Search Results (40)

Background/Objectives: Recessive dystrophic epidermolysis bullosa (RDEB) is a severe congenital genodermatosis characterized by skin and mucosa fragility, chronic inflammation, recurrent infections and high nutritional demands due to increased metabolism and epithelial barrier-related losses, placing patients at risk of zinc deficiency. We aimed to investigate the clinical relevance and biochemical determinants of zinc deficiency as a potentially modifiable contributor to disease burden in RDEB. Methods: In this cross-sectional study (n = 84), serum zinc levels were analyzed in association with sex, age, disease severity, percentage of body surface area (BSA) affected, inflammatory markers, infection burden, and common clinical complications including anemia and growth impairment. Results: Zinc deficiency, defined as levels below 670 µg/L, was identified in 35% of patients and became more frequent after age 5 and during adulthood, particularly among those with more severe disease. Deficiency was strongly associated with anemia, inflammation, infection burden, growth impairment, and extensive skin involvement. A revised cutoff of 780 µg/L is proposed, showing improved diagnostic performance for identifying patients at risk of systemic complications, and offering a more suitable threshold for starting preventive supplementation. Multivariate logistic modeling confirmed that low serum zinc independently predicted anemia risk, alongside transferrin saturation and C- reactive protein levels. Serum albumin was identified as the strongest determinant of zinc levels, partially mediating the effects of inflammation and skin involvement. Conclusions: These findings identify serum zinc as a clinically relevant marker of nutritional status and complication burden in RDEB. While no causal or therapeutic effects can be inferred from this cross-sectional study, the strong and biologically plausible associations observed suggest a rationale for systematic monitoring and correction of zinc deficiency as part of comprehensive supportive care, and warrant prospective studies to assess clinical benefit. Full article

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with incidence steadily increasing due to cumulative ultraviolet (UV) exposure, impaired immune surveillance, and chronic tissue damage. While most cases are effectively managed with surgical excision, a subset progress to locally advanced or metastatic disease, associated with high recurrence rates, limited curative options, and poor prognosis. The introduction of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis has significantly altered the management of advanced cSCC. Cemiplimab and pembrolizumab are now established systemic therapies, producing durable responses in a proportion of patients. These outcomes reflect the typically high tumor mutational burden and immunogenic microenvironment of cSCC. However, therapeutic decision-making remains particularly complex in several high-risk populations, including solid organ transplant recipients at risk of allograft rejection, patients with chronic dermatologic disorders or non-healing wounds that predispose to carcinogenesis, and individuals with rare hereditary syndromes such as recessive dystrophic epidermolysis bullosa. These so-called challenging populations are frequently excluded from pivotal trials, resulting in limited evidence regarding efficacy, safety, and optimal treatment strategies. This review summarizes current evidence on the management of advanced cSCC in high-risk and underserved patient groups, integrating trial data, real-world evidence, and contemporary guidelines. It also highlights key gaps in knowledge and outlines future directions, with particular focus on the interplay between host immune status, tumor biology, and therapeutic response. Full article

Epidermolysis bullosa (EB) is a group of debilitating, genetic skin disorders characterized by excessive skin fragility, blistering, and ulcerations that cause a cyclical wound healing process. EB presents itself in various subtypes, such as EB simplex (EBS), junctional EB (JEB), dystrophic (DEB), and Kindler Syndrome (KS), which all differ in their genetic cause, severity, and harbor different causes of mortality. Of these variants, JEB and DEB are the most severe, with EBS being the mildest form of the disease and KS presenting in extremely rare cases. The JEB variant tends to cause mortality early on in children less than two years of age due to failure to thrive, sepsis from wound infections, and airway obstruction. In the recessive form of DEB (RDEB), cutaneous squamous cell carcinoma (cSCC) is the major cause of death in patients, with one study reporting a mere 4-year survival after the first EB-cSCC diagnosis. Cutaneous SCCs in the setting of RDEB are particularly concerning because they are often more aggressive and show greater metastatic potential, as compared to ultraviolet-induced SCCs. This review aims to explore the pathophysiology of these EB variants as well as their implications for developing cSCCs. It will also discuss elements of the clinical presentation of such lesions in EB patients and the challenges associated with making a definitive diagnosis. Additionally, we will illuminate various diagnostic techniques, current and future management and treatment strategies for both cSCC and EB, and the importance of early screening and education for patients with EB to maximize patient lifespan and quality of life. Full article

