RARE DISEASE
Epidermolysis bullosa acquisita
Epidermolysis bullosa acquisita
Epidermolysis bullosa acquisita
Synonyms: Acquired epidermolysis bullosa
Synonyms: Acquired epidermolysis bullosa
Synonyms: Acquired epidermolysis bullosa
Drug discovery
1
drug
With orphan designation
Overview
Epidermolysis bullosa acquisita (EBA) is a rare, chronic autoimmune subepidermal blistering disorder caused by IgG autoantibodies targeting type VII collagen, a critical component of dermal-epidermal anchoring fibrils. It manifests as trauma-induced blisters, mucosal involvement, and healing with scarring/milia. Diagnosis requires skin biopsy with direct immunofluorescence and salt-split indirect immunofluorescence. Treatment combines immunosuppression with meticulous wound care, but disease control remains challenging due to frequent resistance to therapy [1][2][7][12].
Population
Incidence: 0.08–0.5 cases/million/year, with higher rates in Germany (2.8/million) [2][12]
Onset: Bimodal peaks in early adulthood (20–30s) and later decades (50–70s); 5% pediatric cases [6][7][12]
Associations: Systemic lupus erythematosus, inflammatory bowel disease, and lichen planus (HR 3.1–26.9) [4][7][14]
Burden
Morbidity: Chronic scarring, nail dystrophy, ocular/corrosive mucosal lesions (50–65% of cases), and sepsis risk (HR 1.94) [4][7][12][14]
Cancer risk: 2.5× higher mortality vs. general population; squamous cell carcinoma in chronic lesions [4][9][12]
Quality of life: Severe pain, pruritus, and financial strain from wound care costs (~$20k/month in severe cases) [5][10][20]
Therapies
First-line: Systemic corticosteroids (0.5–2 mg/kg/day) ± dapsone or colchicine [1][2][7]
Refractory disease: Rituximab, IV immunoglobulin (IVIG), immunoadsorption, or cyclosporine; combination therapies show superior remission rates [3][8][14][18]
Supportive care: Infection prevention, non-adherent dressings, and nutritional support for mucosal lesions [6][10][12]
Categories: rare skin diseases
Research Papers
371 drug discovery papers about Epidermolysis bullosa acquisita, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
371 drug discovery papers about Epidermolysis bullosa acquisita, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-24 | Targeting neutrophil signaling networks in immune complex-mediated autoimmune disease
Abstract Fragment crystallizable gamma receptor (FcγR)-induced signaling is a crucial process that determines the cellular response to immune complexes (IC) in autoimmune diseases. In several diseases including pemphigoid diseases (PD), such as epidermolysis bullosa acquisita (EBA), or rheumatoid arthritis (RA), neutrophils are prominently involved as effector cells, while others such as immune thrombocytopenia (ITP) are independent of neutrophils. At the same time, most diseases are commonly treated by broad-range immunosuppression accompanied by severe risk for adverse effects. Signal transduction inhibitors (STIs) have been successfully applied in cancer therapy. However, their use in autoimmune diseases is an emerging, but so far understudied potential treatment avenue. Therefore, we screened a target-selective compound library consisting of 155 STIs in a neutrophil-based assay and conducted a multiplex kinase activity profiling with IC-stimulated neutrophils. Thus, we found novel potential therapeutic targets that were validated both in vitro in functional neutrophil assays and in vivo in murine models of EBA Here, we demonstrate that both systemic and topical treatment with several individual STIs is effective in a prophylactic approach in these models. Furthermore, therapeutic treatment with the BTK inhibitor ibrutinib in the immunization-induced EBA model reduced disease severity by approximately 85 % and showed efficacy in additional experimental models of EBA, arthritis, and ITP. Together, the present study contributes to the elucidation of FcγR-dependent signaling in neutrophils and identifies multiple novel promising treatment options including inhibition of PLC, PDK-1, PKC, p38, DNA-PK, KSP, c-Met, TBK-1 and BTK for IC-mediated autoimmune diseases.
2026-03-30 | Tyrosine kinase signaling pathways as therapeutic targets in autoimmune subepidermal blistering skin diseases (pemphigoid diseases).
Pemphigoid diseases, such as bullous pemphigoid and epidermolysis bullosa acquisita, are severe organ-specific autoimmune diseases characterized by subepidermal skin blistering with increasing incidence in recent years. Although there have been substantial advances in understanding the pathomechanism of these diseases in the last decades, and the first specific therapy targeting the IL-4 and IL-13 pathway (dupilumab) has been approved by the FDA for bullous pemphigoid, further research is needed to eventually improve patient care. The characteristics of pemphigoid diseases include the formation of immune complexes and their recognition by Fcγ-receptors, as well as the development of a characteristic inflammatory cytokine microenvironment in the skin of the affected patients. Several non-receptor tyrosine kinases are involved in these events, playing a very important role in various signaling processes of immune cells. While certain Src-family kinases and the Syk tyrosine kinase play a very important role in signaling by Fcγ-receptors, JAK-family kinases are crucial players in the signaling of various cytokine receptors including, among others, the receptors of IL-4 and IL-13. The inhibition of these tyrosine kinases with small molecule inhibitors is an emerging therapeutic option in the treatment of an increasing number of immune-mediated diseases. Moreover, numerous studies have been conducted to examine proteins (including PLCγ2 and CARD9) in signal transduction following Fcγ-receptor activation in in vitro and in vivo experimental pemphigoid models, and an increasing number of case studies involving JAK inhibitors report the successful application of these drugs in various pemphigoid diseases. This review summarizes our current understanding of the therapeutically most promising tyrosine kinase signaling pathways in the pathogenesis of pemphigoid diseases.
2026-03-14 | Mechanical Skin Stress-Induced Lesion Development via ATP-Amplified Neutrophil Extracellular Trap Formation
ABSTRACT Neutrophilic skin diseases, including Behçet disease, Sweet syndrome, pyoderma gangrenosum (PG), and epidermolysis bullosa acquisita (EBA), are characterized by an exaggerated inflammatory response following mechanical skin stimulation, yet the underlying mechanisms remain unclear. We identify adenosine triphosphate (ATP) released from keratinocytes as a key mediator of this phenomenon, promoting neutrophil extracellular trap (NET) formation. Using an EBA murine model as a model of neutrophilic skin disease, where scratching (a prototypic mechanical stimulation) exacerbates lesional severity, we observed abundant NET deposition in lesional skin. Degradation of these NETs with DNase1 reduced clinical and histopathological severities. In vitro, purified NET components increased IL-8 secretion from keratinocytes and fibroblasts, suggesting that NETs amplify inflammation via a self-amplifying loop of neutrophil recruitment. In the EBA mouse, scratch restriction with neck collars not only attenuated clinical and histological disease severities but also decreased lesional NETosis and neutrophils. Mechanistically, keratinocytes released ATP in response to mechanical stress in vitro, and pharmacologic purinergic blockade in the EBA mice with suramin phenocopied the protective effects of scratch restriction. While ATP alone did not induce NETosis, ATP enhanced complement component 5a (C5a)-induced NET formation in vitro. These findings indicate that keratinocyte-derived ATP, released in response to mechanical stress, contributes to NETosis in a C5a-dependent manner, thereby exaggerating neutrophilic inflammation, leading to blistering and further NETosis. Histopathological analyses of EBA and PG cases also demonstrated NETs accumulation localized to the upper dermis, suggesting a conserved ATP-NET axis. Targeting this pathway may represent a promising therapeutic strategy for neutrophilic skin diseases.
2026-02-12 | Moxifloxacin Inhibits Neutrophil Responses to Immune Complexes and Ameliorates Skin Inflammation in a Model of Pemphigoid Diseases.
Moxifloxacin, a fluoroquinolone antibiotic with immunomodulatory activity, has not been evaluated for effects on autoantibody-driven inflammation. Pemphigoid diseases are a group of autoimmune blistering skin diseases driven by pathogenic autoantibodies and granulocytes. With current treatments for pemphigoid diseases associated with substantial adverse effects, there is a high medical need for new treatment strategies. We investigated the effect of moxifloxacin on skin inflammation in the antibody transfer mouse model of bullous pemphigoid-like epidermolysis bullosa acquisita. Moxifloxacin attenuated skin inflammation in this model markedly. In vitro, moxifloxacin inhibited responses of neutrophils to fixed IgG immune complexes, including the release of leukotriene B4 (LTB4), a lipid mediator essential for disease propagation in this model. Moxifloxacin also reduced the maximal respiration rate of mitochondria and inhibited mitochondrial complex I. Consistent with a hypothetical direct link between mitochondrial complex I actions and the release of LTB4, the mitochondria-targeted antioxidant 10-(6'-plastoquinonyl)-decyltriphenylphosphonium (SkQ1; visomitin) reduced the immune complex-induced release of LTB4 from neutrophils dose-dependently. Collectively, our results demonstrate that moxifloxacin can ameliorate autoantibody-induced granulocytic skin inflammation. The disruption of select mitochondrial functions and of the immune complex-induced release of LTB4 from neutrophils might contribute to these therapeutic effects. Hence, moxifloxacin should be assessed as a drug for the treatment of patients with pemphigoid diseases.
2026-01-19 | Bruton tyrosine kinase (Btk) in neutrophils is indispensable for initiating and maintaining skin inflammation in a model of pemphigoid diseases.
