSCC, and targeting the monocyte–macrophage plasticity via the JAK/STAT3 pathway could be a potential early intervention strategy for treating RDEB-cSCC.
2026-05-30 | N -acetylcysteine exerts senescence-selective antifibrotic effects in fibroblast from chronic wounds in recessive dystrophic epidermolysis bullosa
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited skin disease caused by pathogenic biallelic variants in COL7A1, resulting in dermoepidermal fragility and chronic, nonhealing wounds. We investigated the contribution of fibroblast senescence to RDEB wound pathology and evaluated whether N-acetylcysteine can modulate this process.
gene therapies
2026-08-11 | Topical gene therapy for severe recessive dystrophic epidermolysis bullosa: clinical outcomes and multidisciplinary management in three patients treated with beremagene geperpavec (B-VEC) in Italy - a case series.
Recessive dystrophic epidermolysis bullosa is a severe inherited blistering disorder characterized by chronic wounds, fibrosis and systemic complications. Beremagene geperpavec (B-VEC), a topical HSV1-based gene therapy delivering full-length COL7A1, has shown efficacy in clinical trials; however, real-world data remain limited. This retrospective, descriptive case series reports on three patients with genetically confirmed recessive dystrophic epidermolysis bullosa - two children and one young adult - treated between 2024 and 2026 at two Italian tertiary centres. All patients had extensive chronic skin involvement and received weekly topical B-VEC. Clinical data included wound characteristics, response to therapy, supportive care and adverse events. All patients showed clinically meaningful improvement in target wound healing. One child achieved ~70% reduction in the wound area needing treatment; the second had ~50% with shallower morphology and reduced bleeding. The adult, previously enrolled in the GEM-3 trial, achieved over 60% wound closure after reinitiating B-VEC via Italy's 5% Italian Medicines Agency (AIFA) access programme. No treatment-related adverse events occurred. Adjunctive care included wound hygiene optimization, nutritional and iron support, and pain control. In this small descriptive case series, B-VEC was well tolerated and associated with clinically meaningful improvement in wound healing though outcomes were more variable and, in some cases, less pronounced than those reported in pivotal trials, nevertheless supporting its integration into a comprehensive care model that addresses infection risk, anaemia, nutrition, and wound management.
2026-06-23 | P28 In vivo targeting of basal keratinocytes using lipid nanoparticles in a dominant dystrophic epidermolysis bullosa mouse model
Abstract Introduction and aims Gene editing holds strong therapeutic promise for inherited skin disorders, but translation to in vivo application requires clinically relevant animal models. Dystrophic epidermolysis bullosa (DEB), caused by pathogenic COL7A1 variants, is a severe condition for which existing mouse models are poorly suited to testing gene-editing therapies. This study aimed to establish and characterize a dominant DEB (DDEB) mouse model for in vivo gene-editing evaluation and to assess the feasibility of lipid nanoparticle (LNP)-mediated delivery to skin cells. Methods A DDEB mouse model heterozygous for the Col7a1 exon 73 c.6085G>C variant was utilized. Phenotypic assessment focused on blistering severity and wound-healing dynamics. Cells isolated from mouse skin biopsies were analysed by Western blot to assess intracellular accumulation and extracellular secretion of type VII collagen. Topical delivery of self-formulated LNPs encapsulating mCherry mRNA was tested on wounded mouse skin to evaluate cellular targeting and delivery efficiency. In parallel, two gene-editing strategies were established in vitro: a deaminase-free, glycosylase-based cytosine base editor (gCBE) to correct the C>G mutation, and CRISPR-Cas9-mediated knockout of the mutant allele to mitigate the dominant-negative effect. Results The DDEB mouse model exhibited a mild baseline blistering phenotype, enabling longer-term studies, but showed delayed wound healing following injury, providing a suitable context for therapeutic testing. Western blot analysis revealed intracellular accumulation of C7 with reduced extracellular secretion. Topical application of LNPs resulted in mCherry expression in basal keratinocytes within the migrating epithelial tongue of healing wounds, indicating effective delivery to a therapeutically relevant target cell population. Gene-editing approaches are being established in vitro, with ongoing optimization to identify the most efficient strategy. Conclusions This DDEB mouse model provides a clinically relevant platform for in vivo gene-editing studies. Our results demonstrate topical LNP-mediated delivery to basal keratinocytes, supporting further development of gene-editing therapies for DDEB and other inherited skin disorders.
2026-06-10 | So Much More Than Just Structural Support: Laminin-332 and Its Multifaceted Functions in Skin Homeostasis and Disease.
The extracellular matrix (ECM) is increasingly recognised as a dynamic regulator of tissue function beyond its traditional structural role. In the skin, the ECM supports tissue integrity while also controlling processes such as stem cell maintenance, wound healing and disease progression. This review focuses on laminin-332, a key component of the epidermal-dermal junction. Its essential role in maintaining epidermal cohesion is illustrated by junctional epidermolysis bullosa, a severe inherited blistering disorder and recent advances in laminin-332-targeted genetic therapies are discussed. Beyond structural support, laminin-332 also mediates signalling through integrins and syndecans, thereby influencing epidermal homeostasis, migration, repair and the development of cutaneous squamous cell carcinoma. Its role in epidermal stem cell maintenance further links laminin-332 to skin ageing. The review also examines its functions in hair follicle biology, melanocyte behaviour, skin immunity and emerging evidence implicating laminin-332 in epidermal metabolism-an exciting area for future investigation. Finally, the structure and functions of other cutaneous laminins are compared with laminin-332 to help explain its specialised roles.
2026-03-03 | Supplementary file: Clinical and Molecular Spectrum of Inherited Epidermolysis Bullosa in a Thai Cohort: A 12-Year Retrospective Study
This dataset provides a detailed clinical and genetic characterization of inherited epidermolysis bullosa (EB) within a Thai patient cohort. The supplementary material includes high-resolution photography documenting a wide spectrum of phenotypic presentations, ranging from characteristic blistering and scarring in dominant dystrophic EB (DDEB) to severe mitten deformities in recessive dystrophic EB (RDEB). It further illustrates specific manifestations such as pruritic plaques in EB pruriginosa, perioral crusting in junctional EB (JEB) linked to LAMB3 mutations, localized pressure-induced blisters in EB simplex (EBS), and the poikiloderma seen in Kindler syndrome. Additionally, the data captures specialized clinical findings including vertex and occipital alopecia in patients with ITGB4 variants, subungual hyperkeratosis, and mottled post-inflammatory hyperpigmentation of the trunk and limbs associated with KRT14 variants. Accompanying these visual records is a comprehensive genotype-phenotype ledger (Supplementary Table 1) that catalogs pathogenic and likely pathogenic variants across several key genes, including COL7A1, FERMT1, ITGB4, LAMB3, KRT5, and KRT14. This table details cDNA variants, protein changes, inheritance patterns, and ACMG pathogenicity classifications, supported by computational prediction scores from MutationTaster, SIFT, PolyPhen-2, CADD, and DANN. Notably, the dataset identifies and describes several novel variants, indicated by a dagger (†) symbol, contributing new insights into the molecular diversity of EB.
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.
oligonucleotides
2023-04-17 | 896 Exon skipping using palmitoyl conjugated tricyclo-DNA antisense oligonucleotides for recessive dystrophic epidermolysis bullosa
Dystrophic Epidermolysis Bullosa (DEB) is a group of rare inherited genodermatoses causing skin and mucosal blistering and a wide range of local and systemic severe complications. DEB can be recessively (RDEB) or dominantly (DDEB) inherited, both forms being due to mutations in COL7A1 encoding type VII collagen (C7), the component of anchoring fibrils (AFs) which are essential for dermal-epidermal adhesion. COL7A1 consists of 118 small exons of which 82 encoding the central collagenous domain are in frame, making it an attractive target for antisense oligonucleotide (AON)-mediated exon skipping. Among them, exon 73 carries the largest number of recessive and dominant mutations. We have designed a palmitoyl conjugated tricyclo-DNA (Palm-tcDNA) AON targeting exon 73 in COL7A1. Palm-tcDNAs show enhanced activity in extra-hepatic tissues, better cellular uptake, higher affinity to pre-mRNA and reduced toxicity compared to 2'OMePS AONs, allowing more efficient systemic delivery. Transfection of this selected AON in primary RDEB keratinocytes and fibroblasts induced efficient skipping of exon 73 (up to 72%) and re-expression of C7, demonstrated by Western Blot and immunohistofluorescence. We injected this AON subcutaneously or intravenously into transgenic mice (mCol7a1-/- ; TghCOL7A1) carrying the human COL7A1 genomic locus. RT-PCR experiments demonstrated efficientin vivo exon skipping in line with the biodistribution of the AON in the relevant tissues (skin, eyes, esophagus). Experiments using local and systemic administrations of this AON in a murine model grafted with human RDEB skin equivalents are ongoing to demonstrate restoration of C7 expression and AF formation in vivo. Our data show that Palm-tcDNA AON mediated-exon 73 skipping of COL7A1 mRNA has a therapeutic potential in DEB.