Gene therapy involves introducing genetic material into cells to treat or prevent disease and offers highly targeted and potentially curative approaches for both inherited and acquired conditions. The skin is an especially suitable organ for gene therapy due to its accessibility, ease of sampling, rapid cell turnover, and the possibility for localized treatment with minimal systemic exposure. Gene therapy is being actively explored across a range of dermatological conditions, including recessive dystrophic epidermolysis bullosa, ichthyosis, psoriasis, chronic wounds, and melanoma, with therapeutic strategies encompassing viral vectors, non-viral delivery systems, gene editing technologies, RNA-based treatments, and cell-based approaches. These diverse methods aim to correct genetic defects, modulate immune responses, promote tissue repair, or selectively target malignant cells. This review examines the advancements and potential of gene therapies in addressing complex skin diseases, providing hope for improved patient outcomes and long-term care. Full article

Inherited epidermolysis bullosa (EB) comprises a group of genetic disorders characterized by fragile skin that blisters easily. Targeted therapies for EB necessitate personalized approaches, underscoring the importance of precise diagnostics through genetic analysis and skin biopsy using transmission electron microscopy and/or immunohistochemistry. This study highlights the application of whole-exome sequencing (WES) to identify key pathogenic variants associated with EB. Most identified variants were associated with the recessive form of dystrophic EB, including four novel COL7A1 mutations: p.Leu1488ArgfsTer222, c.7759-3C>G, p.Gln1886Ter, and c.6501+6T>C, as well as recurrent variants p.Lys142Arg and p.Gly2049Glu. Additionally, variants were detected in KRT5 (c.971T>C, p.Val324Ala), associated with EB simplex, and in LAMB3 (c.2500C>T, p.Gln834Ter) in the homozygous state, associated with junctional EB. In silico splice prediction tools suggested disrupted splicing in both cases. One patient received topical gentamicin therapy targeting the nonsense mutation p.Gln1886Ter. These findings underscore the utility of WES in EB diagnostics, broaden the mutation spectrum, and contribute to the understanding of genotype–phenotype correlations in adult patients with EB. Full article

Epidermolysis bullosa (EB) is a debilitating genetic skin disorder characterized by extreme fragility, chronic wounds, and severe complications, particularly in its most severe form, recessive dystrophic EB (RDEB). Current treatments focus on symptomatic relief through wound care and pain management, with recent FDA approvals of Vyjuvek and Filsuvez providing new but limited therapeutic options. However, emerging research highlights the potential of extracellular vesicles (EVs) derived from mesenchymal stem cells as a promising approach to address both the symptoms and underlying pathology of EB. EVs function as carriers of bioactive molecules, modulating inflammation, promoting tissue regeneration, and even delivering functional type VII collagen to RDEB patient cells. Unlike whole-cell therapies, EVs are non-immunogenic, have greater stability, and avoid risks such as graft-versus-host disease or tumorigenic transformation. Additionally, EVs offer diverse administration routes, including topical application, local injection, and intravenous delivery, which could extend their therapeutic reach beyond skin lesions to systemic manifestations of EB. However, challenges remain, including standardization of EV production, scalability, and ensuring consistent therapeutic potency. Despite these hurdles, EV-based therapies represent a transformative step toward addressing the complex pathology of EB, with the potential to improve wound healing, reduce fibrosis, and enhance patient quality of life. Full article