Bruton tyrosine kinase (Btk) is essential for B cell function. Its role in myeloid cells is less understood. Greater insights into Btk significance in myeloid cells are needed to evaluate its potential as a therapeutic target during the effector phase of antibody-induced autoimmune diseases, where inhibiting autoantibody production suppresses tissue inflammation only after a delay. Such a situation can be observed, for example, in acute flares of pemphigoid diseases, a group of autoimmune blistering skin diseases. We examined the effect of neutrophil-specific Btk gene deficiency and of the Btk inhibitor ibrutinib on disease in the antibody-transfer model of bullous pemphigoid (BP)-like epidermolysis bullosa acquisita (EBA), a model that solely reflects the effector phase. We additionally investigated the effect of Btk inhibitors on responses of neutrophils relevant for autoimmune diseases in vitro. Both neutrophil-specific Btk deficiency and ibrutinib administration, systemic or topical, markedly protected against skin inflammation and disrupted established inflammation. Stimulation of murine neutrophils with immune complexes activated Btk and induced the release of leukotriene B4 (LTB4) and reactive oxygen species (ROS). Btk deficiency abolished LTB4 but not ROS release, indicating distinct signalling pathways regulating LTB4 and ROS following Fcγ receptor activation. Our findings demonstrate that EBA skin inflammation is critically controlled by a Fcγ receptor-Btk-LTB4 axis in neutrophils. This highlights Btk as promising drug target to treat EBA and potentially other antibody-induced autoimmune diseases.
cell therapies
2025-11-01 | Revitalizing Treg function in Epidermolysis bullosa acquisita: a promising therapeutic insight 2332
Abstract Description Epidermolysis bullosa acquisita (EBA) is a severe autoimmune blistering disease characterized by autoantibodies against type VII collagen (COL7). Neutrophils are the key effector cells of tissue destruction but regulatory T cells (Tregs) direct their recruitment and activation. In vitro experiments revealed a decrease of the effect of Tregs from EBA-diseased mice after transfer of anti-mCOL7 IgG in contrast to Treg from healthy mice on neutrophils and effector T cells. These findings suggest that Tregs may lose their function in EBA, similar to other autoimmune diseases. To deepen this understanding, we also performed RNA analysis of lesional skin and of Tregs isolated from lesional skin and lymph nodes of mice with experimental EBA. Whereas Tregs from lymph nodes showed no differences, Tregs isolated from lesional skin were significantly different in their gene expression profile compared to Tregs from healthy mice. In particular, gene expression related to T cell receptor, Th17 and Th1/Th2 differentiation was altered in Tregs from lesional skin showing the development of a possible instable phenotype of exhausted Tregs in EBA. To investigate a possible therapeutic impact of Tregs, adoptively transferred Tregs from healthy mice were administered prior disease induction utilizing the antibody transfer-induced mouse model of EBA. A significant reduction in clinical disease manifestation and reduction of neutrophils in the skin was observed by rescuing the Treg function in EBA. Funding Sources Supported by EXC 2167, SFB 1526, GRK 2633, all from the Deutsche Forschungsgemeinschaft. Topic Categories Basic Autoimmunity (BA)
2023-05-01 | 844 Improvement of in vivo survival of mesenchymal stromal cells in immunodeficient mice
Recessive dystrophic epidermolysis bullosa (RDEB) is one of the most severe skin diseases and is caused by loss-of-function mutations in COL7A1 encoding type VII collagen (C7). Patients with RDEB suffer since birth from skin and mucosal blistering and develop severe local and systemic complications resulting in a poor prognosis. Mesenchymal stromal cells (MSC) have demonstrated potential to improve wound healing and skin inflammation in RDEB patients due to their capacity to express C7 and their anti-inflammatory properties. The aim of this work is to optimize in vitro conditioning of human bone marrow-derived MSC (hBM-MSC) and to test several routes of administration in murine models in order to improve their survival. We first transduced healthy hBM-MSC with a dual reporter lentiviral vector expressing firefly luciferase and mCherry without modifying their MSC phenotype. Transduced hBM-MSC were cultured under different conditions prior to their delivery: subcutaneous, intradermal, intravenous or intra-arterial in immunodeficient mice. Survival and distribution of hBM-MSC in mice were assessed using the bioluminescent reporter by in vivo imaging. Local injections resulted in 90% cell death during the first 2 months. Interestingly, 10% of injected cells survived at least one year post-injection. We now plan to analyze this subpopulation by flow cytometry and single-cell RNAseq to determine whether these cells were already present in the injected population or whether they have acquired a new phenotype in vivo enabling better survival. After systemic injection, hBM-MSC were mainly detected in the lungs and were eliminated after 10 days. Interestingly, lung entrapment seemed to be less important with some cell culture conditioning. Optimization of in vitroconditioning and routes of administration of BM-MSC to improve their biodistribution and survival in murine models should contribute to better cell therapy protocols in the perspective of clinical translation for RDEB.
2023-03-01 | A scalable, GMP-compatible, autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa
Gene editing in induced pluripotent stem (iPS) cells has been hailed to enable new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa (DEB). However, manufacturing, efficacy and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies.We developed Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a new generation GMP-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7). DEBCT uses a combined high-efficiency reprogramming and CRISPR-based genetic correction single step to generate genome scar-free, COL7A1 corrected clonal iPS cells from primary patient fibroblasts. Validated iPS cells are converted into epidermal, dermal and melanocyte progenitors with a novel 2D organoid differentiation protocol, followed by CD49f enrichment and expansion to minimize maturation heterogeneity. iSC product characterization by single cell transcriptomics was followed by mouse xenografting for disease correcting activity at 1 month and toxicology analysis at 1-6 months. Culture-acquired mutations, potential CRISPR-off targets, and cancer-driver variants were evaluated by targeted and whole genome sequencing.iPS cell-derived iSC grafts were reproducibly generated from four recessive DEB patients with different pathogenic mutations. Organotypic iSC grafts onto immune-compromised mice developed into stable stratified skin with functional C7 restoration. Single cell transcriptomic characterization of iSCs revealed prominent holoclone stem cell signatures in keratinocytes and the recently described Gibbin-dependent signature in dermal fibroblasts. The latter correlated with enhanced graftability. Multiple orthogonal sequencing and subsequent computational approaches identified random and non-oncogenic mutations introduced by the manufacturing process. Toxicology revealed no detectable tumors after 3-6 months in DEBCT-treated mice.DEBCT successfully overcomes previous roadblocks and represents a robust, scalable, and safe cGMP manufacturing platform for production of a CRISPR-corrected autologous organotypic skin graft to heal DEB patient wounds.
2023-01-06 | Highly concentrated trehalose induces prohealing senescence-like state in fibroblasts via CDKN1A/p21
Trehalose is the nonreducing disaccharide of glucose, evolutionarily conserved in invertebrates. The living skin equivalent (LSE) is an organotypic coculture containing keratinocytes cultivated on fibroblast-populated dermal substitutes. We demonstrated that human primary fibroblasts treated with highly concentrated trehalose promote significantly extensive spread of the epidermal layer of LSE without any deleterious effects. The RNA-seq analysis of trehalose-treated 2D and 3D fibroblasts at early time points revealed the involvement of the CDKN1A pathway, the knockdown of which significantly suppressed the upregulation of DPT, ANGPT2, VEGFA, EREG, and FGF2. The trehalose-treated fibroblasts were positive for senescence-associated β-galactosidase. Finally, transplantation of the dermal substitute with trehalose-treated fibroblasts accelerated wound closure and increased capillary formation significantly in the experimental mouse wounds in vivo, which was canceled by the CDKN1A knockdown. These data indicate that high-concentration trehalose can induce the senescence-like state in fibroblasts via CDKN1A/p21, which may be therapeutically useful for optimal wound repair.
2022-11-18 | 566 DermaCult™ Keratinocyte Expansion Medium, a Serum- and BPE-free Medium Supporting Long-term Feeder-free Expansion of Primary Human Epidermal and Pluripotent Stem Cell-Derived Keratinocytes
Human epidermal keratinocytes (HEKs) typically undergo growth arrest after 15 - 30 population doublings (PDs) when maintained in traditional feeder-free culture medium formulations. To circumvent this early senescence, we developed DermaCult™ Keratinocyte Expansion Medium (KEM), a serum- and bovine pituitary extract (BPE)-free medium that promotes long-term growth (> 30 PDs) of HEKs while maintaining their air liquid interface (ALI) differentiation potential. To measure expansion over the lifespan of the culture, HEKs derived from neonatal (HEKn) or adult (HEKa) skin were thawed and seeded onto uncoated tissue cultureware at a density of 1 - 2.5 x 103 cells/cm2, and passaged once the cultures reached approximately 50 - 70% confluence. HEKs were assessed by qPCR and flow cytometry to detect the expression of cell markers of the basal and suprabasal epidermal layers. Differentiation potential was also assessed through ALI culture. DermaCult™ KEM supported 50 - 70 HEKa PDs and > 70 HEKn PDs before cell senescence (n = 4). HEKs cultured in DermaCult™ KEM maintained a cobblestone morphology, expressed basal cell markers (TP63, KRT14, ITGA6), and were devoid of suprabasal marker KRT10 (n = 4). In ALI culture, HEKs generated a stratified epithelium with the appropriate cellular architecture and expression of basal and suprabasal markers comparable to their in vivo counterparts (n = 2). Finally, keratinocytes obtained from human pluripotent stem cell (hPSC)-derived hair-bearing skin organoids and expanded in DermaCult™ KEM resembled those generated from primary HEKs, expressed basal keratinocyte markers (TP63, KRT14, KRT5), and sustained > 50 PDs before senescence (n = 4). In summary, DermaCult™ KEM is an improved serum- and BPE-free medium that supports the long-term expansion of primary and hPSC-derived HEKs while maintaining their downstream differentiation potential.
