RARE DISEASE
Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form
Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form
Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form
Synonyms: Autosomal recessive dystrophic epidermolysis bullosa generalisata gravis, Autosomal recessive dystrophic epidermolysis bullosa, Hallopeau-Siemens type, Generalized RDEB, severe form, RDEB generalisata gravis, RDEB, Hallopeau-Siemens type, Severe generalized RDEB
Synonyms: Autosomal recessive dystrophic epidermolysis bullosa generalisata gravis, Autosomal recessive dystrophic epidermolysis bullosa, Hallopeau-Siemens type, Generalized RDEB, severe form, RDEB generalisata gravis, RDEB, Hallopeau-Siemens type, Severe generalized RDEB
Synonyms: Autosomal recessive dystrophic epidermolysis bullosa generalisata gravis, Autosomal recessive dystrophic epidermolysis bullosa, Hallopeau-Siemens type, Generalized RDEB, severe form, RDEB generalisata gravis, RDEB, Hallopeau-Siemens type, Severe generalized RDEB
Drug discovery
1
drug
With orphan designation
Overview
Autosomal recessive generalized dystrophic epidermolysis bullosa (RDEB), severe form, is a genetic blistering disorder caused by biallelic COL7A1 mutations, resulting in deficient type VII collagen and impaired dermal-epidermal adhesion. Neonates present with widespread skin/mucosal blistering, progressing to scarring, digit fusion, and extracutaneous complications (esophageal strictures, malnutrition, corneal scarring). Lifelong risks include aggressive squamous cell carcinoma (90% cumulative risk by age 55) and chronic renal failure [1][3][9]. Diagnosis combines immunofluorescence mapping, electron microscopy, and genetic testing [1][4].
Burden
Morbidity/Mortality: Median life expectancy <35 years due to metastatic SCC (80% mortality rate by age 55) [1][5]. Chronic anemia, growth retardation, and organ dysfunction prevalent [7][16].
Economic impact: Annual direct costs >€100,000 in severe cases; ~40% of costs attributed to dressings [11][18].
Quality of life: Severe pruritus/pain (comparable to chronic urticaria), ≥17h/week spent on wound care, and caregiver dependency [7][11][17].
Therapies
Supportive care: Protective wound dressings, infection control, nutritional support (e.g., gastrostomy), and surgical interventions for strictures/hand deformities [1][17].
Emerging therapies: Topical gene therapy (beremagene geperpavec/B-VEC), ex vivo COL7A1-corrected keratinocyte grafts (EB-101), and intradermal allogeneic fibroblast injections [6][10][14].
Symptom management: Multidisciplinary pain control, vitamin/mineral supplementation, and SCC surveillance [1][7].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare ophthalmic disorders, rare skin diseases
Research Papers
220 drug discovery papers about Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
220 drug discovery papers about Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-09-18 | Disrupted Skin-Nerve Homeostasis in Recessive Dystrophic Epidermolysis Bullosa: a Neurocutaneous Unit Perspective on Pain.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited disorder characterised by type VII collagen impairment, leading to dermo-epidermal junction (DEJ) instability and chronic skin fragility. Pain is a near-universal and quality-of-life-limiting feature; however, explanations centred solely on tissue injury and inflammation do not fully account for its persistence or treatment resistance. Increasing evidence supports a broader framework in which disrupted skin-nerve homeostasis within the neurocutaneous unit (NCU) contributes to pain generation. This narrative, hypothesis-driven review integrates clinical, experimental and translational evidence to examine the role of the NCU, the functional interface between keratinocytes and intraepidermal sensory fibres, in RDEB pain. Chronic injury, persistent inflammation and DEJ disruption create a microenvironment that is unfavourable for sensory nerve maintenance and repair. Clinical and experimental findings support the presence of small-fibre pathology, reflected by reduced intraepidermal nerve fibre density, altered sensory thresholds and neuropathic pain descriptors. Mechanistically, repeated injury appears to impair reinnervation and contribute to progressive distal sensory fibre loss within a hostile cutaneous microenvironment. Keratinocyte dysfunction drives this process through impaired neurotrophic support and the sustained release of pro-inflammatory mediators that directly sensitise nociceptors. In parallel, dermal fibrosis and extracellular matrix remodelling may constrain axonal regeneration. Molecular studies further demonstrate a persistent inflammatory and pro-fibrotic signature in RDEB skin, including clinically non-lesional areas. These converging abnormalities suggest that disrupted skin-nerve homeostasis is an important contributor to disease-associated pain. Translational evidence suggests partial reversibility, with pain reduction observed following therapies targeting neuropathic mechanisms or restoring DEJ integrity. Together, these findings support a framework in which altered neurocutaneous interactions contribute substantially to pain in RDEB, underscoring the need for mechanism-based and potentially early neuroprotective strategies.