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic disease caused by COL7A1 mutations. It leads to skin fragility, chronic inflammation, and impaired wound healing. The condition often results in fibrotic scarring, pseudosyndactyly, and cutaneous squamous cell carcinoma (SCC). However, current animal models fail to fully replicate chronic RDEB wounds. In this study, we used Collagen VII-hypomorphic mice (Col7a1^flNeo/flNeo) and created full-thickness wounds on their paw skin, an area prone to fibrosis due to mechanical stress. We analyzed the healing process using histology, immunofluorescence, and electron microscopy. The RDEB mice showed delayed wound closure, increased inflammation, and poor granulation tissue formation. At 30 days post-injury, we observed persistent fibrosis, with elevated levels of Collagen I, α-SMA+ myofibroblasts, and tenascin-C. These mice also had fewer intraepidermal nerve fibers, which may help explain the neuropathic pain associated with RDEB. Our model reproduces the main features of chronic RDEB wounds. It offers a useful tool for evaluating therapies aimed at reducing inflammation, fibrosis, and tumor risk in these patients. Full article

This detailed review describes innovative strategies and current products for gene and cell therapy at different stages of research and development to treat recessive dystrophic epidermolysis bullosa (RDEB) which is associated with the functional deficiency of collagen type VII alpha 1 (C7) caused by defects in the COL7A1 gene. The use of allogenic mesenchymal stem/stromal cells, which can be injected intradermally and intravenously, appears to be the most promising approach in the field of RDEB cell therapy. Injections of genetically modified autologous dermal fibroblasts are also worth mentioning under this framework. The most common methods of RDEB gene therapy are gene replacement using viral vectors and gene editing using programmable nucleases. Ex vivo epidermal transplants (ETs) based on autologous keratinocytes (Ks) have been developed using gene therapy methods; one such ET successively passed phase III clinical trials. Products based on the use of two-layer transplants have also been developed with both types of skin cells producing C7. Gene products have also been developed for local use. To date, significant progress has been achieved in the development of efficient biomedical products to treat RDEB, one of the most severe hereditary diseases. Full article

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare severe hereditary skin disease characterized by skin and mucosa fragility, resulting in blister formation. The most severe complication in RDEB patients is the development of cutaneous squamous cell carcinoma (SCC), leading to premature death. There is a great deal of evidence suggesting a permissive tumor microenvironment (TME) as a driver of SCC development in RDEB patients. In a cohort of RDEB patients, we characterized the immune profiles of RDEB-SCCs and compared them with clinical, histopathological, and prognostic features. RDEB-SCCs were subdivided into four groups based on their occurrence (first onset or recurrences) and grading according to clinical, histopathological parameters of aggressiveness. Thirty-eight SCCs from 20 RDEB patients were analyzed. Five RDEB patients experienced an unfavorable course after the diagnosis of the first SCC, with early recurrence or metastasis, whereas 15 patients developed multiple SCCs without metastasis. High-risk primary RDEB-SCCs showed a higher neutrophil-to-lymphocyte ratio in the tumor microenvironment and an increased proportion of neutrophil extracellular traps (NETs). Additionally, citrullinated histone H3, a marker of NETs, was increased in the serum of RDEB patients with high-risk primary SCC, suggesting that this modified form of histone H3 may serve as a potential blood marker of unfavorable prognosis in RDEB-SCCs. Full article

Epidermolysis Bullosa (EB) is an extremely rare and disabling inherited genetic skin disease with a predisposition to develop bullous lesions on the skin and inner mucous membranes, occurring after mild friction or trauma, or even spontaneously. Within the spectrum of EB forms, dystrophic EB (DEB) represents the most intriguing and challenging in terms of clinical management, especially with regard to pregnancy, due to the highly disabling and life-threatening phenotype. Disappointingly, in the literature little focus has been directed towards pregnancy and childbirth in DEB patients, resulting in a lack of sound evidence and guidance for patients themselves and clinicians. The current study aims to contribute to the DEB literature with an updated summary of the existing evidence regarding the obstetrical and anesthesiological management of this rare disease. Furthermore, this literature review sought to answer the question of whether, and if so, in which way, the pregnancy condition may alter the course of the underlying dermatologic skin disease. Having all this information is indispensable when counseling a patient with DEB who desires a child or is expecting one. Finally, we reported own experience with a pregnant woman with a recessive DEB whom we recently managed, with a favorable outcome. Full article