antibodies
2026-06-01 | Stenosing Esophageal Involvement in Acquired Epidermolysis Bullosa
Introduction Acquired epidermolysis bullosa (AEB) is a rare autoimmune subepidermal blistering disorder mediated by autoantibodies against type VII collagen. Mucosal lesions are frequent, but esophageal involvement remains exceptional. When present, it may cause progressive dysphagia linked to cicatricial strictures, with major nutritional impact and impaired quality of life. Case Report A 50-year-old man presented with bullous and post-bullous lesions on friction areas, associated with atrophic scarring and milia. Oral and nasal mucosal erosions were noted, with an 8-kg weight loss. Histopathology showed a subepidermal blister; direct immunofluorescence revealed linear IgG/C3 at the dermo-epidermal junction. ELISA demonstrated markedly elevated anti–type VII collagen antibodies and marginal anti-envoplakin positivity.Corticosteroids (0.5 mg/kg/day) were ineffective. Dapsone (100 mg/day) produced partial cutaneous improvement only. Endoscopy revealed a 7-cm circumferential mid-esophageal ulceration. Cyclosporine (3 mg/kg/day) induced transient improvement followed by progressive dysphagia.Repeat endoscopy showed an ulcerated cervical stricture with extensive mucosal detachment. Balloon dilation combined with high-dose corticosteroids and IVIG restored swallowing, improved weight, and prevented recurrence despite persistent mucosal fragility. Rituximab was subsequently initiated [ 1 ] [ 2 ] [ 3 ]. Discussion Esophageal involvement in AEB, although rare, represents a severe mucosal manifestation. Blistering, ulceration, and fibrotic strictures may occur, and endoscopy—while essential—is technically hazardous due to high mucosal fragility. Conventional therapies frequently fail to control severe mucosal disease. Endoscopic dilation is often required but carries procedural risks.Recent literature supports IVIG and rituximab as effective options in severe, refractory AEB, including stenosing esophageal forms, with favorable tolerance profiles. Conclusion Esophageal AEB necessitates individualized, multidisciplinary management. Biologic therapies offer promising perspectives for refractory and stenosing mucosal disease. Publication History Article published online: 05 June 2026 © 2026. European Society of Gastrointestinal Endoscopy. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-02-16 | The Changing Trends in the Incidence and Clinical Presentation of Immunobullous Disorders Before and During the COVID-19 Era in a Tertiary Healthcare Centre in Andhra Pradesh.
Background Autoimmune immunobullous disorders (AIBDs) represent a heterogeneous group of chronic blistering dermatoses mediated by autoantibodies against desmosomal and hemidesmosomal adhesion molecules. The COVID-19 pandemic has generated significant interest in the interaction between SARS-CoV-2 infection, vaccination-related immune modulation, and the clinical behaviour of autoimmune diseases. Objective This study's primary objective is to compare hospital-based temporal trends in the frequency, subtype distribution, and clinical presentation of AIBDs before and during the COVID-19 era in a tertiary healthcare centre in Andhra Pradesh. Secondary objectives included evaluation of changes in age at onset, sex distribution, mucosal and nail involvement, recurrence, and the emergence of atypical clinical morphologies requiring histopathology and direct immunofluorescence (DIF) for definitive diagnosis, as well as identification of independent predictors of subepidermal AIBD subtypes using multivariate logistic regression. Methods A retrospective observational analysis was performed on 42 histopathology and/or DIF-confirmed AIBD cases. Eighteen cases were recorded in the pre-COVID period (January 2018-December 2019) and 24 during the COVID era (January 2020-November 2023). Demographic trends, morphological patterns, mucosal involvement, anatomical distribution, severity, recurrence, and atypical phenotypes were compared between the two cohorts. Results A notable increase in overall incidence was observed during the COVID era (57.1%). Disease onset occurred at a younger age during COVID (mean 47.8 years) compared with the pre-COVID period (mean 53.6 years). Mucosal involvement increased from 33.3% pre-COVID to 50% during COVID. The COVID cohort exhibited higher recurrence rates and atypical morphology, including confluent mucosal and oesophageal lesions in epidermolysis bullosa acquisita, a "cluster of jewels" configuration and nail dystrophy in bullous pemphigoid, and healing with scarring and milia. These atypical patterns required more frequent reliance on biopsy and DIF for achieving a definitive diagnosis, as classical clinical presentation alone was insufficient. Conclusion The COVID-19 era was associated with both increased hospital-based case frequency and altered clinical expression of AIBDs, characterised by younger disease onset, greater mucosal involvement, and diagnostically challenging phenotypes. Possible contributors include post-COVID immune dysregulation, vaccination-associated immune activation, psychological stress, and lifestyle changes. Intensified clinical vigilance, early DIF-based confirmation, and timely initiation of steroid-sparing immunomodulatory therapy are essential to optimise outcomes in the evolving post-pandemic context.
2025-12-15 | A systematic review of therapeutic and paradoxical roles of tumor necrosis factor α inhibitors in autoimmune blistering diseases.
Autoimmune blistering diseases (AIBDs), including pemphigus diseases, pemphigoid diseases, linear immunoglobulin A (IgA) bullous dermatosis (LABD), epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH), are a group of diseases clinically characterized by erosions and blisters that involve the skin and mucosa. Tumor necrosis factor-alpha (TNF-α), a key inflammatory cytokine, plays a critical role in their pathogenesis. TNF-α inhibitors are used for their immunomodulatory effects but may also induce paradoxical autoimmune blistering. This systematic review aimed to synthesize current evidence on therapeutic and paradoxical effects of TNF-α inhibitors in these diseases. A systematic search of PubMed, Scopus, and Embase was conducted up to March 7th, 2025, following PRISMA guidelines. Studies eligible for inclusion were original human research articles in English reporting therapeutic or paradoxical effects of TNF-α inhibitors, including infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab, on autoimmune bullous diseases. Risk of bias was evaluated using the NIH and Murad et al. assessment tools. A total of 35 studies with 68 patients were included in the treatment application group and 29 studies with 31 subjects were included in the paradoxical reaction group. Infliximab was most frequently associated with favorable outcomes in pemphigus vulgaris (PV), bullous pemphigoid (BP), and EBA, with multiple reports of sustained remission. Etanercept showed partial to complete responses in some cases of PV and BP; however, it was associated with paradoxical induction of BP in several patients. Adalimumab demonstrated therapeutic efficacy in PV and MMP, yet was the most common agent implicated in paradoxical BP and LABD. Paradoxical effects were most often observed in patients treated for non-dermatologic conditions such as rheumatoid arthritis or Crohn's disease. TNF-α inhibitors, particularly infliximab, show therapeutic promise in refractory AIBDs. However, their potential to paradoxically induce blistering diseases, especially with adalimumab and etanercept, necessitates careful patient selection, close monitoring, and individualized risk-benefit assessment.
2025-11-07 | Successful Treatment of Epidermolysis Bullosa Acquisita with Dupilumab
Epidermolysis Bullosa Acquisita (EBA) is a rare, autoimmune blistering disease which can impact both the skin and mucous membranes. It is not inherited and typically impacts older adults. Not all patients with EBA respond positively to treatment. We are reporting what we believe to be the third case of EBA treated successfully with dupilumab.
2025-10-07 | Type VII Collagen Disorders Simplified.
Epidermolysis bullosa acquisita (EBA) and bullous systemic lupus erythematosus (BSLE) are autoimmune mechanobullous diseases that are caused by autoantibodies directed against type VII collagen. The functionality of type VII collagen is vital to the skin and mucous membranes because it makes up the anchoring fibrils that adhere the epithelium to the underlying connective tissue. Dystrophic epidermolysis bullosa (DEB), which bears some clinical similarities to EBA and BSLE, is caused by mutations in the type VII collagen gene (COL7A1) that may be dominant or recessive, leading to partial or total loss of the anchoring fibrils. Differentiating all 3 of these rare diagnoses variably requires thorough personal and family histories, histopathology, immunopathology, autoantibody profile, electron microscopy, and gene mutation analysis. Treatment of EBA and BSLE involves antineutrophil and immunosuppressive drugs that often give unsatisfactory responses. Rituximab has been successful in resistant cases. Until recently, the treatment of DEB and other heritable epidermolysis bullosa (EB) diseases caused by disparate mutations was limited to supportive care, prevention of trauma to skin and wound infections, regular dressing changes, and skin cancer surveillance. Three major treatment advances recently were approved for DEB and junctional EB.
proteins
2026-05-08 | HLA genotype, clinical and immunofluorescence findings of 30 patients with type VII collagen antibody positive subepidermal bullous disease.
Epidermolysis bullosa acquisita (EBA) and mucous membrane pemphigoid are mucocutaneous blistering disorders that are associated with antibodies that target type VII collagen (anti-col7). There are relatively few studies that closely investigate the clinical phenotype and HLA genotype of patients who are anti-col7 positive. We therefore characterized all patients with anti-col7-positive subepidermal bullous disease that were treated at our centre. In total, 30 patients were identified, 29 had mechanobullous skin lesions and all had oral ulceration. The most common sites for oral lesions were the tongue, lip and palatal mucosa. Laryngeal and oesophageal lesions were seen in five and six patients, respectively. Oesophageal involvement was associated with erosions and stricture formation in the cervical or thoracic oesophagus and the majority of patients with oesophageal involvement had concomitant bullous pemphigoid180/230 antibodies and were of Black African ancestry. IgA deposition on direct immunofluorescence was associated with lower age at disease onset but did not correlate with clinical features or autoantibody profiles. Concomitant BP180/230 antibody positivity was associated with earlier disease onset and Black African ancestry. HLA genotyping was performed in 18 patients and demonstrated HLA-DQB1*03 and HLA-DQB1*06 alleles were most commonly associated with anti-col7 EBA. HLA genotype did not, however, correlate with clinical features of autoantibody profiles. Taken together, this study demonstrates that concomitant BP180/230 and anti-col7 antibodies are associated with earlier disease onset, Black African ancestry and potentially oesophageal involvement.