2022-12-01 | 287 Development of a non-invasive, non-viral RNA therapy approach for dystrophic epidermolysis bullosa
In this study we aim to correct mutations within COL7A1 that cause malfunction, reduction or complete absence of type VII collagen in the skin's basement membrane zone (BMZ), leading to dystrophic epidermolysis bullosa (DEB), a severe and rare skin blistering disease associated with a high risk of skin cancer as well as increased mortality. Therefore, we use a 3'-RTMS6m repair molecule to develop a safe, non-viral, non-invasive and efficient in vivo RNA therapy for DEB. This RTM-S6m, cloned into a non-viral minicircle-GFP vector, is capable to correct all mutations occurring between exon 65 and exon 108 of COL7A1 via a trans-splicing reaction between the repair molecule and the mutated mRNA. We tested the efficiency and specificity of the RTM in vitro in DEB keratinocytes and fibroblasts and confirmed correct trans-splicing on mRNA level via qPCR analysis, NGS as well as type VII collagen expression via immunofluorescence (IF) staining of transfected cells. Additionally we used a complex of 3'-RTMS6m with liposomes to deliver the RTMS6m onto DEB skin equivalents and were able to show a partial restoration of the type VII collagen expression at the BMZ, confirmed via IF staining of cryosections. Based on the conclusion that we can efficiently correct DEB keratinocytes and fibroblasts in an in vitro setting, we are aiming to analyze the functionality of the 3'-RTMS6m repair molecule in a DEB xenograft mouse model in vivo.
2022-11-18 | 302 Availability of mRNA Obtained from Peripheral Blood Mononuclear Cells for Mutational Analysis in Dystrophic Epidermolysis Bullosa
Dystrophic epidermolysis bullosa (DEB) is an inheritable blistering disease caused by mutations in COL7A1, which encodes type VII collagen. To address the issue of genotype-phenotype correlations in DEB, analyzing the consequences of COL7A1 mutations using mRNA is indispensable. Herein we established a novel method for testing the effect of mutations in DEB using COL7A1 mRNA extracted from peripheral blood mononuclear cells (PBMCs). We investigated the consequences of four COL7A1 mutations (c.6573 + 1G > C, c.6216 + 5G > T, c.7270C > T and c.2527C > T) in three Japanese individuals with recessive DEB. The novel method detected the consequences of two recurrent COL7A1 mutations (c.6573 + 1G > C, c.6216 + 5G > T) and a novel COL7A1 mutation (c.7270C > T) accurately. In addition, it detected aberrant splicing resulting from a COL7A1 mutation (c.2527C > T) which was previously reported as a nonsense mutation. Furthermore, we revealed that type VII collagen-expressing cells in PBMCs have similar cell surface markers as mesenchymal stem cells; they were CD105+, CD29+, CD45-, and CD34-, suggesting that a small number of mesenchymal stem cells or mesenchymal stromal cells are circulating in the peripheral blood, which enables us to detect COL7A1 mRNA in PBMCs. Taken together, our novel method for analyzing mutation consequences using mRNA obtained from PBMCs in DEB will significantly contribute to genetic diagnoses and novel therapies for DEB.
2022-03-07 | 5'RNA Trans-Splicing Repair of COL7A1 Mutant Transcripts in Epidermolysis Bullosa.
Mutations within the COL7A1 gene underlie the inherited recessive subtype of the blistering skin disease dystrophic epidermolysis bullosa (RDEB). Although gene replacement approaches for genodermatoses are clinically advanced, their implementation for RDEB is challenging and requires endogenous regulation of transgene expression. Thus, we are using spliceosome-mediated RNA trans-splicing (SMaRT) to repair mutations in COL7A1 at the mRNA level. Here, we demonstrate the capability of a COL7A1-specific RNA trans-splicing molecule (RTM), initially selected using a fluorescence-based screening procedure, to accurately replace COL7A1 exons 1 to 64 in an endogenous setting. Retroviral RTM transduction into patient-derived, immortalized keratinocytes resulted in an increase in wild-type transcript and protein levels, respectively. Furthermore, we revealed accurate deposition of recovered type VII collagen protein within the basement membrane zone of expanded skin equivalents using immunofluorescence staining. In summary, we showed for the first time the potential of endogenous 5' trans-splicing to correct pathogenic mutations within the COL7A1 gene. Therefore, we consider 5' RNA trans-splicing a suitable tool to beneficially modulate the RDEB-phenotype, thus targeting an urgent need of this patient population.
2021-12-17 | Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa.
Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types. The subtype and severity of EB is linked to the gene involved and the specific variants in that gene, which also determine its mode of inheritance. Current treatment is mainly focused on symptomatic relief such as wound care and blister prevention, because truly curative treatment options are still at the preclinical stage. Given the current level of understanding, the broad spectrum of genes and variants underlying EB makes it impossible to develop a single treatment strategy for all patients. It is likely that many different variant-specific treatment strategies will be needed to ultimately treat all patients. Antisense-oligonucleotide (ASO)-mediated exon skipping aims to counteract pathogenic sequence variants by restoring the open reading frame through the removal of the mutant exon from the pre-messenger RNA. This should lead to the restored production of the protein absent in the affected skin and, consequently, improvement of the phenotype. Several preclinical studies have demonstrated that exon skipping can restore protein production in vitro, in skin equivalents, and in skin grafts derived from EB-patient skin cells, indicating that ASO-mediated exon skipping could be a viable strategy as a topical or systemic treatment. The potential value of exon skipping for EB is supported by a study showing reduced phenotypic severity in patients who carry variants that result in natural exon skipping. In this article, we review the substantial progress made on exon skipping for EB in the past 15 years and highlight the opportunities and current challenges of this RNA-based therapy approach. In addition, we present a prioritization strategy for the development of exon skipping based on genomic information of all EB-involved genes.
other
2026-06-23 | O14 Reducing blistering during junctional epidermolysis bullosa by in vivo inhibition of tumour necrosis factor and interleukin-1β signalling
Abstract Introduction and aims Junctional epidermolysis bullosa (JEB) is an inherited, rare blistering disorder caused by loss of laminin-332, a mediator of epidermis–dermis adhesion, causing cutaneous fragility, impaired healing and exacerbating pruritus. Chronic inflammation is prominent, with elevated levels of the inflammatory cytokines tumour necrosis factor (TNF) and interleukin (IL)-1β relative to matched controls, yet in-depth immunological study of JEB is absent. We propose the underlying molecular pathology induces a distinct inflammatory niche, and repurposing TNF and IL-1β signalling inhibitors will improve inflammation and clinical symptoms. Accordingly, we aim to characterize cutaneous leucocyte composition and investigate effects of TNF and IL-1β inhibition on itch, inflammation and cutaneous phenotype. Methods Our inducible Lama3 knockout C57BL/6 murine model of severe, progressive JEB replicates symptoms of the human condition and is employed to investigate cutaneous leucocytes alongside evaluating TNF (adalimumab) and IL-1β (Anakinra) signalling inhibitor treatments on JEB pathology. We developed a murine leucocyte staining panel for spectral flow cytometry alongside a recording system to quantify pruritus during disease progression, a first in JEB research. In preliminary experiments, JEB mice received 2-week courses of adalimumab or anakinra with weekly recordings performed, and cutaneous tissues were harvested for downstream immunohistochemical and flow analyses. Results Blistered JEB skin was dominated by mononuclear phagocytes (prominently Ccr2+ macrophages, F4/80+Ly6clo macrophages, and monocytes), granulocytes, with few lymphocytes. Preliminary experimentation indicates adalimumab treatment arrested exacerbation of pruritus, reduced recruitment of monocytes, eosinophils, basophils and neutrophils, and elevated F4/80+Ly6clo and Ccr2+ macrophages alongside impeding angiogenesis. Conversely, anakinra treatment saw no improvements in pruritus, with mixed effects observed upon inflammatory leucocyte makeup, reducing neutrophil and monocyte infiltration simultaneously with F4/80+Ly6clo and Ccr2+ macrophage populations, while populations of T lymphocytes and eosinophils rose. Conclusions Our data illuminate underlying JEB wound inflammation, indicating repurposing established anti-TNF therapeutics presents a putative opportunity to improve patient quality of life, and that anti-IL-1β treatments may not relieve inflammation during JEB.