2025-12-27 | First experience of the application of beremagene geperpavec genetically engineered drug for treatment of congenital dystrophic epidermolysis bullosa in the Russian Federation
Congenital epidermolysis bullosa (CEB) is a group of heterogenous, hereditary genetic diseases. Emergence of blisters and erosions on the skin, slight vulnerability of the skin cover, formation of disabling deformities and aggressive skin cancer development are the main clinical manifestations of this pathology. The disease is based on a hereditary genetic defect caused by one or several mutations in the COL7A gene, leading to an insufficient synthesis of type VII collagen functional protein (COL7), which contributes to the occurrence of persistent skin wounds and their infection. Generalized recessive dystrophic epidermolysis bullosa (RDEB) leading to death of patients at a young age is the most severe form of the disease. In the Russian Federation, symptomatic methods aimed at accelerating the healing of erosive and ulcerative skin defects and preventing the development of secondary infection and correcting complications are currently being used to treat patients with CEB, including RDEB. The article presents the first experience of treatment of a patient with RDEB with beremagene geperpavec genetically engineered drug in the Russian Federation. A male patient, 14 years old, with a verified congenital dystrophic epidermolysis bullosa, recessive type, Q81.1 diagnosis was under follow-up. Treatment was carried out at the North-East Clinic with the Children’s Center of the Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology (MSPCDC). Beremagene geperpavec gel was applied to the open wounds located on the skin of the back, right axillary region, inguinal folds, lower extremities. In total, 8 applications were done during 2 months. The treatment had a pronounced therapeutic effect, which manifested itself in complete epithelialization of the wound surfaces.
2019-08-01 | Decorin counteracts disease progression in mice with recessive dystrophic epidermolysis bullosa
Loss-of-function mutations in the gene encoding type VII collagen underlie recessive dystrophic epidermolysis bullosa (RDEB), a disease characterized by skin and mucosal blistering, impaired wound healing, and diffuse dermal inflammation and fibrosis. Transforming growth factor-β signaling plays a crucial role in determining RDEB fibrotic microenvironment that leads to the development of disabling secondary disease manifestations, including hand and foot deformities. Experimental findings indicate that expression levels of decorin, a small leucine-rich proteoglycan and an endogenous TGF-β inhibitor, can modulate RDEB disease phenotype by contrasting dermal fibroblast fibrotic behavior. In this study, the ability of decorin to modify RDEB course was investigated by systemically treating RDEB mice with a lentivirus expressing human decorin. Overexpressed decorin was able to enhance survival, and to limit digit contraction and the development of paw deformities. These effects were associated with decreased TGF-β1 levels and TGF-β signaling activation. Fibrotic traits were strongly reduced in paw skin and also attenuated in the non-chronically injured back skin. However, the expression of pro-inflammatory proteins was not decreased in both paw and back skin. Our findings confirm TGF-β role in promoting fibrosis and disease progression in RDEB, and show that decorin counteracts disease manifestations by inhibiting TGF-β activation. More generally, our data indicate that modifying extracellular matrix composition is an option to improve RDEB disease course.
2017-10-01 | 192 Loss of keratinocyte type VII collagen induces increased DNA damage in vitro and in vivo
Epidermolysis Bullosa is a severe blistering disease caused by mutations in basement membrane genes and is characterised by severe blistering of the skin and increased predisposition to cancer. To investigate the function of the skin basement membrane, siRNA knockdown of type IV, VII (Col7) and XVII (Col17) collagens was performed in primary neonatal foreskin keratinocytes. Global transcriptomic analysis was carried out using RNA-Seq. Pathway analysis revealed dysregulation of genes involved in DNA damage and cell cycle control in cells with Col7 and Col17 knockdown predicting reduced proliferation of siCol7 cells and increased proliferation of siCol17 cells which was confirmed in in vitro proliferation assays. Rescue experiments involving addition of recombinant Col7 or knockdown of TGFβ receptor 1 resulted in normalisation of c-Myc and cyclin expression in siCol7 cells. Primary keratinocytes transfected with siC (non-targeting control), siCol7 or siCol17 were treated with UV or mitomycin-C to induce DNA damage. The siCol7 cells have markedly decreased phosphorylation of Chk1 and Chk2 suggesting an inability to recognise DNA damage. Increased g-H2A.X expression was observed in siCol7 cells suggesting the presence of DNA double-strand breaks. Increased g-H2A.X and 53BP1 nuclear foci and decreased Ki-67 were observed in neonatal skin from a mouse model of RDEB indicating increased DNA damage, and injection with human recombinant type VII collagen was sufficient to reduce DNA damage, but not proliferation, to wild type control levels. Our findings suggest that aberrant TGF-beta signalling in RDEB with loss of type VII collagen results in loss of keratinocyte ability to repair DNA, decreased keratinocyte proliferation and genomic instability resulting in early SCC development.