2025-09-23 | A Rare Clinical Association of Type I Hereditary Angioedema and Acquired Epidermolysis Bullosa: A Case Report
Introduction. Both hereditary angioedema (HAE) and acquired epidermolysis bullosa (AEB) are extremely rare disorders, and their coexistence in a single patient is unique. Awareness of this exceptional association can aid in timely diagnosis and guide safe, individualized treatment strategies. Case Report. We present a case of a 38-year-old female with co-occurring type I HAE, associated with a heterozygous SERPING1 variant c.425T>C (p.Leu142Ser) of uncertain significance previously reported in individuals with angioedema, and a rare autoimmune subepidermal blistering disorder mediated by autoantibodies against type VII collagen – AEB. Since adolescence, the patient had experienced recurrent limb edema and atypical dermatological manifestations, including macules, vesicles, and bullae, predominantly in areas exposed to mechanical stress and frequently resulting in scar formation. The disease course later progressed with an episode of acute laryngeal edema following a dental procedure. Laboratory evaluation confirmed a critically low level of C1-inhibitor and an almost complete depletion of C4 in plasma, indicating chronic activation of the classical complement pathway. Given the frequent exacerbations and severe clinical course, long-term prophylactic therapy with intravenous C1-INH (1,000 IU twice weekly) was initiated. This treatment regimen led to sustained clinical remission, resolution of angioedema episodes, notable improvement in dermatologic symptoms of AEB, and a substantial enhancement in overall quality of life. Conclusions. The coexistence of HAE and AEB is exceptionally rare, with no prior cases identified. Complement dysregulation may link these conditions, underscoring the importance of considering autoimmune blistering disorders in HAE patients with atypical skin manifestations. This case highlights a potential role for complement-targeted therapies, warranting further clinical investigation.
2025-06-12 | Epidermolysis Bullosa Acquisita due to Epitope Spreading in a Patient With Recurrent Bullous Pemphigoid
The data that support the findings of this study are available from the corresponding author upon reasonable request.
2025-04-03 | Epidermolysis Bullosa Acquisita as a Rare Late-Onset Immune-Related Adverse Event after Anti-PD-1-Based Immunotherapy: Case Presentation and Review of the Literature
Background: Epidermolysis bullosa acquisita (EBA) is a rare autoimmune blistering disease caused by autoantibodies targeting type VII collagen (COL7), a component of anchoring fibrils in the basement membrane zone. These autoantibodies lead to subepidermal cleavage, resulting in skin and mucosal fragility. Although EBA has been linked to infections, autoimmune diseases, and hematologic conditions, drug-induced EBA is poorly understood.
2025-04-01 | A histopathological study of vesiculobullous skin lesions in a tertiary care hospital in Chhattisgarh, India
Abstract Background: Vesiculobullous skin lesions (VBLs) encompass a heterogeneous group of dermatological disorders, each with distinct clinical and pathological characteristics. Skin punch biopsy remains a fundamental diagnostic tool in evaluating these lesions. Histopathological examination is vital in confirming the diagnosis, guiding targeted therapy, and improving clinical outcomes. Aims and Objectives: To analyze the histopathological features, distribution patterns, and clinicopathological correlations of VBLs over 2 years. Materials and Methods: This study was conducted in the Department of Pathology between June 2022 and May 2024. It included all skin punch biopsies received from patients of all age groups presenting with vesiculobullous lesions during the study period. Results: A total of 84 cases were examined, comprising 32 males and 52 females, with a male-to-female ratio of 1:1.6. Patients were aged 22 to 73 years, with the highest incidence observed in the 31–40-year age group (42 cases). The mean patient age was 38 years. Pemphigus vulgaris (PV) was the most frequently diagnosed condition, accounting for 42 cases, followed by pemphigus foliaceus accounting for 24 cases. Bullous pemphigoid was seen in seven cases, while erythema multiforme accounted for three cases. Rare conditions such as epidermolysis bullosa acquisita, subepidermal bullous lesions, lichen planus pemphigoid, and Darier disease were identified in two cases. Conclusion: The study highlighted a slight female predominance among patients with VBLs, with the 31–40-year age group most commonly affected. The extremities were the most frequent site of involvement. PV emerged as the predominant vesiculobullous disorder in this cohort. The limitation of our study includes the lack of immunofluorescence in our center and single-institute data.
other
2025-05-16 | Wound Care in Blistering Diseases
Blistering conditions manifest with fluid-filled skin lesions, vesicles, and bullae, often leading to erosions covered by crusts. These conditions encompass both inherited and acquired disorders, some frequent and other rare, some mild and other severe, possibly life endangering. Autoimmune blistering diseases can be caused by immune system dysfunction. Management aims to alleviate pain, prevent infections, and promote epithelialization, often involving immunosuppressive medications. Wound care presents challenges due to skin fragility and immunosuppressive effects of the medication, necessitating gentle cleaning, appropriate drainage techniques, and protective dressings. Topical treatments and oral care are integral, alongside pain management and infection monitoring. Stevens-Johnson syndrome and toxic epidermal necrolysis, drug-related mucocutaneous diseases, demand meticulous care to prevent epidermal detachment and infection. Inherited epidermolysis bullosa poses challenges in wound healing due to skin fragility, requiring specialized wound care approaches. Research into novel therapies, such as gene therapy, offers hope for improved management. Multidisciplinary care, nutritional support, and preventive strategies, particularly in neonates, are crucial for optimizing outcomes. Understanding the complexities of blistering conditions and tailoring management strategies are paramount in enhancing patient care and quality of life.
2016-06-11 | Highly branched poly(β-amino ester)s for skin gene therapy
Poly(β-amino ester)s (PAEs) have emerged as a promising class of gene delivery vectors with performances that can even be compared to viruses. However, all of the transfection studies (over 2350 PAEs) have been limited to linear poly(β-amino ester)s (LPAEs) despite increasing evidence that polymer structure significantly affects performance. Herein, we describe the development of highly branched poly(β-amino ester)s (HPAEs) via a new "A2+B3+C2" Michael addition approach demonstrating 2 to 126-fold higher in vitro transfection efficiencies of different cell types in comparison to their linear LPAE counterparts as well as greatly out-performing the leading transfection reagents SuperFect and the "gold-standard" polyethyleneimine (PEI) - especially on skin epidermal cells. More importantly, the ability to correct a skin genetic defect is demonstrated in vivo utilizing a recessive dystrophic epidermolysis bullosa (RDEB) knockout mouse model. Our results provide evidence that the "A2+B3+C2" approach can be controlled and offers sufficient flexibility for the synthesis of HPAEs. The branched structures can significantly improve the transfection efficiency and safety of PAEs highlighting the great promise for the successful application of non-viral gene therapy in skin disease.
2005-05-03 | Assessment of optimal transduction of primary human skin keratinocytes by viral vectors
Abstract Background Genetically modified keratinocytes generate transplantable self‐renewing epithelia suitable for delivery of therapeutic polypeptides. However, the variety of viral vectors and experimental conditions currently used make fragmented or contradictory the information on the transduction efficiency of the human primary keratinocytes. To compare the suitability of the most currently used viral vectors for efficient gene transfer to human keratinocytes, we have performed a comparative study using a panel of recombinant constructs. Methods For each vector, the transduction efficiency and the persistence of the transgene expression were quantified by fluorescence microscopy and flow cytometry analysis of the infected cells. Results We show that: (1) canine and human adenoviral vectors achieve a highly efficient but transient transduction of both primary and immortalized keratinocytes; (2) the adenovirus‐associated virus (AAV) vectors transduce immortalized keratinocytes, albeit with a short‐lived gene expression (<4 days), but fail to infect primary keratinocytes; and (3) under appropriate conditions, the oncoretroviral and lentiviral vectors can permanently transduce up to 100% of primary keratinocytes, but the highly clonogenic keratinocytes are more efficiently targeted by lentiviral vectors. Conclusions Therefore, AAV vectors are unsuitable to transduce primary keratinocytes, while human and canine adenoviral vectors appears to be appropriate to achieve short‐term delivery of therapeutic products. Recombinant retroviruses provide sustained expression of the transgene, but the lentiviral vectors are the most suitable for ex vivo gene therapy because of their ability to transduce clonogenic primary keratinocytes. Copyright © 2005 John Wiley & Sons, Ltd.