2026-03-01 | 271P Efficacy and safety of cemiplimab in the treatment of cutaneous squamous cell carcinoma in patients with dystrophic epidermolysis bullosa
Epidermolysis bullosa (EB) is a group of inherited skin disorders marked by extreme fragility and chronic wounds, predisposing patients to cutaneous squamous cell carcinoma (cSCC). In recessive dystrophic EB (RDEB), cSCC is highly aggressive, often diagnosed late, and remains the leading cause of death. Systemic options for unresectable disease are limited, and evidence for immunotherapy in EB is restricted to isolated reports. We present a case series of patients with RDEB-associated advanced cSCC treated with cemiplimab.
2026-02-20 | In vivo confocal microscopic evaluation of patients with epidermolysis bullosa demonstrates severe loss of corneal nerves.
Epidermolysis bullosa (EB) is a rare inherited genetic disorder associated with severe ocular surface complications and progressive corneal scarring. This case series aimed to structurally characterize and quantitatively analyze central corneal subbasal nerve plexus loss using in vivo confocal microscopy (IVCM) in pediatric patients with recessive dystrophic epidermolysis bullosa (RDEB). This retrospective case series included five pediatric patients with RDEB presenting with ocular and systemic manifestations. In vivo confocal microscopy (IVCM) imaging showed severe central subbasal corneal nerve plexus loss in 85% of eyes, with a median total nerve density of 0 μm/mm2 (IQR: 0-5150.67), main nerve trunk density of 0 μm/mm2 (IQR: 0-2720.56), and branch nerve density of 0 μm/mm2 (IQR: 0-2769.22). Dendritiform reflective structures were qualitatively observed in multiple scans of eyes demonstrating marked central subbasal nerve loss.No immunophenotyping was performed. Corneal sensation testing was not performed due to severe ocular surface fragility and photophobia; therefore, no clinical diagnosis or staging of NK was inferred or concluded from this cohort. This series identifies profound structural corneal denervation of the central subbasal plexus on IVCM in pediatric RDEB-associated ocular surface disease. The findings support future prospective studies investigating corneal nerve-regeneration and epithelial-stabilization frameworks to preserve long-term visual outcomes in children with RDEB.
2025-12-27 | First experience of the application of beremagene geperpavec genetically engineered drug for treatment of congenital dystrophic epidermolysis bullosa in the Russian Federation
Congenital epidermolysis bullosa (CEB) is a group of heterogenous, hereditary genetic diseases. Emergence of blisters and erosions on the skin, slight vulnerability of the skin cover, formation of disabling deformities and aggressive skin cancer development are the main clinical manifestations of this pathology. The disease is based on a hereditary genetic defect caused by one or several mutations in the COL7A gene, leading to an insufficient synthesis of type VII collagen functional protein (COL7), which contributes to the occurrence of persistent skin wounds and their infection. Generalized recessive dystrophic epidermolysis bullosa (RDEB) leading to death of patients at a young age is the most severe form of the disease. In the Russian Federation, symptomatic methods aimed at accelerating the healing of erosive and ulcerative skin defects and preventing the development of secondary infection and correcting complications are currently being used to treat patients with CEB, including RDEB. The article presents the first experience of treatment of a patient with RDEB with beremagene geperpavec genetically engineered drug in the Russian Federation. A male patient, 14 years old, with a verified congenital dystrophic epidermolysis bullosa, recessive type, Q81.1 diagnosis was under follow-up. Treatment was carried out at the North-East Clinic with the Children’s Center of the Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology (MSPCDC). Beremagene geperpavec gel was applied to the open wounds located on the skin of the back, right axillary region, inguinal folds, lower extremities. In total, 8 applications were done during 2 months. The treatment had a pronounced therapeutic effect, which manifested itself in complete epithelialization of the wound surfaces.
2025-12-26 | [Genetic analysis of a Chinese pedigree affected with Epidermolysis bullosa simplex due to a novel variant of KRT5 gene].
To investigate the clinical characteristics and genetic etiology of eight members from a pedigree affected with epidermolysis bullosa (EB). A girl presented with recurrent, unexplained blisters on the palmar and plantar skin for 8 years and sought medical care in October 2024 was enrolled as the study subject. A retrospective study was conducted to collect the child's clinical data, and a detailed medical history was taken for her family members. Peripheral venous blood samples were collected from the child and her parents for genomic DNA extraction. Whole-exome sequencing (WES) was performed. Candidate variant was validated by Sanger sequencing. The pathogenicity of the candidate variants was classified in accordance with the Standards and Guidelines for the Interpretation of Sequence Variants issued by the American College of Medical Genetics and Genomics (ACMG, hereinafter referred to as the "ACMG Guidelines"). This study was approved by the Medical Ethics Committee of the 980th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army (Ethics No.: 2019-KY-01). The proband was an 8-year-and-4-month-old female. Four months after birth, she had developed recurrent blisters on the palmar and plantar skin without obvious triggers, accompanied by significant pain. Symptoms were more severe in summer and slightly relieved in winter. Although symptomatic treatment could alleviate the symptoms, she was unable to participate in physical activities. A detailed family history revealed that her great-grandfather, grandfather, father, half-brother, great-aunt, great-aunt's son and two grandsons, as well as her aunt and aunt's son, had similar clinical manifestations. WES revealed that she has harbored a heterozygous c.556-16(IVS1)C>G (NM_000424.4) variant in the KRT5 gene, which was identified as a splice site mutation. Reverse transcription sequencing confirmed that this variant can disrupt normal splicing, resulting in retention of a 15 bp sequence in the first intron. Sanger sequencing demonstrated that the variant was inherited from the father, and the 6 aforementioned relatives with similar phenotypes have all carried the same variant (the great-grandfather, grandfather, and great-aunt had declined genetic testing due to advanced age). Based on the ACMG guidelines, this variant was classified as pathogenic (PS3+PM2_Supporting+PP3+PP1_strong). Patients with epidermolysis bullosa simplex may exhibit clinical features including blistering on the skin or mucous membranes of friction-prone sites (e.g. hands, feet, elbows, and knees) following minor trauma or friction, as well as increased skin fragility. The c.556-16(IVS1)C>G (rs376462752) variant of the KRT5 gene probably underlay the pathogenesis of EB in this child. Above findings have enriched the mutational spectrum of the KRT5 gene.
cell therapies
2026-06-10 | Intact Fish Skin Graft in the Treatment of EB Hand: A New Weapon in This Challenge?
Background/Objectives: Epidermolysis bullosa (EB) comprises a heterogeneous group of rare inherited skin-fragility disorders in which even minimal trauma can cause blistering, chronic wounds, scarring, and functional impairment. After surgical release of EB hand deformities, wound coverage is challenging because autologous split-thickness skin grafting creates an additional donor-site wound in already fragile tissue. This preliminary case series reports our single-center pediatric experience using intact fish skin grafting (iFSG) as an adjunct after EB hand surgery. Methods: We conducted an observational case series of five pediatric patients with dystrophic EB, including eight operated hands, treated between December 2022 and December 2025. iFSG was applied after the release of contractures and/or pseudosyndactyly. Primary outcomes were time to complete re-epithelialization, need for re-application, need for autologous grafting, and early complications. Secondary outcomes included dressing-related pain assessed with an age-appropriate visual analog scale during awake dressing care, dressing burden, and early recurrence signals. Results: The iFSG application was feasible in all cases. One localized second application was required, and no patient required autologous split-thickness skin grafting. Mean dressing-related pain was 1.6 on the visual analog scale, and mean time to complete re-epithelialization was 47.6 days. No allergic reactions occurred. Healing was slower in the two most severe bilateral mitten-hand cases, and one patient developed limited dorsal disepithelialization attributed to prolonged dressing contact on extremely fragile skin. One partial recurrence of pseudosyndactyly was observed during follow-up without the need for revision surgery. Conclusions: iFSG was feasible in this small preliminary pediatric dystrophic EB hand surgery series and may provide a biologically active scaffold that supports secondary closure while avoiding autologous donor-site creation. Because of the rarity of the disease, the limited sample size, the absence of a comparator group, and the limited follow-up, these findings should be interpreted cautiously. Larger multicenter studies with standardized functional, pain, recurrence, and caregiver-reported outcomes are needed to define the role of iFSG in EB hand reconstruction. ABILHAND-Kids was also administered to patients/caregivers and suggested encouraging perceived improvement in postoperative hand use and independence in daily activities.
2026-05-13 | Amniotic Membrane Transplantation Preserves Vision in Pediatric Recessive Dystrophic Epidermolysis Bullosa: Case Series.
Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited disorder characterized by extreme epithelial fragility and progressive cicatrization, frequently leading to severe ocular surface disease and early visual impairment. Surgical interventions such as ocular surface reconstruction (OSR) in childhood are often delayed because of anesthetic risks and concerns regarding recurrence. Consequently, the effectiveness of OSR, including amniotic membrane transplantation (AMT), and its impact on visual development remain poorly documented. Methods: We report a case series of two pediatric patients (three eyes) with genetically confirmed RDEB who underwent single-step OSR using AMT. Clinical outcomes, long-term visual acuity, perioperative management, and histopathological findings were evaluated. Results: Ocular manifestations included corneal epithelial damage, symblepharon, and pseudopterygium extending over the cornea. One patient underwent symblepharon lysis, superficial keratectomy, and AMT onto the bare sclera in the right eye at age 4 and in the left eye at age 8, both under intubated general anesthesia. The other patient underwent the same procedure in the right eye at age 6. Best spectacle-corrected visual acuity improved from ≤20/300 to 20/30 in all eyes, and pupillary zone clarity was maintained during the follow-up period (up to 6 years). Histopathology confirmed pseudopterygium with squamous metaplasia, goblet cell loss, and fibrovascular stroma. Safe general anesthesia was achieved through meticulous multidisciplinary perioperative planning involving anesthesiologists, dermatologists, and pediatricians. No systemic complications related to anesthesia or perioperative management were observed. Conclusions: Single-step OSR with on-lay AMT can restore and preserve visual function in pediatric RDEB. Early surgical intervention may prevent profound amblyopia and provide durable ocular surface stability. A multidisciplinary approach enables safe general anesthesia and perioperative management.
2026-03-28 | Macrophage Extracellular Vesicles: Therapeutic Strategies for Corneal Fibrosis in Rare Diseases.
Corneal scarring (fibrosis) is a blinding condition affecting millions of sufferers worldwide. It is not only in common ocular injuries but also in genetically inherited rare diseases such as epidermolysis bullosa (EB), keratitis-ichthyosis-deafness (KID) syndrome and aniridia. In rare diseases like EB or KID syndrome, corneal fibrosis arises from chronic inflammation, structural instability and neuro-immune dysfunction driven by genetic mutations. Current therapies are not effective in addressing the needs of affected individuals due to limited efficacy nor the considerable side effects of treatment. Extracellular vesicles (EVs) from various cell types such as mesenchymal stem cells not only possess high biocompatibility but have shown promising results in limiting corneal fibrosis. Rather than targeting a single molecular signaling pathway, EVs which contain regulatory RNAs and proteins are hypothesized to target multiple pathways synergistically. Macrophage-derived EVs (Mac-EVs) with an immunomodulatory nature may offer a promising therapeutic effect for rare diseases. Various EV delivery platforms have been proposed in preclinical studies. However, not all of these delivery techniques are appropriate for the cornea in rare diseases. In this review, we delineate recent advances in understanding corneal fibrosis from a rare disease point of view, including the impact on corneal immune cells and nerves. We then provide critical considerations of therapeutic development for corneal fibrosis in rare diseases. Furthermore, we used this knowledge to comprehensively consider the various EVs, especially Mac-EVs, synthesis methods and delivery techniques. Ultimately, this review aims to enable biomolecule researchers to develop EV-based therapies that not only exert anti-fibrotic effects but also address clinical compatibility for corneal fibrosis in rare diseases.
2025-12-04 | IPSC-derived organoid-sourced skin cells enable functional 3D skin modeling of recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited skin disorder caused by mutations in COL7A1. Patient-derived induced pluripotent stem cells (iPSCs) enable the personalized study of RDEB pathogenesis and potential therapies. However, current skin cell differentiation protocols via 2D culture perform suboptimally when applied to engineered 3D skin constructs (ESC). Here, we present an approach to source fibroblasts (iFBs) and keratinocytes (iKCs) from iPSC-derived skin organoids using an optimized differentiation protocol, and utilize them to engineer ESCs modeling wild-type and RDEB phenotypes. The resulting iPSC-derived skin cells display marker expression consistent with primary counterparts and produce ESCs exhibiting significant extracellular matrix remodeling, protein deposition, and epidermal differentiation. RDEB constructs recapitulated hallmark disease features, including absence of collagen VII and reduced iFB proliferation. This work establishes a robust and scalable strategy for generating physiologically-relevant, iPSC-derived skin constructs, offering a powerful model for studying RDEB mechanisms and advancing personalized regenerative medicine.
2025-11-17 | Mesenchymal stromal cell therapy in epidermolysis bullosa: current perspectives and future directions
Epidermolysis bullosa (EB) is a group of inherited mucocutaneous disorders. Mesenchymal stromal cells (MSCs) are non-hematopoietic self-renewing, multipotent cells that are a promising therapeutic avenue for EB, given their ability to home to injury, low immunogenicity, and demonstrated wound-healing, anti-fibrotic, and pro-collagen effects. This review article synthesizes the current literature and advancement on MSC therapy in EB, and highlights the potential to optimize their use, including exploring MSC-derived extracellular vesicles as a potential cell-free therapy. Innovative delivery methods can also improve the accessibility and effectiveness of MSC therapies by providing localized treatment, minimizing systemic side effects, and increasing patient comfort.
small molecules
2026-07-27 | A Systematic Review of Topical and Systemic Gentamicin for Wound Healing in Patients With Junctional and Dystrophic Epidermolysis Bullosa.
Epidermolysis bullosa (EB) is an inherited mechanobullous genodermatosis caused by a mutation in genes encoding proteins integral to skin integrity. Premature termination codon readthrough therapies, such as gentamicin, have promise in facilitating full-length protein expression in patients with EB. We conducted a systematic review of the effectiveness and adverse effects of gentamicin for wound healing in EB. Six databases were searched to 01 September 2025 for clinical trials investigating gentamicin for EB. Risk of bias was assessed using the ROBINS-I tool, and data were synthesised descriptively. This study was registered with PROSPERO (CRD42024496582). Five studies involving 24 patients with junctional EB or dystrophic EB were included; four were open-label and one was double-blinded. Nineteen of the 24 patients had a known nonsense mutation. Gentamicin was administered topically (two studies), intravenously (two studies) and both topically and intradermally (one study). Wound healing was heterogeneously measured across studies, with all but one showing improved outcomes. All patients demonstrated increased expression of glycoprotein or collagen in skin biopsy specimens after gentamicin treatment. No adverse events were noted. However, four of five studies were at serious risk of bias on ROBINS-I, primarily owing to lack of blinding and absence of control groups, increasing the risk of bias for subjective outcomes such as wound healing. The available evidence suggests gentamicin may improve wound healing in EB caused by nonsense mutations, but the small number of heterogeneous studies precludes high-level evidence. Larger, blinded, randomised trials are required to confirm efficacy and long-term safety.
2026-07-08 | Esophageal Stricture in a 5-Year-Old Child with Epidermolysis Bullosa: Case Report of a Rare Complication at a Very Young Age.
Epidermolysis bullosa (EB) represents a group of rare inherited mechanobullous disorders characterized by extreme skin and mucosal fragility. Dystrophic EB (DEB), caused by mutations in the COL7A1 gene, often leads to cycles of blistering, healing, and scarring with multisystem involvement, including the gastrointestinal tract. Esophageal strictures are not uncommon in recessive DEB (RDEB), appearing after the first decade of life (∼12.6 years). We describe a relatively early complication in a 5-year-old child. A 5-year-old girl with genetically confirmed RDEB presented with 4 months of progressive dysphagia, vomiting, and retrosternal pain, more pronounced with solids. Her disease history included severe skin fragility since birth, scarring, and autoamputation of toes. Examination showed multiple healed ulcers, mitten deformities of all limbs, dental caries, and bilateral corneal opacities. Laboratory evaluation revealed anemia (Hb 7.7 g/dL). Barium swallow demonstrated a short mid-esophageal stricture; upper gastrointestinal endoscopy confirmed focal narrowing at 14 cm from the incisors. Endoscopic balloon dilatation up to 8 mm using a controlled radial expansion was performed, and the patient was initiated on oral losartan (8 mg/day) to reduce transforming growth factors-β-mediated fibrosis and stricture recurrence. Serial dilatations were planned at 3-week intervals. This case represents one of the youngest reported presentations of esophageal stricture in RDEB. The combination of early endoscopic balloon dilatation and adjunct antifibrotic therapy with losartan may reduce recurrence and improve nutritional outcomes. Monitoring for early esophageal involvement in young patients with RDEB is essential for timely intervention.
2026-06-26 | Use of Tramadol in Pain Management of Neonates with Epidermolysis Bullosa: A Single-Center Experience.