2017-09-08 | 568 Investigation of the role of type VII collagen in the HIF1α induced pro-angiogenic pathway
Type VII collagen (Col7) is the main component of anchoring fibrils in the basement membrane of skin. Loss of function mutations in the COL7A1 gene lead to recessive dystrophic epidermolysis bullosa (RDEB) with severe congenital blistering, scarring and later development of aggressive squamous cell carcinomas (SCCs). A recent study from our group has shown an increase in angiogenesis with loss of Col7 in RDEB. One of the main regulators of tumour angiogenesis is hypoxia. The most important regulator of the cellular response to hypoxia is the transcription factor HIF-1 and its subunit HIF-1α. In this study, we investigated the effect of hypoxia on SCC cell lines with loss of Col7 on HIF-1α, VEGFR1 and other angiogenic factors. SCC cells with stable knock down (KD) of Col7 established using lentiviral shRNA were grown in normoxia (20% oxygen) or hypoxia (0.2% oxygen). RNA and protein lysates were prepared and analysed using RT-PCR and western blotting. Findings were confirmed in vivo in mouse xenograft tumours generated using Col7 knockdown cells. Increased HIF-1α mRNA and protein expression were observed with knock down of Col7 (shCol7) compared to control (shC). Global expression profiling identified a number of angiogenesis related genes differentially regulated with loss of Col7 that were further investigated. Increased expression of VEGFR1, Amphiregulin, UPA and Ephrin A1 were all observed with loss of Col7. These changes were amplified by hypoxia and could be reversed in vivo by treatment with human recombinant Col7 (hrCol7). These data demonstrate that loss of Col7 enhances hypoxic signals and the expression of pro-angiogenic factors which are reversed by hrCol7. This work improves our understanding of angiogenesis in RDEB and could lead to new therapeutic strategies for RDEB wounds and SCC targeting angiogenic pathways and the adaptive hypoxic response activated by loss of Col7.
small molecules
2026-09-24 | Minimally Invasive Caries Arrest and Oral Rehabilitation for a Patient With Severe Recessive Dystrophic Epidermolysis Bullosa.
To describe the stepwise, atraumatic dental management of a pediatric patient with severe recessive dystrophic epidermolysis bullosa (RDEB), emphasizing conservative caries arrest, the challenges of restorative care within a severely microstomia-limited oral opening, and coordinated multidisciplinary care. A male patient with severe RDEB was followed at a university pediatric dental clinic from Age 13 to 14 years within a dental home maintained since infancy. Serial silver diamine fluoride applications arrested multiple occlusal carious lesions. Glass ionomer sealants were placed on seven teeth without retraction or mirror use. At Age 14, comprehensive restorative care under general anesthesia included stainless-steel crown placement on a mandibular first molar and glass ionomer restorations on two additional teeth, all accomplished through a maximum interincisal opening of approximately 30 mm. Fiber-optic nasal intubation required multiple attempts. Six-month follow-up confirmed caries-free status and intact restorations. A guideline-driven, stepwise protocol combining conservative caries arrest, glass ionomer sealants and restorations, and targeted general anesthesia care preserved oral function while minimizing mucosal trauma. Multidisciplinary coordination supported the care episode, with anesthesiology managing the difficult airway, dermatology advising on the treatment setting and mucosal protection, and hematology optimizing the patient's baseline iron-deficiency anemia.
2026-06-30 | Clinical outcomes of gentamicin therapy in dystrophic Epidermolysis Bullosa: a case-based literature review
Introduction: Epidermolysis bullosa (EB) comprises a group of inherited disorders characterized by skin fragility and blister formation resulting from mutations in proteins essential for dermoepidermal adhesion. Dystrophic EB (DEB), particularly its recessive form (RDEB), is caused by mutations in the COL7A1 gene, leading to defective type VII collagen and impaired anchoring fibrils. Clinically, severe forms are associated with chronic wounds, scarring, pseudosyndactyly, mucosal involvement, and increased risk of cutaneous squamous cell carcinoma. Current therapeutic options remain limited and largely supportive. Gentamicin has emerged as a potential disease-modifying therapy due to its ability to induce translational readthrough of nonsense mutations, restoring partial production of functional collagen VII. This study aims to analyze published cases of EB treated with gentamicin and identify patterns in clinical response and therapeutic outcomes. Methodology: A case-based literature review was conducted, including studies published between 2020 and 2026, retrieved from the PubMed and SciELO databases, in English, Portuguese, and Spanish. Patients with severe generalized dystrophic epidermolysis bullosa treated with gentamicin were included. Extracted variables comprised age, sex, EB subtype, genetic mutation, route of administration (topical or intravenous), treatment duration, methods used to assess response (including immunofluorescence, quality of life scales, and pain scores), collagen VII expression before and after treatment, clinical improvement, adverse effects, and follow-up duration. Data from four studies were compiled into a comparative table to identify trends in therapeutic response and safety outcomes. Discussion: Across the analyzed cases, gentamicin therapy was consistently associated with increased expression of type VII collagen and corresponding clinical improvement, including enhanced wound healing and reduction of mucocutaneous lesions. These findings support its mechanism of action as a readthrough agent that partially restores protein synthesis in patients with nonsense mutations in COL7A1. Both topical and intravenous routes demonstrated therapeutic benefit, although with different clinical profiles. Topical administration was predominantly associated with localized improvement, particularly in oral and cutaneous lesions, reflecting its direct action on treated areas. In contrast, intravenous administration was associated with more systemic effects. Despite these promising findings, variability in treatment response was observed, likely influenced by mutation type, disease severity, and differences in treatment protocols. Additionally, methodological heterogeneity across studies, such as variation in biopsy sites, outcome measures, and duration of therapy, limits direct comparability. Importantly, no significant adverse effects were reported across the included studies, suggesting a favorable short-term safety profile. Some studies also demonstrated maintenance of collagen VII expression after treatment discontinuation, although without evidence of progressive improvement over time. Conclusion: Gentamicin appears to be a promising therapeutic strategy for patients with dystrophic epidermolysis bullosa, particularly those with nonsense mutations in COL7A1. The available evidence demonstrates increased collagen VII expression and associated clinical improvement, regardless of the route of administration. The absence of significant adverse effects supports its short-term safety. However, further large-scale and controlled studies are needed to establish standardized treatment protocols and confirm long-term efficacy.