2003-10-24 | A Comparison of Targeting Performance of Oncoretroviral Versus Lentiviral Vectors on Human Keratinocytes
The epidermis, like other rapidly renewing tissues, relies on a stem cell compartment to undergo constant regeneration. In order to develop realistic and long-lasting therapeutic approaches for some skin disorders, gene transfer to these critical cells must be obtained. While efficient retroviral ex vivo targeting and transgene integration in human keratinocytes is tightly dependent on proliferation, transferring genetic information to quiescent cells in culture also presents advantages, including the possibility of targeting putative dormant epidermal stem cells. In the present study we compared the efficiency of transduction achieved with a third-generation of human immunodeficiency virus (HIV)-based lentiviral vector to that obtained with a Moloney murine leukemia oncoretroviral vector (MLV) on proliferating and quiescent human keratinocytes growing in vitro in standard Rheinwald and Green cultures as well as in confluent organotypic cultures. Each viral vector contained the enhanced green fluorescent protein (EGFP) as a reporter gene. The lentiviral vector, but not the MLV vector, led to EGFP expression both in nondividing and proliferating epidermal cell populations in vitro. This feature was clearly evident when direct targeting of human keratinocytes, forming part of the epidermal component of an organotypic skin culture, was attempted. Keratinocytes modified by both MLV and the lentiviral vector allowed long-term regeneration of genetically engineered human skin on the backs of immunodeficient nonobese diabetic/severe combined immunodeficiency disorders (NOD/SCID) mice. However, EGFP transgene expression in the context of the MLV (long-terminal repeat [LTR]-driven) or lentiviral vector (cytomegalovirus [CMV]-driven) demonstrated clear differences both in quantitative terms and in the in vivo localization pattern.
small molecules
2026-07-24 | Targeting neutrophil signaling networks in immune complex-mediated autoimmune disease
Abstract Fragment crystallizable gamma receptor (FcγR)-induced signaling is a crucial process that determines the cellular response to immune complexes (IC) in autoimmune diseases. In several diseases including pemphigoid diseases (PD), such as epidermolysis bullosa acquisita (EBA), or rheumatoid arthritis (RA), neutrophils are prominently involved as effector cells, while others such as immune thrombocytopenia (ITP) are independent of neutrophils. At the same time, most diseases are commonly treated by broad-range immunosuppression accompanied by severe risk for adverse effects. Signal transduction inhibitors (STIs) have been successfully applied in cancer therapy. However, their use in autoimmune diseases is an emerging, but so far understudied potential treatment avenue. Therefore, we screened a target-selective compound library consisting of 155 STIs in a neutrophil-based assay and conducted a multiplex kinase activity profiling with IC-stimulated neutrophils. Thus, we found novel potential therapeutic targets that were validated both in vitro in functional neutrophil assays and in vivo in murine models of EBA Here, we demonstrate that both systemic and topical treatment with several individual STIs is effective in a prophylactic approach in these models. Furthermore, therapeutic treatment with the BTK inhibitor ibrutinib in the immunization-induced EBA model reduced disease severity by approximately 85 % and showed efficacy in additional experimental models of EBA, arthritis, and ITP. Together, the present study contributes to the elucidation of FcγR-dependent signaling in neutrophils and identifies multiple novel promising treatment options including inhibition of PLC, PDK-1, PKC, p38, DNA-PK, KSP, c-Met, TBK-1 and BTK for IC-mediated autoimmune diseases.
2026-03-30 | Tyrosine kinase signaling pathways as therapeutic targets in autoimmune subepidermal blistering skin diseases (pemphigoid diseases).
Pemphigoid diseases, such as bullous pemphigoid and epidermolysis bullosa acquisita, are severe organ-specific autoimmune diseases characterized by subepidermal skin blistering with increasing incidence in recent years. Although there have been substantial advances in understanding the pathomechanism of these diseases in the last decades, and the first specific therapy targeting the IL-4 and IL-13 pathway (dupilumab) has been approved by the FDA for bullous pemphigoid, further research is needed to eventually improve patient care. The characteristics of pemphigoid diseases include the formation of immune complexes and their recognition by Fcγ-receptors, as well as the development of a characteristic inflammatory cytokine microenvironment in the skin of the affected patients. Several non-receptor tyrosine kinases are involved in these events, playing a very important role in various signaling processes of immune cells. While certain Src-family kinases and the Syk tyrosine kinase play a very important role in signaling by Fcγ-receptors, JAK-family kinases are crucial players in the signaling of various cytokine receptors including, among others, the receptors of IL-4 and IL-13. The inhibition of these tyrosine kinases with small molecule inhibitors is an emerging therapeutic option in the treatment of an increasing number of immune-mediated diseases. Moreover, numerous studies have been conducted to examine proteins (including PLCγ2 and CARD9) in signal transduction following Fcγ-receptor activation in in vitro and in vivo experimental pemphigoid models, and an increasing number of case studies involving JAK inhibitors report the successful application of these drugs in various pemphigoid diseases. This review summarizes our current understanding of the therapeutically most promising tyrosine kinase signaling pathways in the pathogenesis of pemphigoid diseases.
2026-03-14 | Mechanical Skin Stress-Induced Lesion Development via ATP-Amplified Neutrophil Extracellular Trap Formation
ABSTRACT Neutrophilic skin diseases, including Behçet disease, Sweet syndrome, pyoderma gangrenosum (PG), and epidermolysis bullosa acquisita (EBA), are characterized by an exaggerated inflammatory response following mechanical skin stimulation, yet the underlying mechanisms remain unclear. We identify adenosine triphosphate (ATP) released from keratinocytes as a key mediator of this phenomenon, promoting neutrophil extracellular trap (NET) formation. Using an EBA murine model as a model of neutrophilic skin disease, where scratching (a prototypic mechanical stimulation) exacerbates lesional severity, we observed abundant NET deposition in lesional skin. Degradation of these NETs with DNase1 reduced clinical and histopathological severities. In vitro, purified NET components increased IL-8 secretion from keratinocytes and fibroblasts, suggesting that NETs amplify inflammation via a self-amplifying loop of neutrophil recruitment. In the EBA mouse, scratch restriction with neck collars not only attenuated clinical and histological disease severities but also decreased lesional NETosis and neutrophils. Mechanistically, keratinocytes released ATP in response to mechanical stress in vitro, and pharmacologic purinergic blockade in the EBA mice with suramin phenocopied the protective effects of scratch restriction. While ATP alone did not induce NETosis, ATP enhanced complement component 5a (C5a)-induced NET formation in vitro. These findings indicate that keratinocyte-derived ATP, released in response to mechanical stress, contributes to NETosis in a C5a-dependent manner, thereby exaggerating neutrophilic inflammation, leading to blistering and further NETosis. Histopathological analyses of EBA and PG cases also demonstrated NETs accumulation localized to the upper dermis, suggesting a conserved ATP-NET axis. Targeting this pathway may represent a promising therapeutic strategy for neutrophilic skin diseases.
2026-02-12 | Moxifloxacin Inhibits Neutrophil Responses to Immune Complexes and Ameliorates Skin Inflammation in a Model of Pemphigoid Diseases.
Moxifloxacin, a fluoroquinolone antibiotic with immunomodulatory activity, has not been evaluated for effects on autoantibody-driven inflammation. Pemphigoid diseases are a group of autoimmune blistering skin diseases driven by pathogenic autoantibodies and granulocytes. With current treatments for pemphigoid diseases associated with substantial adverse effects, there is a high medical need for new treatment strategies. We investigated the effect of moxifloxacin on skin inflammation in the antibody transfer mouse model of bullous pemphigoid-like epidermolysis bullosa acquisita. Moxifloxacin attenuated skin inflammation in this model markedly. In vitro, moxifloxacin inhibited responses of neutrophils to fixed IgG immune complexes, including the release of leukotriene B4 (LTB4), a lipid mediator essential for disease propagation in this model. Moxifloxacin also reduced the maximal respiration rate of mitochondria and inhibited mitochondrial complex I. Consistent with a hypothetical direct link between mitochondrial complex I actions and the release of LTB4, the mitochondria-targeted antioxidant 10-(6'-plastoquinonyl)-decyltriphenylphosphonium (SkQ1; visomitin) reduced the immune complex-induced release of LTB4 from neutrophils dose-dependently. Collectively, our results demonstrate that moxifloxacin can ameliorate autoantibody-induced granulocytic skin inflammation. The disruption of select mitochondrial functions and of the immune complex-induced release of LTB4 from neutrophils might contribute to these therapeutic effects. Hence, moxifloxacin should be assessed as a drug for the treatment of patients with pemphigoid diseases.
2026-01-19 | Bruton tyrosine kinase (Btk) in neutrophils is indispensable for initiating and maintaining skin inflammation in a model of pemphigoid diseases.
Bruton tyrosine kinase (Btk) is essential for B cell function. Its role in myeloid cells is less understood. Greater insights into Btk significance in myeloid cells are needed to evaluate its potential as a therapeutic target during the effector phase of antibody-induced autoimmune diseases, where inhibiting autoantibody production suppresses tissue inflammation only after a delay. Such a situation can be observed, for example, in acute flares of pemphigoid diseases, a group of autoimmune blistering skin diseases. We examined the effect of neutrophil-specific Btk gene deficiency and of the Btk inhibitor ibrutinib on disease in the antibody-transfer model of bullous pemphigoid (BP)-like epidermolysis bullosa acquisita (EBA), a model that solely reflects the effector phase. We additionally investigated the effect of Btk inhibitors on responses of neutrophils relevant for autoimmune diseases in vitro. Both neutrophil-specific Btk deficiency and ibrutinib administration, systemic or topical, markedly protected against skin inflammation and disrupted established inflammation. Stimulation of murine neutrophils with immune complexes activated Btk and induced the release of leukotriene B4 (LTB4) and reactive oxygen species (ROS). Btk deficiency abolished LTB4 but not ROS release, indicating distinct signalling pathways regulating LTB4 and ROS following Fcγ receptor activation. Our findings demonstrate that EBA skin inflammation is critically controlled by a Fcγ receptor-Btk-LTB4 axis in neutrophils. This highlights Btk as promising drug target to treat EBA and potentially other antibody-induced autoimmune diseases.