Background: Inherited Epidermolysis Bullosa (EB) is a wide group of rare genetic disorders characterized by mucocutaneous fragility and blister formation. In neonates with EB, pain control is particularly complex because painful skin lesions coexist with developmental vulnerability, repeated handling, and the need for frequent wound care. Traditional opioid use carries a risk of adverse effects such as respiratory depression. Tramadol, a centrally acting weak opioid with a dual mechanism of action, may offer a safer alternative. Methods: This retrospective observational study analyzed neonates with different EB subtypes admitted to our tertiary neonatal care center between January 2020 and October 2022. Genetic diagnosis was confirmed via next-generation sequencing. Pain was assessed using the Neonatal Infant Pain Scale (NIPS). Tramadol was administered intravenously (1-2 mg/kg bolus or 0.1-0.2 mg/kg/h infusion) before daily wound dressings, then transitioned to oral dosing when appropriate. Pain scores before and after tramadol administration were compared. Results: Six neonates with various EB subtypes were included. All patients received tramadol for procedural pain control. No significant differences in NIPS scores were observed before and after tramadol administration (p = 0.997), indicating adequate pain control, although baseline pain scores were low, limiting interpretation of analgesic efficacy. No immediate adverse events were observed during hospitalization or reported during follow-up. Conclusions: Scheduled tramadol administration appears to be a safe and effective option for pain management in neonates with EB, with no observed hemodynamic or respiratory complications. Given the scarcity of data in this population, our findings highlight the need for multicenter studies to establish standardized analgesia protocols for EB neonates.
2026-06-23 | O2 Innate immune dysregulation drives recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma
Abstract Introduction and aims Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited, immunologically active, skin disorder, characterized by skin fragility and chronic inflammation, predisposing patients to aggressive early-onset squamous cell carcinoma (cSCC). Despite this, immunopathogenic mechanisms driving tumour progression remain poorly understood, while current treatments fail to address cancer initiation. This study aimed to characterize the RDEB-cSCC innate immune landscape to identify targetable pathways for therapeutic intervention. Methods We performed an integrated immune analysis using bulk RNA sequencing of matched nonlesional, perilesional and lesional biopsies as a strategy to model disease progression. This was complemented by peripheral blood immunophenotyping of healthy donors, patients with RDEB and patients with RDEB-cSCC to identify innate immune alterations associated with disease severity. To validate therapeutic targets, a patient-derived three-dimensional immunocompetent spheroid model was established, designed to recapitulate key tumour-promoting immune features, observed in patients with RDEB-cSCC. Results Transcriptomic profiling revealed a severity-dependent macrophage enrichment and activation of the immunoregulatory pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT)3, previously identified as a promising target in RDEB-cSCC. Lesional tissue and patient plasma exhibited concurrent upregulation of both pro- and anti-inflammatory cytokine signatures, indicating a dysregulated immune response. Peripheral immune profiling further revealed a significant shift towards alternatively activated monocytes, expressing CD163 and Tim4, suggesting a prepriming of precursor tumour-associated macrophages, linked to aggressive disease progression. Uniform manifold approximation and projection analysis identified unique monocyte clusters specific to RDEB-cSCC, associated with aggressive tumour behaviour. To functionally validate these tumour-promoting immune features, an immunocompetent spheroid model was developed recapitulating protumour macrophage differentiation and cytokines release associated with JAK/STAT3 activation. Targeting the model with the clinically approved JAK1/2 inhibitor, ruxolitinib, resulted in reduced spheroid growth, increase necrosis and a significant shift in monocyte polarization towards antitumour phenotype. Conclusions These findings highlight the innate immune dysregulation as a central driver of RDEB-cSCC, and targeting the monocyte–macrophage plasticity via the JAK/STAT3 pathway could be a potential early intervention strategy for treating RDEB-cSCC.
2026-05-30 | N -acetylcysteine exerts senescence-selective antifibrotic effects in fibroblast from chronic wounds in recessive dystrophic epidermolysis bullosa
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited skin disease caused by pathogenic biallelic variants in COL7A1, resulting in dermoepidermal fragility and chronic, nonhealing wounds. We investigated the contribution of fibroblast senescence to RDEB wound pathology and evaluated whether N-acetylcysteine can modulate this process.
gene therapies
2026-08-11 | Topical gene therapy for severe recessive dystrophic epidermolysis bullosa: clinical outcomes and multidisciplinary management in three patients treated with beremagene geperpavec (B-VEC) in Italy - a case series.
Recessive dystrophic epidermolysis bullosa is a severe inherited blistering disorder characterized by chronic wounds, fibrosis and systemic complications. Beremagene geperpavec (B-VEC), a topical HSV1-based gene therapy delivering full-length COL7A1, has shown efficacy in clinical trials; however, real-world data remain limited. This retrospective, descriptive case series reports on three patients with genetically confirmed recessive dystrophic epidermolysis bullosa - two children and one young adult - treated between 2024 and 2026 at two Italian tertiary centres. All patients had extensive chronic skin involvement and received weekly topical B-VEC. Clinical data included wound characteristics, response to therapy, supportive care and adverse events. All patients showed clinically meaningful improvement in target wound healing. One child achieved ~70% reduction in the wound area needing treatment; the second had ~50% with shallower morphology and reduced bleeding. The adult, previously enrolled in the GEM-3 trial, achieved over 60% wound closure after reinitiating B-VEC via Italy's 5% Italian Medicines Agency (AIFA) access programme. No treatment-related adverse events occurred. Adjunctive care included wound hygiene optimization, nutritional and iron support, and pain control. In this small descriptive case series, B-VEC was well tolerated and associated with clinically meaningful improvement in wound healing though outcomes were more variable and, in some cases, less pronounced than those reported in pivotal trials, nevertheless supporting its integration into a comprehensive care model that addresses infection risk, anaemia, nutrition, and wound management.
2026-06-23 | P28 In vivo targeting of basal keratinocytes using lipid nanoparticles in a dominant dystrophic epidermolysis bullosa mouse model
Abstract Introduction and aims Gene editing holds strong therapeutic promise for inherited skin disorders, but translation to in vivo application requires clinically relevant animal models. Dystrophic epidermolysis bullosa (DEB), caused by pathogenic COL7A1 variants, is a severe condition for which existing mouse models are poorly suited to testing gene-editing therapies. This study aimed to establish and characterize a dominant DEB (DDEB) mouse model for in vivo gene-editing evaluation and to assess the feasibility of lipid nanoparticle (LNP)-mediated delivery to skin cells. Methods A DDEB mouse model heterozygous for the Col7a1 exon 73 c.6085G>C variant was utilized. Phenotypic assessment focused on blistering severity and wound-healing dynamics. Cells isolated from mouse skin biopsies were analysed by Western blot to assess intracellular accumulation and extracellular secretion of type VII collagen. Topical delivery of self-formulated LNPs encapsulating mCherry mRNA was tested on wounded mouse skin to evaluate cellular targeting and delivery efficiency. In parallel, two gene-editing strategies were established in vitro: a deaminase-free, glycosylase-based cytosine base editor (gCBE) to correct the C>G mutation, and CRISPR-Cas9-mediated knockout of the mutant allele to mitigate the dominant-negative effect. Results The DDEB mouse model exhibited a mild baseline blistering phenotype, enabling longer-term studies, but showed delayed wound healing following injury, providing a suitable context for therapeutic testing. Western blot analysis revealed intracellular accumulation of C7 with reduced extracellular secretion. Topical application of LNPs resulted in mCherry expression in basal keratinocytes within the migrating epithelial tongue of healing wounds, indicating effective delivery to a therapeutically relevant target cell population. Gene-editing approaches are being established in vitro, with ongoing optimization to identify the most efficient strategy. Conclusions This DDEB mouse model provides a clinically relevant platform for in vivo gene-editing studies. Our results demonstrate topical LNP-mediated delivery to basal keratinocytes, supporting further development of gene-editing therapies for DDEB and other inherited skin disorders.
2026-06-10 | So Much More Than Just Structural Support: Laminin-332 and Its Multifaceted Functions in Skin Homeostasis and Disease.
The extracellular matrix (ECM) is increasingly recognised as a dynamic regulator of tissue function beyond its traditional structural role. In the skin, the ECM supports tissue integrity while also controlling processes such as stem cell maintenance, wound healing and disease progression. This review focuses on laminin-332, a key component of the epidermal-dermal junction. Its essential role in maintaining epidermal cohesion is illustrated by junctional epidermolysis bullosa, a severe inherited blistering disorder and recent advances in laminin-332-targeted genetic therapies are discussed. Beyond structural support, laminin-332 also mediates signalling through integrins and syndecans, thereby influencing epidermal homeostasis, migration, repair and the development of cutaneous squamous cell carcinoma. Its role in epidermal stem cell maintenance further links laminin-332 to skin ageing. The review also examines its functions in hair follicle biology, melanocyte behaviour, skin immunity and emerging evidence implicating laminin-332 in epidermal metabolism-an exciting area for future investigation. Finally, the structure and functions of other cutaneous laminins are compared with laminin-332 to help explain its specialised roles.