2025-11-25 | Assessment of Growth Hormone and Insulin-Like Growth Factor 1 in Children With Epidermolysis Bullosa Dystrophica.
Epidermolysis bullosa dystrophica (EBD) is characterized by mucocutaneous fragility with blistering, scarring and severe growth retardation attributed to many factors. This cross-sectional study included 51 patients aged 1-12 years with recessive dystrophic EB (RDEB). Weight and height were measured, with the calculation of weight standard deviation (SD), height SD, and body mass index (BMI), followed by plotting them on Egyptian growth curves. Serum levels of basal growth hormone (GH), insulin-like growth factor 1 (IGF-1), hemoglobin (Hb) level, erythrocyte sedimentation rate (ESR), and thyroid functions (TSH and free T4) were measured. Growth hormone stimulation test was performed in 11 patients. Weight SD and height SD were lower than normal measurements (p < 0.05*). Growth hormone, growth hormone stimulation, and IGF-1 were lower than the normal range (p < 0.05*). Hb levels were lower than normal, whereas ESR levels were elevated (p < 0.001*). A negative correlation was found between ESR and basal GH, and a positive correlation between ESR and IGF-1. Children with generalized RDEB have poor growth and low circulating GH and IGF-1 levels, likely due not only to malnutrition and anemia, but possibly also as a consequence of inflammation that suppresses the GH/IGF-1 axis. Future treatments targeting the correction of GH and IGF-1 levels as well as the chronic inflammatory state should be considered. ClinicalTrials.gov identifier: NCT05390073.
2025-09-03 | Safety and Efficacy of Angiotensin Receptor Antagonists in Recessive Dystrophic Epidermolysis Bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited progressive blistering skin disorder caused by mutations in the COL7A1 gene. Chronic wounds lead to cycles of scarring and healing, causing severe functional deformities. Losartan is an angiotensin II type 1 receptor (AT1R) antagonist that has been shown to have antifibrotic activity via inhibiting the production of transforming growth factor beta (TGF-B) and has a favourable safety profile in children. In this systematic review, there were five studies found, with a total of 59 patients including case series, case-control and an open label phase 2 clinical trial. These studies have demonstrated the safety of losartan with no significant adverse effects such as hypotension, hyperkalaemia and hypersensitivity. They have also demonstrated evidence of efficacy utilising subjective assessments and objective criteria such as the Birmingham Epidermolysis Bullosa Severity score (BEBS) and Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI). Although safe and effective, further clinical trials are required to fully elucidate the role of this treatment; whether this approach should be standardised across the RDEB patient cohort is yet to be determined from the current evidence. Trial Registration: PROSPERO ID: CRD42024557126.
2025-01-24 | Repurposing diacerein for the treatment of chronic wounds in recessive-dystrophic epidermolysis bullosa patients by modulating matrix metalloproteinase-9 expression.
Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in COL7A1, leading to loss or dysfunction of type-VII collagen (C7), a protein essential for skin stability. Clinically, patients suffer from severe skin blistering, chronic or recurrent wounds, and scarring, which predispose to early onset of aggressive squamous cell carcinoma. Previous studies showed that RDEB-keratinocytes (RDEB-KC) express high levels of matrix-metalloproteinase 9 (MMP-9), a molecule known to play a crucial role in wound chronification if dysregulated. We investigated the potential of diacerein, a small molecule that interferes with the MMP-9 regulatory pathway, to improve wound healing in a 5-year old RDEB patient presenting with chronic, generalized skin involvement unresponsive to previous treatment approaches. Upon 4 weeks of topical therapy applied to the patient's back, parents reported a nearly complete wound closure and a significant increase in quality of life. We also provide evidence that diacerein treatment of patient keratinocytes results in a downregulation of MMP-9 expression, accompanied by a reduction in their ability to degrade a fibrinogen matrix. These data characterize diacerein as a potential candidate for improving wound healing in RDEB through its impact on inflammatory as well as epithelial cells.
cell therapies
2026-06-28 | Identification of a long-term surviving human mesenchymal stromal cell subpopulation and implications for recessive dystrophic epidermolysis bullosa treatment.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by loss-of-function pathogenic variants in COL7A1 encoding type VII collagen (C7). Patients with RDEB suffer since birth from skin and mucosal blistering and develop severe local and systemic complications resulting in poor prognosis. Mesenchymal stromal cells (MSCs) have demonstrated their potential to enhance wound healing and reduce skin inflammation in RDEB patients due to their anti-inflammatory properties and capacity to express C7. We aim to optimize in vitro conditioning of human bone marrow-derived MSCs (BM-MSCs) to improve their limited survival following local injection in a murine model. BM-MSCs from healthy human donors were transduced with a lentiviral vector encoding firefly luciferase and mCherry reporter proteins and then subjected to various culture conditions: monolayer on plastic or spheroid culture, either in hypoxia (5% O2) or in normoxia (21% O2). These cells were subsequently injected intradermally (ID) in immunodeficient mice and their survival was assessed by in vivo imaging. BM-MSCs populations were analyzed prior to injection by single-cell RNA sequencing (scRNAseq). Murine skin injected with BM-MSCs were sampled two months post-injection and the surviving subpopulations were characterized by spatial transcriptomic. scRNAseq analysis revealed marked variations between monolayer and spheroid conditions, which were significantly impacted by oxygen level. Although most injected cells gradually died within the first 2 months in all tested conditions, 1% of live bioluminescent cells persisted for 54 up to 61 weeks post-injection. Spatial transcriptomics data analysis demonstrated that all surviving cells, regardless of their in vitro preconditioning, retained the expression of the MSC markers THY1, ENG, and NT5E, shared features with fibroblasts, and exhibited enriched expression in genes related to extracellular matrix and collagen fibril organization, which are key processes in wound healing. Spatial transcriptomic and scRNAseq data integration suggested that surviving BM-MSCs were initially present in the injected population, regardless of their culture condition. Remarkably, none of the in vitro preconditioning strategies appeared to affect their survival capacity or functional properties following local injection. The identification and characterization of a BM-MSC subpopulation capable of long-term survival following ID injection hold promise for the development of improved cell therapy protocols for RDEB.
2026-05-21 | MesenSistem-EB: systemic haploidentical mesenchymal stem cell therapy in recessive dystrophic epidermolysis bullosa associated with clinical benefits and correlated with MCP1 and sCD40L dynamics.
Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating genodermatosis caused by biallelic COL7A1 mutations, where chronic inflammation drives disabling complications affecting quality of life and survival. Effective inflammatory control remains a major unmet need. While systemic administration of mesenchymal stromal cells (MSC) from various sources has proven safe with transient benefits yet only one recent placebo-controlled study in RDEB. Consistent type VII collagen (C7) deposition is lacking, and therapeutic mechanisms and predictive biomarkers remain undefined. The MesenSistem-EB trial evaluated for the first time the use of haploidentical BM-MSC and extensively explored their anti-inflammatory potential as a monotherapy in RDEB. Phase I/II, single-center, open-label trial, in which nine children with severe RDEB were recruited and eight completed the study after three intravenous infusions of haploidentical BM-MSC (2-3×106 cells/kg) at 21-day intervals. Safety, clinical and patient-reported outcomes, systemic inflammatory mediators and peripheral blood immune profiles were assessed over 12 months. MSC therapy was well-tolerated without serious adverse events. Long-term pruritus, sleep and fatigue were globally reduced. In 7/8 patients at least one key domain significantly improved (disease severity, pruritus, or inflammation) with five classified as good responders. Global median CRP and fibrinogen levels remained stable throughout the study period. Responses correlated with sCD40L and MCP1 dynamics. Flow cytometry revealed altered circulating myeloid and lymphoid compartments at baseline. Post-infusion, immune cell subset changes did not consistently distinguish responders while typically including increased CLA expression on monocytes, partial recovery of memory CD8+ T cells and disappearance of an aberrant granulocyte population, potentially linked to immature myeloid mobilization driven by chronic inflammation. Haploidentical MSC did not consistently confer durable engraftment or sustained C7 deposition. BM-MSC is a safe and potentially effective anti-inflammatory intervention that mitigates the expected escalation of systemic inflammatory markers during a critical phase of RDEB progression. MCP1 and sCD40L modulation, with both potentially serving as predictive biomarkers. MSC appear to exert both shared and patient-specific immunomodulatory effects depending on baseline inflammatory cues. Findings provide insights into individual variability, underlying mechanisms and potential therapeutic responsiveness, supporting their use also as a complementary strategy. ClinicalTrials.gov, identifier NCT04153630.