cell therapies
2025-11-01 | Revitalizing Treg function in Epidermolysis bullosa acquisita: a promising therapeutic insight 2332
Abstract Description Epidermolysis bullosa acquisita (EBA) is a severe autoimmune blistering disease characterized by autoantibodies against type VII collagen (COL7). Neutrophils are the key effector cells of tissue destruction but regulatory T cells (Tregs) direct their recruitment and activation. In vitro experiments revealed a decrease of the effect of Tregs from EBA-diseased mice after transfer of anti-mCOL7 IgG in contrast to Treg from healthy mice on neutrophils and effector T cells. These findings suggest that Tregs may lose their function in EBA, similar to other autoimmune diseases. To deepen this understanding, we also performed RNA analysis of lesional skin and of Tregs isolated from lesional skin and lymph nodes of mice with experimental EBA. Whereas Tregs from lymph nodes showed no differences, Tregs isolated from lesional skin were significantly different in their gene expression profile compared to Tregs from healthy mice. In particular, gene expression related to T cell receptor, Th17 and Th1/Th2 differentiation was altered in Tregs from lesional skin showing the development of a possible instable phenotype of exhausted Tregs in EBA. To investigate a possible therapeutic impact of Tregs, adoptively transferred Tregs from healthy mice were administered prior disease induction utilizing the antibody transfer-induced mouse model of EBA. A significant reduction in clinical disease manifestation and reduction of neutrophils in the skin was observed by rescuing the Treg function in EBA. Funding Sources Supported by EXC 2167, SFB 1526, GRK 2633, all from the Deutsche Forschungsgemeinschaft. Topic Categories Basic Autoimmunity (BA)
2023-05-01 | 844 Improvement of in vivo survival of mesenchymal stromal cells in immunodeficient mice
Recessive dystrophic epidermolysis bullosa (RDEB) is one of the most severe skin diseases and is caused by loss-of-function mutations in COL7A1 encoding type VII collagen (C7). Patients with RDEB suffer since birth from skin and mucosal blistering and develop severe local and systemic complications resulting in a poor prognosis. Mesenchymal stromal cells (MSC) have demonstrated potential to improve wound healing and skin inflammation in RDEB patients due to their capacity to express C7 and their anti-inflammatory properties. The aim of this work is to optimize in vitro conditioning of human bone marrow-derived MSC (hBM-MSC) and to test several routes of administration in murine models in order to improve their survival. We first transduced healthy hBM-MSC with a dual reporter lentiviral vector expressing firefly luciferase and mCherry without modifying their MSC phenotype. Transduced hBM-MSC were cultured under different conditions prior to their delivery: subcutaneous, intradermal, intravenous or intra-arterial in immunodeficient mice. Survival and distribution of hBM-MSC in mice were assessed using the bioluminescent reporter by in vivo imaging. Local injections resulted in 90% cell death during the first 2 months. Interestingly, 10% of injected cells survived at least one year post-injection. We now plan to analyze this subpopulation by flow cytometry and single-cell RNAseq to determine whether these cells were already present in the injected population or whether they have acquired a new phenotype in vivo enabling better survival. After systemic injection, hBM-MSC were mainly detected in the lungs and were eliminated after 10 days. Interestingly, lung entrapment seemed to be less important with some cell culture conditioning. Optimization of in vitroconditioning and routes of administration of BM-MSC to improve their biodistribution and survival in murine models should contribute to better cell therapy protocols in the perspective of clinical translation for RDEB.
2023-03-01 | A scalable, GMP-compatible, autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa
Gene editing in induced pluripotent stem (iPS) cells has been hailed to enable new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa (DEB). However, manufacturing, efficacy and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies.We developed Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a new generation GMP-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7). DEBCT uses a combined high-efficiency reprogramming and CRISPR-based genetic correction single step to generate genome scar-free, COL7A1 corrected clonal iPS cells from primary patient fibroblasts. Validated iPS cells are converted into epidermal, dermal and melanocyte progenitors with a novel 2D organoid differentiation protocol, followed by CD49f enrichment and expansion to minimize maturation heterogeneity. iSC product characterization by single cell transcriptomics was followed by mouse xenografting for disease correcting activity at 1 month and toxicology analysis at 1-6 months. Culture-acquired mutations, potential CRISPR-off targets, and cancer-driver variants were evaluated by targeted and whole genome sequencing.iPS cell-derived iSC grafts were reproducibly generated from four recessive DEB patients with different pathogenic mutations. Organotypic iSC grafts onto immune-compromised mice developed into stable stratified skin with functional C7 restoration. Single cell transcriptomic characterization of iSCs revealed prominent holoclone stem cell signatures in keratinocytes and the recently described Gibbin-dependent signature in dermal fibroblasts. The latter correlated with enhanced graftability. Multiple orthogonal sequencing and subsequent computational approaches identified random and non-oncogenic mutations introduced by the manufacturing process. Toxicology revealed no detectable tumors after 3-6 months in DEBCT-treated mice.DEBCT successfully overcomes previous roadblocks and represents a robust, scalable, and safe cGMP manufacturing platform for production of a CRISPR-corrected autologous organotypic skin graft to heal DEB patient wounds.
2023-01-06 | Highly concentrated trehalose induces prohealing senescence-like state in fibroblasts via CDKN1A/p21
Trehalose is the nonreducing disaccharide of glucose, evolutionarily conserved in invertebrates. The living skin equivalent (LSE) is an organotypic coculture containing keratinocytes cultivated on fibroblast-populated dermal substitutes. We demonstrated that human primary fibroblasts treated with highly concentrated trehalose promote significantly extensive spread of the epidermal layer of LSE without any deleterious effects. The RNA-seq analysis of trehalose-treated 2D and 3D fibroblasts at early time points revealed the involvement of the CDKN1A pathway, the knockdown of which significantly suppressed the upregulation of DPT, ANGPT2, VEGFA, EREG, and FGF2. The trehalose-treated fibroblasts were positive for senescence-associated β-galactosidase. Finally, transplantation of the dermal substitute with trehalose-treated fibroblasts accelerated wound closure and increased capillary formation significantly in the experimental mouse wounds in vivo, which was canceled by the CDKN1A knockdown. These data indicate that high-concentration trehalose can induce the senescence-like state in fibroblasts via CDKN1A/p21, which may be therapeutically useful for optimal wound repair.
2022-11-18 | 566 DermaCult™ Keratinocyte Expansion Medium, a Serum- and BPE-free Medium Supporting Long-term Feeder-free Expansion of Primary Human Epidermal and Pluripotent Stem Cell-Derived Keratinocytes
Human epidermal keratinocytes (HEKs) typically undergo growth arrest after 15 - 30 population doublings (PDs) when maintained in traditional feeder-free culture medium formulations. To circumvent this early senescence, we developed DermaCult™ Keratinocyte Expansion Medium (KEM), a serum- and bovine pituitary extract (BPE)-free medium that promotes long-term growth (> 30 PDs) of HEKs while maintaining their air liquid interface (ALI) differentiation potential. To measure expansion over the lifespan of the culture, HEKs derived from neonatal (HEKn) or adult (HEKa) skin were thawed and seeded onto uncoated tissue cultureware at a density of 1 - 2.5 x 103 cells/cm2, and passaged once the cultures reached approximately 50 - 70% confluence. HEKs were assessed by qPCR and flow cytometry to detect the expression of cell markers of the basal and suprabasal epidermal layers. Differentiation potential was also assessed through ALI culture. DermaCult™ KEM supported 50 - 70 HEKa PDs and > 70 HEKn PDs before cell senescence (n = 4). HEKs cultured in DermaCult™ KEM maintained a cobblestone morphology, expressed basal cell markers (TP63, KRT14, ITGA6), and were devoid of suprabasal marker KRT10 (n = 4). In ALI culture, HEKs generated a stratified epithelium with the appropriate cellular architecture and expression of basal and suprabasal markers comparable to their in vivo counterparts (n = 2). Finally, keratinocytes obtained from human pluripotent stem cell (hPSC)-derived hair-bearing skin organoids and expanded in DermaCult™ KEM resembled those generated from primary HEKs, expressed basal keratinocyte markers (TP63, KRT14, KRT5), and sustained > 50 PDs before senescence (n = 4). In summary, DermaCult™ KEM is an improved serum- and BPE-free medium that supports the long-term expansion of primary and hPSC-derived HEKs while maintaining their downstream differentiation potential.
antibodies
2026-06-01 | Stenosing Esophageal Involvement in Acquired Epidermolysis Bullosa
Introduction Acquired epidermolysis bullosa (AEB) is a rare autoimmune subepidermal blistering disorder mediated by autoantibodies against type VII collagen. Mucosal lesions are frequent, but esophageal involvement remains exceptional. When present, it may cause progressive dysphagia linked to cicatricial strictures, with major nutritional impact and impaired quality of life. Case Report A 50-year-old man presented with bullous and post-bullous lesions on friction areas, associated with atrophic scarring and milia. Oral and nasal mucosal erosions were noted, with an 8-kg weight loss. Histopathology showed a subepidermal blister; direct immunofluorescence revealed linear IgG/C3 at the dermo-epidermal junction. ELISA demonstrated markedly elevated anti–type VII collagen antibodies and marginal anti-envoplakin positivity.Corticosteroids (0.5 mg/kg/day) were ineffective. Dapsone (100 mg/day) produced partial cutaneous improvement only. Endoscopy revealed a 7-cm circumferential mid-esophageal ulceration. Cyclosporine (3 mg/kg/day) induced transient improvement followed by progressive dysphagia.Repeat endoscopy showed an ulcerated cervical stricture with extensive mucosal detachment. Balloon dilation combined with high-dose corticosteroids and IVIG restored swallowing, improved weight, and prevented recurrence despite persistent mucosal fragility. Rituximab was subsequently initiated [ 1 ] [ 2 ] [ 3 ]. Discussion Esophageal involvement in AEB, although rare, represents a severe mucosal manifestation. Blistering, ulceration, and fibrotic strictures may occur, and endoscopy—while essential—is technically hazardous due to high mucosal fragility. Conventional therapies frequently fail to control severe mucosal disease. Endoscopic dilation is often required but carries procedural risks.Recent literature supports IVIG and rituximab as effective options in severe, refractory AEB, including stenosing esophageal forms, with favorable tolerance profiles. Conclusion Esophageal AEB necessitates individualized, multidisciplinary management. Biologic therapies offer promising perspectives for refractory and stenosing mucosal disease. Publication History Article published online: 05 June 2026 © 2026. European Society of Gastrointestinal Endoscopy. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-02-16 | The Changing Trends in the Incidence and Clinical Presentation of Immunobullous Disorders Before and During the COVID-19 Era in a Tertiary Healthcare Centre in Andhra Pradesh.