Antisense oligonucleotides (ASOs) represent an emerging therapeutic platform for targeting genetic diseases by influencing various aspects of (pre-)mRNA biology, such as splicing, stability, and translation. In this study, we investigated the potential of modulating the splicing pattern in recessive dystrophic epidermolysis bullosa (RDEB) patient cells carrying a frequent genomic variant (c.425A > G) that disrupts splicing in the COL7A1 gene by using short 2′-O-(2-Methoxyethyl) oligoribo-nucleotides (2′-MOE ASOs). COL7A1-encoded type VII collagen (C7) forms the anchoring fibrils within the skin that are essential for the attachment of the epidermis to the underlying dermis. As such, gene variants of COL7A1 leading to functionally impaired or absent C7 manifest in the form of extensive blistering and wounding. The severity of the disease pattern warrants the development of novel therapies for patients. The c.425A > G variant at the COL7A1 exon 3/intron 3 junction lowers the efficiency of splicing at this junction, resulting in non-functional C7 transcripts. However, we found that correct splicing still occurs, albeit at a very low level, highlighting an opportunity for intervention by modulating the splicing reaction. We therefore screened 2′-MOE ASOs that bind along the COL7A1 target region ranging from exon 3 to the intron 3/exon 4 junction for their ability to modulate splicing. We identified ASOs capable of increasing the relative levels of correctly spliced COL7A1 transcripts by RT-PCR, sqRT-PCR, and ddPCR. Furthermore, RDEB-derived skin equivalents treated with one of the most promising ASOs exhibited an increase in full-length C7 expression and its accurate deposition along the basement membrane zone (BMZ). Full article

Objective: Epidermolysis bullosa (EB) is a group of rare hereditary skin disorders characterized by the formation of painful blisters, erosions, and ulcers. In addition, the wounds can easily become infected with different pathogens. Therefore, the dynamics in the microbial populations across the various stages of EB can shed light on pathophysiology, the effect of treatment, and the factors involved in its recovery, but they are understudied. We thus sought to characterize the skin microbiome among patients with EB over time. Methods: A prospective study conducted in the pediatric dermatology clinic at Soroka Medical Center, Beer-Sheva, Israel. Children (0–18) with simplex and recessive dystrophic EB were sampled at two different time points: before a therapeutic regimen and 90 days (±14 days) later. Samples were obtained from lesional skin (wound), healthy, non-lesional skin, and seborrheic skin (forehead). Samples were subject to 16S rRNA amplicon sequencing. Analyses performed included comparisons of relative abundance at the phyla and genera taxonomic levels, alpha and beta diversity comparisons, and differential abundance. Results: 32 children with EB were enrolled, for whom 192 skin microbiome samples were obtained. Lesional skin samples harbored significantly less Bacteroidota and Fusobacteriota before the initiation of treatment. Following topical dressing, we observed more Firmicutes and less Proteobacteria in lesional skin samples than healthy and seborrheic skin samples. In addition, Staphylococcus was significantly more abundant in lesional samples than in non-lesional and seborrheic samples following treatment. Conclusions: Our study recaptured the reduced bacterial diversity and increased staphylococcal carriage in EB patients, showing a potential effect of topical dressing either directly on the wound microbiome or indirectly through the contribution towards skin healing. The detection of Firmicutes in general, and S. aureus specifically, commensurate with the application of a wound dressing may warrant the use of additional treatment methods to facilitate wound healing. Future studies in these patients should prospectively correlate the temporal changes in the microbiome associated with various treatment modalities in order to optimize the care of EB patients. Full article