2026-05-13 | Amniotic Membrane Transplantation Preserves Vision in Pediatric Recessive Dystrophic Epidermolysis Bullosa: Case Series.
Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited disorder characterized by extreme epithelial fragility and progressive cicatrization, frequently leading to severe ocular surface disease and early visual impairment. Surgical interventions such as ocular surface reconstruction (OSR) in childhood are often delayed because of anesthetic risks and concerns regarding recurrence. Consequently, the effectiveness of OSR, including amniotic membrane transplantation (AMT), and its impact on visual development remain poorly documented. Methods: We report a case series of two pediatric patients (three eyes) with genetically confirmed RDEB who underwent single-step OSR using AMT. Clinical outcomes, long-term visual acuity, perioperative management, and histopathological findings were evaluated. Results: Ocular manifestations included corneal epithelial damage, symblepharon, and pseudopterygium extending over the cornea. One patient underwent symblepharon lysis, superficial keratectomy, and AMT onto the bare sclera in the right eye at age 4 and in the left eye at age 8, both under intubated general anesthesia. The other patient underwent the same procedure in the right eye at age 6. Best spectacle-corrected visual acuity improved from ≤20/300 to 20/30 in all eyes, and pupillary zone clarity was maintained during the follow-up period (up to 6 years). Histopathology confirmed pseudopterygium with squamous metaplasia, goblet cell loss, and fibrovascular stroma. Safe general anesthesia was achieved through meticulous multidisciplinary perioperative planning involving anesthesiologists, dermatologists, and pediatricians. No systemic complications related to anesthesia or perioperative management were observed. Conclusions: Single-step OSR with on-lay AMT can restore and preserve visual function in pediatric RDEB. Early surgical intervention may prevent profound amblyopia and provide durable ocular surface stability. A multidisciplinary approach enables safe general anesthesia and perioperative management.
2025-12-04 | IPSC-derived organoid-sourced skin cells enable functional 3D skin modeling of recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited skin disorder caused by mutations in COL7A1. Patient-derived induced pluripotent stem cells (iPSCs) enable the personalized study of RDEB pathogenesis and potential therapies. However, current skin cell differentiation protocols via 2D culture perform suboptimally when applied to engineered 3D skin constructs (ESC). Here, we present an approach to source fibroblasts (iFBs) and keratinocytes (iKCs) from iPSC-derived skin organoids using an optimized differentiation protocol, and utilize them to engineer ESCs modeling wild-type and RDEB phenotypes. The resulting iPSC-derived skin cells display marker expression consistent with primary counterparts and produce ESCs exhibiting significant extracellular matrix remodeling, protein deposition, and epidermal differentiation. RDEB constructs recapitulated hallmark disease features, including absence of collagen VII and reduced iFB proliferation. This work establishes a robust and scalable strategy for generating physiologically-relevant, iPSC-derived skin constructs, offering a powerful model for studying RDEB mechanisms and advancing personalized regenerative medicine.
2025-05-22 | Mesenchymal intravenous stromal cell infusions in children with recessive dystrophic epidermolysis bullosa: MissionEB protocol for a randomised, double-blinded, placebo-controlled, two-centre, crossover trial with an internal phase I dose de-escalation phase and open-label extension.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic mucocutaneous fragility disorder characterised by chronic blistering, slow wound healing and increased risk of squamous cell carcinoma. Current management options are very limited. This is a randomised (1:1), placebo-controlled, double-blinded crossover (A/B) trial with an internal phase I dose de-escalation (4+5 design) in the first 3 months and a 12-month continued treatment follow-on open-label study if 3-month outcome data from the crossover trial indicate safe and beneficial effects. RDEB is a rare condition, so we expect to recruit a maximum of 36 participants based on feasibility and not formal power considerations. Participants aged>6 months and <16 years will be recruited at Great Ormond Street Hospital and Birmingham Children's Hospital. They will receive 2-3×106 cells/kg intravenous infusion of umbilical cord-derived mesenchymal stem cells or placebo at the start of each crossover period (day 0) and 14 days later. The dose will be de-escalated to 1-1.5×106 cells/kg depending on observed toxicity. For the main crossover trial, the primary outcome is the change in disease severity as measured by the Epidermolysis Bullosa Disease Activity and Scarring Index at 3 months from day 0 infusion. Secondary outcomes measured at 3 and 6 months from day 0 infusion include changes in general clinical appearance of skin disease, pain and itch, and quality of life. Adverse events and serious adverse events will be monitored throughout the trial. North East-York Research Ethics Committee approved the protocol (ref: 21/NE/0016) on 16 March 2021. Findings will be published in peer-reviewed scientific journals, presented at relevant national and international conferences, and an open-access final report submitted to the funder. ISRCTN14409785. Protocol V. 8.0, 14 November 2022.
gene therapies
2026-08-11 | Topical gene therapy for severe recessive dystrophic epidermolysis bullosa: clinical outcomes and multidisciplinary management in three patients treated with beremagene geperpavec (B-VEC) in Italy - a case series.