Background Autoimmune immunobullous disorders (AIBDs) represent a heterogeneous group of chronic blistering dermatoses mediated by autoantibodies against desmosomal and hemidesmosomal adhesion molecules. The COVID-19 pandemic has generated significant interest in the interaction between SARS-CoV-2 infection, vaccination-related immune modulation, and the clinical behaviour of autoimmune diseases. Objective This study's primary objective is to compare hospital-based temporal trends in the frequency, subtype distribution, and clinical presentation of AIBDs before and during the COVID-19 era in a tertiary healthcare centre in Andhra Pradesh. Secondary objectives included evaluation of changes in age at onset, sex distribution, mucosal and nail involvement, recurrence, and the emergence of atypical clinical morphologies requiring histopathology and direct immunofluorescence (DIF) for definitive diagnosis, as well as identification of independent predictors of subepidermal AIBD subtypes using multivariate logistic regression. Methods A retrospective observational analysis was performed on 42 histopathology and/or DIF-confirmed AIBD cases. Eighteen cases were recorded in the pre-COVID period (January 2018-December 2019) and 24 during the COVID era (January 2020-November 2023). Demographic trends, morphological patterns, mucosal involvement, anatomical distribution, severity, recurrence, and atypical phenotypes were compared between the two cohorts. Results A notable increase in overall incidence was observed during the COVID era (57.1%). Disease onset occurred at a younger age during COVID (mean 47.8 years) compared with the pre-COVID period (mean 53.6 years). Mucosal involvement increased from 33.3% pre-COVID to 50% during COVID. The COVID cohort exhibited higher recurrence rates and atypical morphology, including confluent mucosal and oesophageal lesions in epidermolysis bullosa acquisita, a "cluster of jewels" configuration and nail dystrophy in bullous pemphigoid, and healing with scarring and milia. These atypical patterns required more frequent reliance on biopsy and DIF for achieving a definitive diagnosis, as classical clinical presentation alone was insufficient. Conclusion The COVID-19 era was associated with both increased hospital-based case frequency and altered clinical expression of AIBDs, characterised by younger disease onset, greater mucosal involvement, and diagnostically challenging phenotypes. Possible contributors include post-COVID immune dysregulation, vaccination-associated immune activation, psychological stress, and lifestyle changes. Intensified clinical vigilance, early DIF-based confirmation, and timely initiation of steroid-sparing immunomodulatory therapy are essential to optimise outcomes in the evolving post-pandemic context.
2025-12-15 | A systematic review of therapeutic and paradoxical roles of tumor necrosis factor α inhibitors in autoimmune blistering diseases.
Autoimmune blistering diseases (AIBDs), including pemphigus diseases, pemphigoid diseases, linear immunoglobulin A (IgA) bullous dermatosis (LABD), epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH), are a group of diseases clinically characterized by erosions and blisters that involve the skin and mucosa. Tumor necrosis factor-alpha (TNF-α), a key inflammatory cytokine, plays a critical role in their pathogenesis. TNF-α inhibitors are used for their immunomodulatory effects but may also induce paradoxical autoimmune blistering. This systematic review aimed to synthesize current evidence on therapeutic and paradoxical effects of TNF-α inhibitors in these diseases. A systematic search of PubMed, Scopus, and Embase was conducted up to March 7th, 2025, following PRISMA guidelines. Studies eligible for inclusion were original human research articles in English reporting therapeutic or paradoxical effects of TNF-α inhibitors, including infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab, on autoimmune bullous diseases. Risk of bias was evaluated using the NIH and Murad et al. assessment tools. A total of 35 studies with 68 patients were included in the treatment application group and 29 studies with 31 subjects were included in the paradoxical reaction group. Infliximab was most frequently associated with favorable outcomes in pemphigus vulgaris (PV), bullous pemphigoid (BP), and EBA, with multiple reports of sustained remission. Etanercept showed partial to complete responses in some cases of PV and BP; however, it was associated with paradoxical induction of BP in several patients. Adalimumab demonstrated therapeutic efficacy in PV and MMP, yet was the most common agent implicated in paradoxical BP and LABD. Paradoxical effects were most often observed in patients treated for non-dermatologic conditions such as rheumatoid arthritis or Crohn's disease. TNF-α inhibitors, particularly infliximab, show therapeutic promise in refractory AIBDs. However, their potential to paradoxically induce blistering diseases, especially with adalimumab and etanercept, necessitates careful patient selection, close monitoring, and individualized risk-benefit assessment.
2025-11-07 | Successful Treatment of Epidermolysis Bullosa Acquisita with Dupilumab
Epidermolysis Bullosa Acquisita (EBA) is a rare, autoimmune blistering disease which can impact both the skin and mucous membranes. It is not inherited and typically impacts older adults. Not all patients with EBA respond positively to treatment. We are reporting what we believe to be the third case of EBA treated successfully with dupilumab.
2025-10-07 | Type VII Collagen Disorders Simplified.
Epidermolysis bullosa acquisita (EBA) and bullous systemic lupus erythematosus (BSLE) are autoimmune mechanobullous diseases that are caused by autoantibodies directed against type VII collagen. The functionality of type VII collagen is vital to the skin and mucous membranes because it makes up the anchoring fibrils that adhere the epithelium to the underlying connective tissue. Dystrophic epidermolysis bullosa (DEB), which bears some clinical similarities to EBA and BSLE, is caused by mutations in the type VII collagen gene (COL7A1) that may be dominant or recessive, leading to partial or total loss of the anchoring fibrils. Differentiating all 3 of these rare diagnoses variably requires thorough personal and family histories, histopathology, immunopathology, autoantibody profile, electron microscopy, and gene mutation analysis. Treatment of EBA and BSLE involves antineutrophil and immunosuppressive drugs that often give unsatisfactory responses. Rituximab has been successful in resistant cases. Until recently, the treatment of DEB and other heritable epidermolysis bullosa (EB) diseases caused by disparate mutations was limited to supportive care, prevention of trauma to skin and wound infections, regular dressing changes, and skin cancer surveillance. Three major treatment advances recently were approved for DEB and junctional EB.
proteins
2026-05-08 | HLA genotype, clinical and immunofluorescence findings of 30 patients with type VII collagen antibody positive subepidermal bullous disease.
Epidermolysis bullosa acquisita (EBA) and mucous membrane pemphigoid are mucocutaneous blistering disorders that are associated with antibodies that target type VII collagen (anti-col7). There are relatively few studies that closely investigate the clinical phenotype and HLA genotype of patients who are anti-col7 positive. We therefore characterized all patients with anti-col7-positive subepidermal bullous disease that were treated at our centre. In total, 30 patients were identified, 29 had mechanobullous skin lesions and all had oral ulceration. The most common sites for oral lesions were the tongue, lip and palatal mucosa. Laryngeal and oesophageal lesions were seen in five and six patients, respectively. Oesophageal involvement was associated with erosions and stricture formation in the cervical or thoracic oesophagus and the majority of patients with oesophageal involvement had concomitant bullous pemphigoid180/230 antibodies and were of Black African ancestry. IgA deposition on direct immunofluorescence was associated with lower age at disease onset but did not correlate with clinical features or autoantibody profiles. Concomitant BP180/230 antibody positivity was associated with earlier disease onset and Black African ancestry. HLA genotyping was performed in 18 patients and demonstrated HLA-DQB1*03 and HLA-DQB1*06 alleles were most commonly associated with anti-col7 EBA. HLA genotype did not, however, correlate with clinical features of autoantibody profiles. Taken together, this study demonstrates that concomitant BP180/230 and anti-col7 antibodies are associated with earlier disease onset, Black African ancestry and potentially oesophageal involvement.