Machine learning has been proven to be a powerful tool in the identification of diagnostic tumor biomarkers but is often impeded in rare cancers due to small patient numbers. In patients suffering from recessive dystrophic epidermolysis bullosa (RDEB), early-in-life development of particularly aggressive cutaneous squamous-cell carcinomas (cSCCs) represents a major threat and timely detection is crucial to facilitate prompt tumor excision. As miRNAs have been shown to hold great potential as liquid biopsy markers, we characterized miRNA signatures derived from cultured primary cells specific for the potential detection of tumors in RDEB patients. To address the limitation in RDEB-sample accessibility, we analyzed the similarity of RDEB miRNA profiles with other tumor entities derived from the Cancer Genome Atlas (TCGA) repository. Due to the similarity in miRNA expression with RDEB-SCC, we used HN-SCC data to train a tumor prediction model. Three models with varying complexity using 33, 10 and 3 miRNAs were derived from the elastic net logistic regression model. The predictive performance of all three models was determined on an independent HN-SCC test dataset (AUC-ROC: 100%, 83% and 96%), as well as on cell-based RDEB miRNA-Seq data (AUC-ROC: 100%, 100% and 91%). In addition, the ability of the models to predict tumor samples based on RDEB exosomes (AUC-ROC: 100%, 93% and 100%) demonstrated the potential feasibility in a clinical setting. Our results support the feasibility of this approach to identify a diagnostic miRNA signature, by exploiting publicly available data and will lay the base for an improvement of early RDEB-SCC detection. Full article

Recessive dystrophic epidermolysis (RDEB) is a rare, inherited, and currently incurable skin blistering disorder characterized by cyclically recurring wounds coexisting with chronic non-healing wounds. In a recent clinical trial, three intravenous infusions of skin-derived ABCB5⁺ mesenchymal stromal cells (MSCs) to 14 patients with RDEB improved the healing of wounds that were present at baseline. Since in RDEB even minor mechanical forces perpetually provoke the development of new or recurrent wounds, a post-hoc analysis of patient photographs was performed to specifically assess the effects of ABCB5⁺ MSCs on new or recurrent wounds by evaluating 174 wounds that occurred after baseline. During 12 weeks of systemic treatment with ABCB5⁺ MSCs, the number of newly occurring wounds declined. When compared to the previously reported healing responses of the wounds present at baseline, the newly occurring wounds healed faster, and a greater portion of healed wounds remained stably closed. These data suggest a previously undescribed skin-stabilizing effect of treatment with ABCB5⁺ MSCs and support repeated dosing of ABCB5⁺ MSCs in RDEB to continuously slow the wound development and accelerate the healing of new or recurrent wounds before they become infected or progress to a chronic, difficult-to-heal stage. Full article

Mutations in the COL7A1 gene lead to malfunction, reduction or complete absence of type VII collagen (C7) in the skin’s basement membrane zone (BMZ), impairing skin integrity. In epidermolysis bullosa (EB), more than 800 mutations in COL7A1 have been reported, leading to the dystrophic form of EB (DEB), a severe and rare skin blistering disease associated with a high risk of developing an aggressive form of squamous cell carcinoma. Here, we leveraged a previously described 3′-RTMS6m repair molecule to develop a non-viral, non-invasive and efficient RNA therapy to correct mutations within COL7A1 via spliceosome-mediated RNA trans-splicing (SMaRT). RTM-S6m, cloned into a non-viral minicircle-GFP vector, is capable of correcting all mutations occurring between exon 65 and exon 118 of COL7A1 via SMaRT. Transfection of the RTM into recessive dystrophic EB (RDEB) keratinocytes resulted in a trans-splicing efficiency of ~1.5% in keratinocytes and ~0.6% in fibroblasts, as confirmed on mRNA level via next-generation sequencing (NGS). Full-length C7 protein expression was primarily confirmed in vitro via immunofluorescence (IF) staining and Western blot analysis of transfected cells. Additionally, we complexed 3′-RTMS6m with a DDC642 liposomal carrier to deliver the RTM topically onto RDEB skin equivalents and were subsequently able to detect an accumulation of restored C7 within the basement membrane zone (BMZ). In summary, we transiently corrected COL7A1 mutations in vitro in RDEB keratinocytes and skin equivalents derived from RDEB keratinocytes and fibroblasts using a non-viral 3′-RTMS6m repair molecule. Full article