Recessive dystrophic epidermolysis bullosa is a severe inherited blistering disorder characterized by chronic wounds, fibrosis and systemic complications. Beremagene geperpavec (B-VEC), a topical HSV1-based gene therapy delivering full-length COL7A1, has shown efficacy in clinical trials; however, real-world data remain limited. This retrospective, descriptive case series reports on three patients with genetically confirmed recessive dystrophic epidermolysis bullosa - two children and one young adult - treated between 2024 and 2026 at two Italian tertiary centres. All patients had extensive chronic skin involvement and received weekly topical B-VEC. Clinical data included wound characteristics, response to therapy, supportive care and adverse events. All patients showed clinically meaningful improvement in target wound healing. One child achieved ~70% reduction in the wound area needing treatment; the second had ~50% with shallower morphology and reduced bleeding. The adult, previously enrolled in the GEM-3 trial, achieved over 60% wound closure after reinitiating B-VEC via Italy's 5% Italian Medicines Agency (AIFA) access programme. No treatment-related adverse events occurred. Adjunctive care included wound hygiene optimization, nutritional and iron support, and pain control. In this small descriptive case series, B-VEC was well tolerated and associated with clinically meaningful improvement in wound healing though outcomes were more variable and, in some cases, less pronounced than those reported in pivotal trials, nevertheless supporting its integration into a comprehensive care model that addresses infection risk, anaemia, nutrition, and wound management.
2025-11-19 | Base edited skin equivalents with clinical potential for ex vivo correction of recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic disorder caused by bi-allelic null mutations in the COL7A1 gene. Among various therapeutic genome editing (GE) strategies, adenine base editors (ABEs) have demonstrated particular efficacy in nonsense mutations. Previous studies have predominantly focused on RDEB fibroblasts, which produce significantly less type VII collagen (C7) than keratinocytes. This study evaluates the efficacy and safety of ABE8e, via mRNA electroporation, to correct three different COL7A1 nonsense mutations (one homozygous and two heterozygous [patients 1, 2, and 3]), and a cryptic splice site mutation (patient 4) in primary cells from RDEB patients. Sanger and next-generation sequencing revealed high efficiency (>90%) at the intended mutation-causing nucleotides. Bystander effects were observed in two of the four loci analyzed. Deeper off-target study was performed in the first two patients. A safe off-target profile was observed in the homozygous patient (P1), while off-target effects were identified in the heterozygous patient (P2). The restoration of C7 expression in treated cells was consistent with genotypic correction. Additionally, functional assessments, including transplantation of skin equivalents formed by both base-edited keratinocytes and fibroblasts, demonstrated sustained in vivo skin regeneration and proper C7 deposition at the basement membrane. ABE8e-mediated base editing shows high efficacy and safety correcting COL7A1 mutations in the two cell types, broadening the scope of this GE therapeutic modality for RDEB treatment.
2025-05-28 | Safe and Efficacious Permanent Removal of Large COL7A1 Exons for Gene Reframing as a Reliable Therapeutic Strategy for Recessive Dystrophic Epidermolysis Bullosa.
Mutations leading to premature termination codons in COL7A1 are commonly associated with severe generalized recessive dystrophic epidermolysis bullosa (RDEB). Previous research, including our own, has indicated that removing mutated COL7A1 exons along with the consequent reframing of COL7A1 may not pose noticeable impact on protein function, offering a potential therapeutic strategy. However, investigations into the long-term in vivo effects of genome editing-mediated removal of mutant exons have only focused on the small exon 80 thus far. Hence, this study focuses on exons 73 and 105 of COL7A1 to explore whether targeted exon removal, through a CRISPR/Cas9-assisted, Non-homologous end joining (NHEJ)-mediated approach, could be extended to other larger exons. Introducing ribonucleoprotein complexes carrying Cas9 and optimized sgRNA guide pairs for each exon (73 and 105) through electroporation efficiently led to their removal, consequently restoring type VII collagen (C7) synthesis in RDEB primary patient cells carrying frameshift mutations in these exons. In vitro tests indicated the normal stability of the resulting C7 variants expressed at physiological levels, while in vivo analyses of regenerated skin grafted onto immunodeficient mice using E73 or E105 RDEB edited cells demonstrated the proper deposition of C7 at the basement membrane zone, thereby restoring normal dermo-epidermal adherence. This study enhances the broader potential of the exon deletion approach in the treatment of RDEB.