2026-03-03 | Supplementary file: Clinical and Molecular Spectrum of Inherited Epidermolysis Bullosa in a Thai Cohort: A 12-Year Retrospective Study
This dataset provides a detailed clinical and genetic characterization of inherited epidermolysis bullosa (EB) within a Thai patient cohort. The supplementary material includes high-resolution photography documenting a wide spectrum of phenotypic presentations, ranging from characteristic blistering and scarring in dominant dystrophic EB (DDEB) to severe mitten deformities in recessive dystrophic EB (RDEB). It further illustrates specific manifestations such as pruritic plaques in EB pruriginosa, perioral crusting in junctional EB (JEB) linked to LAMB3 mutations, localized pressure-induced blisters in EB simplex (EBS), and the poikiloderma seen in Kindler syndrome. Additionally, the data captures specialized clinical findings including vertex and occipital alopecia in patients with ITGB4 variants, subungual hyperkeratosis, and mottled post-inflammatory hyperpigmentation of the trunk and limbs associated with KRT14 variants. Accompanying these visual records is a comprehensive genotype-phenotype ledger (Supplementary Table 1) that catalogs pathogenic and likely pathogenic variants across several key genes, including COL7A1, FERMT1, ITGB4, LAMB3, KRT5, and KRT14. This table details cDNA variants, protein changes, inheritance patterns, and ACMG pathogenicity classifications, supported by computational prediction scores from MutationTaster, SIFT, PolyPhen-2, CADD, and DANN. Notably, the dataset identifies and describes several novel variants, indicated by a dagger (†) symbol, contributing new insights into the molecular diversity of EB.
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.
oligonucleotides
2023-04-17 | 896 Exon skipping using palmitoyl conjugated tricyclo-DNA antisense oligonucleotides for recessive dystrophic epidermolysis bullosa
Dystrophic Epidermolysis Bullosa (DEB) is a group of rare inherited genodermatoses causing skin and mucosal blistering and a wide range of local and systemic severe complications. DEB can be recessively (RDEB) or dominantly (DDEB) inherited, both forms being due to mutations in COL7A1 encoding type VII collagen (C7), the component of anchoring fibrils (AFs) which are essential for dermal-epidermal adhesion. COL7A1 consists of 118 small exons of which 82 encoding the central collagenous domain are in frame, making it an attractive target for antisense oligonucleotide (AON)-mediated exon skipping. Among them, exon 73 carries the largest number of recessive and dominant mutations. We have designed a palmitoyl conjugated tricyclo-DNA (Palm-tcDNA) AON targeting exon 73 in COL7A1. Palm-tcDNAs show enhanced activity in extra-hepatic tissues, better cellular uptake, higher affinity to pre-mRNA and reduced toxicity compared to 2'OMePS AONs, allowing more efficient systemic delivery. Transfection of this selected AON in primary RDEB keratinocytes and fibroblasts induced efficient skipping of exon 73 (up to 72%) and re-expression of C7, demonstrated by Western Blot and immunohistofluorescence. We injected this AON subcutaneously or intravenously into transgenic mice (mCol7a1-/- ; TghCOL7A1) carrying the human COL7A1 genomic locus. RT-PCR experiments demonstrated efficientin vivo exon skipping in line with the biodistribution of the AON in the relevant tissues (skin, eyes, esophagus). Experiments using local and systemic administrations of this AON in a murine model grafted with human RDEB skin equivalents are ongoing to demonstrate restoration of C7 expression and AF formation in vivo. Our data show that Palm-tcDNA AON mediated-exon 73 skipping of COL7A1 mRNA has a therapeutic potential in DEB.
2022-12-01 | 287 Development of a non-invasive, non-viral RNA therapy approach for dystrophic epidermolysis bullosa
In this study we aim to correct mutations within COL7A1 that cause malfunction, reduction or complete absence of type VII collagen in the skin's basement membrane zone (BMZ), leading to dystrophic epidermolysis bullosa (DEB), a severe and rare skin blistering disease associated with a high risk of skin cancer as well as increased mortality. Therefore, we use a 3'-RTMS6m repair molecule to develop a safe, non-viral, non-invasive and efficient in vivo RNA therapy for DEB. This RTM-S6m, cloned into a non-viral minicircle-GFP vector, is capable to correct all mutations occurring between exon 65 and exon 108 of COL7A1 via a trans-splicing reaction between the repair molecule and the mutated mRNA. We tested the efficiency and specificity of the RTM in vitro in DEB keratinocytes and fibroblasts and confirmed correct trans-splicing on mRNA level via qPCR analysis, NGS as well as type VII collagen expression via immunofluorescence (IF) staining of transfected cells. Additionally we used a complex of 3'-RTMS6m with liposomes to deliver the RTMS6m onto DEB skin equivalents and were able to show a partial restoration of the type VII collagen expression at the BMZ, confirmed via IF staining of cryosections. Based on the conclusion that we can efficiently correct DEB keratinocytes and fibroblasts in an in vitro setting, we are aiming to analyze the functionality of the 3'-RTMS6m repair molecule in a DEB xenograft mouse model in vivo.
2022-11-18 | 302 Availability of mRNA Obtained from Peripheral Blood Mononuclear Cells for Mutational Analysis in Dystrophic Epidermolysis Bullosa
Dystrophic epidermolysis bullosa (DEB) is an inheritable blistering disease caused by mutations in COL7A1, which encodes type VII collagen. To address the issue of genotype-phenotype correlations in DEB, analyzing the consequences of COL7A1 mutations using mRNA is indispensable. Herein we established a novel method for testing the effect of mutations in DEB using COL7A1 mRNA extracted from peripheral blood mononuclear cells (PBMCs). We investigated the consequences of four COL7A1 mutations (c.6573 + 1G > C, c.6216 + 5G > T, c.7270C > T and c.2527C > T) in three Japanese individuals with recessive DEB. The novel method detected the consequences of two recurrent COL7A1 mutations (c.6573 + 1G > C, c.6216 + 5G > T) and a novel COL7A1 mutation (c.7270C > T) accurately. In addition, it detected aberrant splicing resulting from a COL7A1 mutation (c.2527C > T) which was previously reported as a nonsense mutation. Furthermore, we revealed that type VII collagen-expressing cells in PBMCs have similar cell surface markers as mesenchymal stem cells; they were CD105+, CD29+, CD45-, and CD34-, suggesting that a small number of mesenchymal stem cells or mesenchymal stromal cells are circulating in the peripheral blood, which enables us to detect COL7A1 mRNA in PBMCs. Taken together, our novel method for analyzing mutation consequences using mRNA obtained from PBMCs in DEB will significantly contribute to genetic diagnoses and novel therapies for DEB.
2022-03-07 | 5'RNA Trans-Splicing Repair of COL7A1 Mutant Transcripts in Epidermolysis Bullosa.
Mutations within the COL7A1 gene underlie the inherited recessive subtype of the blistering skin disease dystrophic epidermolysis bullosa (RDEB). Although gene replacement approaches for genodermatoses are clinically advanced, their implementation for RDEB is challenging and requires endogenous regulation of transgene expression. Thus, we are using spliceosome-mediated RNA trans-splicing (SMaRT) to repair mutations in COL7A1 at the mRNA level. Here, we demonstrate the capability of a COL7A1-specific RNA trans-splicing molecule (RTM), initially selected using a fluorescence-based screening procedure, to accurately replace COL7A1 exons 1 to 64 in an endogenous setting. Retroviral RTM transduction into patient-derived, immortalized keratinocytes resulted in an increase in wild-type transcript and protein levels, respectively. Furthermore, we revealed accurate deposition of recovered type VII collagen protein within the basement membrane zone of expanded skin equivalents using immunofluorescence staining. In summary, we showed for the first time the potential of endogenous 5' trans-splicing to correct pathogenic mutations within the COL7A1 gene. Therefore, we consider 5' RNA trans-splicing a suitable tool to beneficially modulate the RDEB-phenotype, thus targeting an urgent need of this patient population.
2021-12-17 | Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa.
Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types. The subtype and severity of EB is linked to the gene involved and the specific variants in that gene, which also determine its mode of inheritance. Current treatment is mainly focused on symptomatic relief such as wound care and blister prevention, because truly curative treatment options are still at the preclinical stage. Given the current level of understanding, the broad spectrum of genes and variants underlying EB makes it impossible to develop a single treatment strategy for all patients. It is likely that many different variant-specific treatment strategies will be needed to ultimately treat all patients. Antisense-oligonucleotide (ASO)-mediated exon skipping aims to counteract pathogenic sequence variants by restoring the open reading frame through the removal of the mutant exon from the pre-messenger RNA. This should lead to the restored production of the protein absent in the affected skin and, consequently, improvement of the phenotype. Several preclinical studies have demonstrated that exon skipping can restore protein production in vitro, in skin equivalents, and in skin grafts derived from EB-patient skin cells, indicating that ASO-mediated exon skipping could be a viable strategy as a topical or systemic treatment. The potential value of exon skipping for EB is supported by a study showing reduced phenotypic severity in patients who carry variants that result in natural exon skipping. In this article, we review the substantial progress made on exon skipping for EB in the past 15 years and highlight the opportunities and current challenges of this RNA-based therapy approach. In addition, we present a prioritization strategy for the development of exon skipping based on genomic information of all EB-involved genes.
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2026-06-23 | O14 Reducing blistering during junctional epidermolysis bullosa by in vivo inhibition of tumour necrosis factor and interleukin-1β signalling
Abstract Introduction and aims Junctional epidermolysis bullosa (JEB) is an inherited, rare blistering disorder caused by loss of laminin-332, a mediator of epidermis–dermis adhesion, causing cutaneous fragility, impaired healing and exacerbating pruritus. Chronic inflammation is prominent, with elevated levels of the inflammatory cytokines tumour necrosis factor (TNF) and interleukin (IL)-1β relative to matched controls, yet in-depth immunological study of JEB is absent. We propose the underlying molecular pathology induces a distinct inflammatory niche, and repurposing TNF and IL-1β signalling inhibitors will improve inflammation and clinical symptoms. Accordingly, we aim to characterize cutaneous leucocyte composition and investigate effects of TNF and IL-1β inhibition on itch, inflammation and cutaneous phenotype. Methods Our inducible Lama3 knockout C57BL/6 murine model of severe, progressive JEB replicates symptoms of the human condition and is employed to investigate cutaneous leucocytes alongside evaluating TNF (adalimumab) and IL-1β (Anakinra) signalling inhibitor treatments on JEB pathology. We developed a murine leucocyte staining panel for spectral flow cytometry alongside a recording system to quantify pruritus during disease progression, a first in JEB research. In preliminary experiments, JEB mice received 2-week courses of adalimumab or anakinra with weekly recordings performed, and cutaneous tissues were harvested for downstream immunohistochemical and flow analyses. Results Blistered JEB skin was dominated by mononuclear phagocytes (prominently Ccr2+ macrophages, F4/80+Ly6clo macrophages, and monocytes), granulocytes, with few lymphocytes. Preliminary experimentation indicates adalimumab treatment arrested exacerbation of pruritus, reduced recruitment of monocytes, eosinophils, basophils and neutrophils, and elevated F4/80+Ly6clo and Ccr2+ macrophages alongside impeding angiogenesis. Conversely, anakinra treatment saw no improvements in pruritus, with mixed effects observed upon inflammatory leucocyte makeup, reducing neutrophil and monocyte infiltration simultaneously with F4/80+Ly6clo and Ccr2+ macrophage populations, while populations of T lymphocytes and eosinophils rose. Conclusions Our data illuminate underlying JEB wound inflammation, indicating repurposing established anti-TNF therapeutics presents a putative opportunity to improve patient quality of life, and that anti-IL-1β treatments may not relieve inflammation during JEB.
2026-03-01 | 271P Efficacy and safety of cemiplimab in the treatment of cutaneous squamous cell carcinoma in patients with dystrophic epidermolysis bullosa
Epidermolysis bullosa (EB) is a group of inherited skin disorders marked by extreme fragility and chronic wounds, predisposing patients to cutaneous squamous cell carcinoma (cSCC). In recessive dystrophic EB (RDEB), cSCC is highly aggressive, often diagnosed late, and remains the leading cause of death. Systemic options for unresectable disease are limited, and evidence for immunotherapy in EB is restricted to isolated reports. We present a case series of patients with RDEB-associated advanced cSCC treated with cemiplimab.
2026-02-20 | In vivo confocal microscopic evaluation of patients with epidermolysis bullosa demonstrates severe loss of corneal nerves.
Epidermolysis bullosa (EB) is a rare inherited genetic disorder associated with severe ocular surface complications and progressive corneal scarring. This case series aimed to structurally characterize and quantitatively analyze central corneal subbasal nerve plexus loss using in vivo confocal microscopy (IVCM) in pediatric patients with recessive dystrophic epidermolysis bullosa (RDEB). This retrospective case series included five pediatric patients with RDEB presenting with ocular and systemic manifestations. In vivo confocal microscopy (IVCM) imaging showed severe central subbasal corneal nerve plexus loss in 85% of eyes, with a median total nerve density of 0 μm/mm2 (IQR: 0-5150.67), main nerve trunk density of 0 μm/mm2 (IQR: 0-2720.56), and branch nerve density of 0 μm/mm2 (IQR: 0-2769.22). Dendritiform reflective structures were qualitatively observed in multiple scans of eyes demonstrating marked central subbasal nerve loss.No immunophenotyping was performed. Corneal sensation testing was not performed due to severe ocular surface fragility and photophobia; therefore, no clinical diagnosis or staging of NK was inferred or concluded from this cohort. This series identifies profound structural corneal denervation of the central subbasal plexus on IVCM in pediatric RDEB-associated ocular surface disease. The findings support future prospective studies investigating corneal nerve-regeneration and epithelial-stabilization frameworks to preserve long-term visual outcomes in children with RDEB.
2025-12-27 | First experience of the application of beremagene geperpavec genetically engineered drug for treatment of congenital dystrophic epidermolysis bullosa in the Russian Federation
Congenital epidermolysis bullosa (CEB) is a group of heterogenous, hereditary genetic diseases. Emergence of blisters and erosions on the skin, slight vulnerability of the skin cover, formation of disabling deformities and aggressive skin cancer development are the main clinical manifestations of this pathology. The disease is based on a hereditary genetic defect caused by one or several mutations in the COL7A gene, leading to an insufficient synthesis of type VII collagen functional protein (COL7), which contributes to the occurrence of persistent skin wounds and their infection. Generalized recessive dystrophic epidermolysis bullosa (RDEB) leading to death of patients at a young age is the most severe form of the disease. In the Russian Federation, symptomatic methods aimed at accelerating the healing of erosive and ulcerative skin defects and preventing the development of secondary infection and correcting complications are currently being used to treat patients with CEB, including RDEB. The article presents the first experience of treatment of a patient with RDEB with beremagene geperpavec genetically engineered drug in the Russian Federation. A male patient, 14 years old, with a verified congenital dystrophic epidermolysis bullosa, recessive type, Q81.1 diagnosis was under follow-up. Treatment was carried out at the North-East Clinic with the Children’s Center of the Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology (MSPCDC). Beremagene geperpavec gel was applied to the open wounds located on the skin of the back, right axillary region, inguinal folds, lower extremities. In total, 8 applications were done during 2 months. The treatment had a pronounced therapeutic effect, which manifested itself in complete epithelialization of the wound surfaces.
2025-12-26 | [Genetic analysis of a Chinese pedigree affected with Epidermolysis bullosa simplex due to a novel variant of KRT5 gene].
To investigate the clinical characteristics and genetic etiology of eight members from a pedigree affected with epidermolysis bullosa (EB). A girl presented with recurrent, unexplained blisters on the palmar and plantar skin for 8 years and sought medical care in October 2024 was enrolled as the study subject. A retrospective study was conducted to collect the child's clinical data, and a detailed medical history was taken for her family members. Peripheral venous blood samples were collected from the child and her parents for genomic DNA extraction. Whole-exome sequencing (WES) was performed. Candidate variant was validated by Sanger sequencing. The pathogenicity of the candidate variants was classified in accordance with the Standards and Guidelines for the Interpretation of Sequence Variants issued by the American College of Medical Genetics and Genomics (ACMG, hereinafter referred to as the "ACMG Guidelines"). This study was approved by the Medical Ethics Committee of the 980th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army (Ethics No.: 2019-KY-01). The proband was an 8-year-and-4-month-old female. Four months after birth, she had developed recurrent blisters on the palmar and plantar skin without obvious triggers, accompanied by significant pain. Symptoms were more severe in summer and slightly relieved in winter. Although symptomatic treatment could alleviate the symptoms, she was unable to participate in physical activities. A detailed family history revealed that her great-grandfather, grandfather, father, half-brother, great-aunt, great-aunt's son and two grandsons, as well as her aunt and aunt's son, had similar clinical manifestations. WES revealed that she has harbored a heterozygous c.556-16(IVS1)C>G (NM_000424.4) variant in the KRT5 gene, which was identified as a splice site mutation. Reverse transcription sequencing confirmed that this variant can disrupt normal splicing, resulting in retention of a 15 bp sequence in the first intron. Sanger sequencing demonstrated that the variant was inherited from the father, and the 6 aforementioned relatives with similar phenotypes have all carried the same variant (the great-grandfather, grandfather, and great-aunt had declined genetic testing due to advanced age). Based on the ACMG guidelines, this variant was classified as pathogenic (PS3+PM2_Supporting+PP3+PP1_strong). Patients with epidermolysis bullosa simplex may exhibit clinical features including blistering on the skin or mucous membranes of friction-prone sites (e.g. hands, feet, elbows, and knees) following minor trauma or friction, as well as increased skin fragility. The c.556-16(IVS1)C>G (rs376462752) variant of the KRT5 gene probably underlay the pathogenesis of EB in this child. Above findings have enriched the mutational spectrum of the KRT5 gene.