2025-09-23 | A Rare Clinical Association of Type I Hereditary Angioedema and Acquired Epidermolysis Bullosa: A Case Report
Introduction. Both hereditary angioedema (HAE) and acquired epidermolysis bullosa (AEB) are extremely rare disorders, and their coexistence in a single patient is unique. Awareness of this exceptional association can aid in timely diagnosis and guide safe, individualized treatment strategies. Case Report. We present a case of a 38-year-old female with co-occurring type I HAE, associated with a heterozygous SERPING1 variant c.425T>C (p.Leu142Ser) of uncertain significance previously reported in individuals with angioedema, and a rare autoimmune subepidermal blistering disorder mediated by autoantibodies against type VII collagen – AEB. Since adolescence, the patient had experienced recurrent limb edema and atypical dermatological manifestations, including macules, vesicles, and bullae, predominantly in areas exposed to mechanical stress and frequently resulting in scar formation. The disease course later progressed with an episode of acute laryngeal edema following a dental procedure. Laboratory evaluation confirmed a critically low level of C1-inhibitor and an almost complete depletion of C4 in plasma, indicating chronic activation of the classical complement pathway. Given the frequent exacerbations and severe clinical course, long-term prophylactic therapy with intravenous C1-INH (1,000 IU twice weekly) was initiated. This treatment regimen led to sustained clinical remission, resolution of angioedema episodes, notable improvement in dermatologic symptoms of AEB, and a substantial enhancement in overall quality of life. Conclusions. The coexistence of HAE and AEB is exceptionally rare, with no prior cases identified. Complement dysregulation may link these conditions, underscoring the importance of considering autoimmune blistering disorders in HAE patients with atypical skin manifestations. This case highlights a potential role for complement-targeted therapies, warranting further clinical investigation.
2025-06-12 | Epidermolysis Bullosa Acquisita due to Epitope Spreading in a Patient With Recurrent Bullous Pemphigoid
The data that support the findings of this study are available from the corresponding author upon reasonable request.
2025-04-03 | Epidermolysis Bullosa Acquisita as a Rare Late-Onset Immune-Related Adverse Event after Anti-PD-1-Based Immunotherapy: Case Presentation and Review of the Literature
Background: Epidermolysis bullosa acquisita (EBA) is a rare autoimmune blistering disease caused by autoantibodies targeting type VII collagen (COL7), a component of anchoring fibrils in the basement membrane zone. These autoantibodies lead to subepidermal cleavage, resulting in skin and mucosal fragility. Although EBA has been linked to infections, autoimmune diseases, and hematologic conditions, drug-induced EBA is poorly understood.
2025-04-01 | A histopathological study of vesiculobullous skin lesions in a tertiary care hospital in Chhattisgarh, India
Abstract Background: Vesiculobullous skin lesions (VBLs) encompass a heterogeneous group of dermatological disorders, each with distinct clinical and pathological characteristics. Skin punch biopsy remains a fundamental diagnostic tool in evaluating these lesions. Histopathological examination is vital in confirming the diagnosis, guiding targeted therapy, and improving clinical outcomes. Aims and Objectives: To analyze the histopathological features, distribution patterns, and clinicopathological correlations of VBLs over 2 years. Materials and Methods: This study was conducted in the Department of Pathology between June 2022 and May 2024. It included all skin punch biopsies received from patients of all age groups presenting with vesiculobullous lesions during the study period. Results: A total of 84 cases were examined, comprising 32 males and 52 females, with a male-to-female ratio of 1:1.6. Patients were aged 22 to 73 years, with the highest incidence observed in the 31–40-year age group (42 cases). The mean patient age was 38 years. Pemphigus vulgaris (PV) was the most frequently diagnosed condition, accounting for 42 cases, followed by pemphigus foliaceus accounting for 24 cases. Bullous pemphigoid was seen in seven cases, while erythema multiforme accounted for three cases. Rare conditions such as epidermolysis bullosa acquisita, subepidermal bullous lesions, lichen planus pemphigoid, and Darier disease were identified in two cases. Conclusion: The study highlighted a slight female predominance among patients with VBLs, with the 31–40-year age group most commonly affected. The extremities were the most frequent site of involvement. PV emerged as the predominant vesiculobullous disorder in this cohort. The limitation of our study includes the lack of immunofluorescence in our center and single-institute data.
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2025-05-16 | Wound Care in Blistering Diseases
Blistering conditions manifest with fluid-filled skin lesions, vesicles, and bullae, often leading to erosions covered by crusts. These conditions encompass both inherited and acquired disorders, some frequent and other rare, some mild and other severe, possibly life endangering. Autoimmune blistering diseases can be caused by immune system dysfunction. Management aims to alleviate pain, prevent infections, and promote epithelialization, often involving immunosuppressive medications. Wound care presents challenges due to skin fragility and immunosuppressive effects of the medication, necessitating gentle cleaning, appropriate drainage techniques, and protective dressings. Topical treatments and oral care are integral, alongside pain management and infection monitoring. Stevens-Johnson syndrome and toxic epidermal necrolysis, drug-related mucocutaneous diseases, demand meticulous care to prevent epidermal detachment and infection. Inherited epidermolysis bullosa poses challenges in wound healing due to skin fragility, requiring specialized wound care approaches. Research into novel therapies, such as gene therapy, offers hope for improved management. Multidisciplinary care, nutritional support, and preventive strategies, particularly in neonates, are crucial for optimizing outcomes. Understanding the complexities of blistering conditions and tailoring management strategies are paramount in enhancing patient care and quality of life.
2016-06-11 | Highly branched poly(β-amino ester)s for skin gene therapy
Poly(β-amino ester)s (PAEs) have emerged as a promising class of gene delivery vectors with performances that can even be compared to viruses. However, all of the transfection studies (over 2350 PAEs) have been limited to linear poly(β-amino ester)s (LPAEs) despite increasing evidence that polymer structure significantly affects performance. Herein, we describe the development of highly branched poly(β-amino ester)s (HPAEs) via a new "A2+B3+C2" Michael addition approach demonstrating 2 to 126-fold higher in vitro transfection efficiencies of different cell types in comparison to their linear LPAE counterparts as well as greatly out-performing the leading transfection reagents SuperFect and the "gold-standard" polyethyleneimine (PEI) - especially on skin epidermal cells. More importantly, the ability to correct a skin genetic defect is demonstrated in vivo utilizing a recessive dystrophic epidermolysis bullosa (RDEB) knockout mouse model. Our results provide evidence that the "A2+B3+C2" approach can be controlled and offers sufficient flexibility for the synthesis of HPAEs. The branched structures can significantly improve the transfection efficiency and safety of PAEs highlighting the great promise for the successful application of non-viral gene therapy in skin disease.
2005-05-03 | Assessment of optimal transduction of primary human skin keratinocytes by viral vectors
Abstract Background Genetically modified keratinocytes generate transplantable self‐renewing epithelia suitable for delivery of therapeutic polypeptides. However, the variety of viral vectors and experimental conditions currently used make fragmented or contradictory the information on the transduction efficiency of the human primary keratinocytes. To compare the suitability of the most currently used viral vectors for efficient gene transfer to human keratinocytes, we have performed a comparative study using a panel of recombinant constructs. Methods For each vector, the transduction efficiency and the persistence of the transgene expression were quantified by fluorescence microscopy and flow cytometry analysis of the infected cells. Results We show that: (1) canine and human adenoviral vectors achieve a highly efficient but transient transduction of both primary and immortalized keratinocytes; (2) the adenovirus‐associated virus (AAV) vectors transduce immortalized keratinocytes, albeit with a short‐lived gene expression (<4 days), but fail to infect primary keratinocytes; and (3) under appropriate conditions, the oncoretroviral and lentiviral vectors can permanently transduce up to 100% of primary keratinocytes, but the highly clonogenic keratinocytes are more efficiently targeted by lentiviral vectors. Conclusions Therefore, AAV vectors are unsuitable to transduce primary keratinocytes, while human and canine adenoviral vectors appears to be appropriate to achieve short‐term delivery of therapeutic products. Recombinant retroviruses provide sustained expression of the transgene, but the lentiviral vectors are the most suitable for ex vivo gene therapy because of their ability to transduce clonogenic primary keratinocytes. Copyright © 2005 John Wiley & Sons, Ltd.
2003-10-24 | A Comparison of Targeting Performance of Oncoretroviral Versus Lentiviral Vectors on Human Keratinocytes
The epidermis, like other rapidly renewing tissues, relies on a stem cell compartment to undergo constant regeneration. In order to develop realistic and long-lasting therapeutic approaches for some skin disorders, gene transfer to these critical cells must be obtained. While efficient retroviral ex vivo targeting and transgene integration in human keratinocytes is tightly dependent on proliferation, transferring genetic information to quiescent cells in culture also presents advantages, including the possibility of targeting putative dormant epidermal stem cells. In the present study we compared the efficiency of transduction achieved with a third-generation of human immunodeficiency virus (HIV)-based lentiviral vector to that obtained with a Moloney murine leukemia oncoretroviral vector (MLV) on proliferating and quiescent human keratinocytes growing in vitro in standard Rheinwald and Green cultures as well as in confluent organotypic cultures. Each viral vector contained the enhanced green fluorescent protein (EGFP) as a reporter gene. The lentiviral vector, but not the MLV vector, led to EGFP expression both in nondividing and proliferating epidermal cell populations in vitro. This feature was clearly evident when direct targeting of human keratinocytes, forming part of the epidermal component of an organotypic skin culture, was attempted. Keratinocytes modified by both MLV and the lentiviral vector allowed long-term regeneration of genetically engineered human skin on the backs of immunodeficient nonobese diabetic/severe combined immunodeficiency disorders (NOD/SCID) mice. However, EGFP transgene expression in the context of the MLV (long-terminal repeat [LTR]-driven) or lentiviral vector (cytomegalovirus [CMV]-driven) demonstrated clear differences both in quantitative terms and in the in vivo localization pattern.
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Drug Discovery Landscape
1 orphan drug designation for Epidermolysis bullosa acquisita.
1 orphan drug designation for Epidermolysis bullosa acquisita.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
(S)-2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-5-carbonitrile | small molecules | FDA | 2017-01-05 | — | Almirall, S.A. |
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