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Drug Discovery Landscape
49 orphan drug designations for Inherited epidermolysis bullosa, including 3 approved therapies.
49 orphan drug designations for Inherited epidermolysis bullosa, including 3 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
sterile, processed, homogenized amniotic fluid solution | other | FDA | 2025-09-12 | — | Eliksa Therapeutics, Inc. |
aseptic, allogeneic, pooled human umbilical cord derived mesenchymal stromal cells | cell therapies | FDA | 2025-01-06 | — | INmune Bio Inc. |
25 C-terminal amino acids of human thrombin | peptides | FDA | 2024-12-23 | — | Xinnate AB |
DNA plasmid containing the COL7A1 gene | gene therapies | EMA | 2024-05-17 | — | Branca Bunus Limited |
allantoin (5-ureidohydantoin or glyoxyldiureide) | small molecules | FDA | 2024-03-28 | — | Paradigm Therapeutics |
Adenine | gene therapies | EMA | 2024-01-12 | — | Raremoon Consulting Esp S.L. |
4-Hydroxy-4'-methyoxytolan | small molecules | FDA | 2023-05-01 | — | BioMendics, LLC |
Human decorin, natural anti-fibrotic protein, fused to the C-terminal vascular homing peptide tCRK | proteins | FDA | 2023-01-31 | — | Theravia |
Adenine | gene therapies | FDA | 2022-12-22 | — | Energenesis Biomedical Co. Ltd. |
Human decorin fused to the truncated homing peptide CRK | proteins | EMA | 2022-07-18 | — | THERAVIA |
Cannabidiol | small molecules | EMA | 2022-05-16 | — | Tetra Bio-Pharma Europe Limited |
Ribonucleoprotein complex composed of two sgRNA and a Cas9 nuclease targeting the human COL7A1 gene | gene editing enzymes | EMA | 2021-12-10 | — | Branca Bunus Limited |
epidermal stem cells genetically modified with a gamma-retroviral (rv) vector expressing the full-length LAMB3 cDNA | cell therapies | FDA | 2020-11-05 | — | Holostem S.r.l. |
Highly branched poly(beta-amino ester) complexed with a nanoplasmid containing the human COL7A1 gene | gene therapies | EMA | 2020-10-19 | — | Amryt Genetics Limited |
cannabidiol | small molecules | FDA | 2020-04-20 | — | Tetra Bio-Pharma Inc. |
delta-9-tetrahydrocannabinol and cannabidiol | small molecules | FDA | 2020-04-14 | — | Tetra Bio-Pharma Inc. |
Autologous skin equivalent graft composed of keratinocytes and fibroblasts genetically corrected by CRISPR/Cas9-mediated excision of mutation-carrying COL7A1 exon 80 | gene editing enzymes | EMA | 2020-02-28 | — | Consorcio Centro de Investigación Biomédica en Red |
Hypotonic, acid oxidizing solution containing hypochlorous acid (HClO) | small molecules | FDA | 2019-11-26 | — | APR Applied Pharma Research s.a. |
Diacerein | small molecules | EMA | 2019-05-29 | — | Worphmed S.r.l. |
Allogeneic skin-derived ABCB5-positive mesenchymal stem cells | cell therapies | EMA | 2019-05-29 | — | Rheacell GmbH & Co. KG |
allogeneic skin-derived ABCB5-positive mesenchymal stem cells | cell therapies | FDA | 2019-05-01 | — | RHEACELL GmbH & Co. KG |
Losartan | small molecules | EMA | 2019-02-26 | — | Crowd Pharma Losartan GmbH & Co. KG |
Losartan | small molecules | FDA | 2019-01-29 | — | Crowd Pharma Losartan GmbH & Co. KG |
Diacerein | small molecules | FDA | 2018-11-02 | — | WORPHMED Srl |
adipose-derived mesenchymal stem cells in a hydrogel sheet | cell therapies | FDA | 2018-10-25 | — | Anterogen Co., Ltd. |
ubidecarenone | small molecules | FDA | 2018-04-16 | — | BPGbio, Inc |
Genetically modified replication-incompetent herpes simplex virus-1 expressing collagen VII [Vyjuvek] | gene therapies | EMA | 2018-04-16 | 2025-04-24 | Krystal Biotech Netherlands B.V. |
ANTISENSE OLIGONUCLEOTIDE TARGETING EXON 73 IN THE COL7A1 GENE | oligonucleotides | EMA | 2017-11-08 | — | IDEA Innovative Drug European Associates (Ireland) Limited |
Asp-Arg-Val-Tyr-Ile-His-Pro | peptides | EMA | 2017-06-20 | — | Eliquent Life Sciences Limited |
Ex-vivo-expanded autologous keratinocytes transduced with retroviral vector containing the COL7A1 gene | cell therapies | EMA | 2017-02-27 | — | Pharma Gateway AB |
Autologous dermal fibroblasts genetically modified ex vivo with a lentiviral vector containing the human COL7A1 gene | gene therapies | EMA | 2016-04-28 | — | Intrexon Actobiotics N.V. |
Ex-vivo-expanded autologous fibroblasts transduced with lentiviral vector containing the COL7A1 gene | gene therapies | EMA | 2016-02-17 | — | Dr Waseem Qasim |
Ex-vivo-expanded autologous human keratinocytes containing epidermal stem cells transduced with a COL17A1-encoding retroviral vector | gene therapies | EMA | 2015-03-19 | — | Holostem S.r.l. |
Ex-vivo-expanded autologous human keratinocytes containing epidermal stem cells transduced with a LAMB3-encoding retroviral vector | gene therapies | EMA | 2015-03-19 | — | Holostem S.r.l. |
Ex-vivo-expanded autologous human keratinocytes containing epidermal stem cells transduced with a COL7A1-encoding retroviral vector | cell therapies | EMA | 2015-03-19 | — | Holostem S.r.l. |
Allogeneic adipose-derived adult mesenchymal stem cells contained in a fibrin-based bioengineered dermis | cell therapies | EMA | 2014-12-16 | — | Biodan Yelah S.L. |
diacerein | small molecules | FDA | 2014-10-15 | — | TWi Biotechnology, Inc. |
birch triterpenes [Filsuvez] | small molecules | FDA | 2014-08-07 | 2023-12-18 | Chiesi Farmaceutici S.p.A. |
Recombinant human alpha 1 chain homotrimer of type VII collagen | proteins | EMA | 2014-06-04 | — | Voisin Consulting Life Sciences |
Diacerein | small molecules | EMA | 2014-02-19 | — | FGK Representative Service GmbH |
Allantoin | small molecules | EMA | 2014-01-16 | — | Amicus Therapeutics Europe Limited |
Allogeneic neonatal dermal fibroblasts [Dermagraft] | cell therapies | EMA | 2011-06-21 | — | Shire Pharmaceuticals Ireland Limited |
Dry extract from birch bark (DER 5-10 : 1), extraction solvent n-heptane 95% (w/w) [Filsuvez] | small molecules | EMA | 2011-02-23 | 2022-06-23 | Chiesi Farmaceutici S.p.A. |
Dermagraft | cell therapies | FDA | 2010-12-13 | — | Shire Regenerative Medicine, Inc. |
Allogeneic human dermal fibroblasts | cell therapies | EMA | 2010-09-20 | — | Intercytex Ltd |
Bilayer engineered skin composed of keratinocytes from the patient (autologous) and fibroblasts from a donor (allogeneic) embedded in a plasma matrix | cell therapies | EMA | 2006-05-22 | — | Biodan Yelah S.L. |
Thymosin beta 4 | peptides | FDA | 2004-05-28 | — | HLB Therapeutics Co., Ltd |
allantoin | small molecules | FDA | 2002-11-21 | — | Scioderm, Inc. |
Metronidazole (topical) | — | FDA | 1987-11-24 | — | Searle |
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