2023-06-01 | Innovations in the Treatment of Dystrophic Epidermolysis Bullosa (DEB): Current Landscape and Prospects
Abstract: Dystrophic epidermolysis bullosa (DEB) is one of the major types of EB, a rare hereditary group of trauma-induced blistering skin disorders. DEB is caused by inherited pathogenic variants in the COL7A1 gene, which encodes type VII collagen, the major component of anchoring fibrils which maintain adhesion between the outer epidermis and underlying dermis. DEB can be subclassified into dominant (DDEB) and recessive (RDEB) forms. Generally, DDEB has a milder phenotype, while RDEB patients often have more extensive blistering, chronic inflammation, skin fibrosis, and a propensity for squamous cell carcinoma development, collectively impacting on daily activities and life expectancy. At present, best practice treatments are mostly supportive, and thus there is a considerable burden of disease with unmet therapeutic need. Over the last 20 years, considerable translational research efforts have focused on either trying to cure DEB by direct correction of the COL7A1 gene pathology, or by modifying secondary inflammation to lessen phenotypic severity and improve patient symptoms such as poor wound healing, itch, and pain. In this review, we provide an overview and update on various therapeutic innovations for DEB, including gene therapy, cell-based therapy, protein therapy, and disease-modifying and symptomatic control agents. We outline the progress and challenges for each treatment modality and identify likely prospects for future clinical impact. Keywords: skin, blister, gene therapy, cell therapy, inflammation, fibrosis
2022-10-17 | Long-term safety and efficacy of gene-corrected autologous keratinocyte grafts for recessive dystrophic epidermolysis bullosa
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating blistering genodermatosis caused by mutations in the COL7A1 gene, which encodes for type VII collagen and is necessary for dermal-epidermal adhesion and integrity. Disease manifestations include severe and debilitating wounds, aggressive squamous cell carcinomas, and premature death; however, there are currently no approved therapies. This Phase 1/2a, open-label study evaluated the long-term efficacy and safety of gene-corrected autologous keratinocyte grafts (EB-101) for chronic RDEB wounds.Autologous keratinocytes were harvested from participants with severe RDEB, transduced with a retrovirus containing the full-length COL7A1 gene, and grown into 5 × 7 cm (35 cm2) sheets. Gene-corrected keratinocyte sheets were then transplanted onto chronic RDEB wounds present for ≥ 12 weeks.Seven adult participants with severe RDEB were grafted with six sheets each (42 total sheets) onto wounds and followed for a mean of 5.9 years (range 4-8 years). Long-term improvements in wound healing and symptoms were observed. At year five, 70% (21/30) of treated sites demonstrated ≥ 50% wound healing compared to baseline by investigator global assessment. No sites with ≥ 50% wound healing were painful or pruritic, compared to 67% (6/9) of sites with < 50% wound healing (p < 0.001) at year five. Grafts were well-tolerated throughout long-term follow-up. No serious adverse events related to treatment were reported over a mean of 5.9 years of follow-up. No persistent systemic autoimmunity against type VII collagen or replication-competent retrovirus infections were identified, and no participants developed squamous cell carcinomas related to treatment during long-term follow-up.Treatment with EB-101 appears safe and efficacious, and produces long-term improvements in wound healing, pain, and itch for RDEB patients. Results from the Phase 3 randomized controlled trial are forthcoming.ClinicalTrials.gov, NCT01263379. Registered December 15, 2010. https://clinicaltrials.gov/ct2/show/NCT01263379.
other
2024-08-19 | Splice modulation strategy applied to deep intronic variants in COL7A1 causing recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and most often severe genetic disease characterized by recurrent blistering and erosions of the skin and mucous membranes after minor trauma, leading to major local and systemic complications. The disease is caused by loss-of-function variants in COL7A1 encoding type VII collagen (C7), the main component of anchoring fibrils, which form attachment structures stabilizing the cutaneous basement membrane zone. Alterations in C7 protein structure and/or expression lead to abnormal, rare or absent anchoring fibrils resulting in loss of dermal-epidermal adherence and skin blistering. To date, more than 1,200 distinct COL7A1 deleterious variants have been reported and 19% are splice variants. Here, we describe two RDEB patients for whom we identified two pathogenic deep intronic pathogenic variants in COL7A1. One of these variants (c.7795-97C > G) promotes the inclusion of a pseudoexon between exons 104 and 105 in the COL7A1 transcript, while the other causes partial or complete retention of intron 51. We used antisense oligonucleotide (ASO) mediated exon skipping to correct these aberrant splicing events in vitro. This led to increased normal mRNA splicing above 94% and restoration of C7 protein expression at a level (up to 56%) that should be sufficient to reverse the phenotype. This first report of exon skipping applied to counteract deep intronic variants in COL7A1 represents a promising therapeutic strategy for personalized medicine directed at patients with intronic variants at a distance of consensus splice sites.
2023-06-20 | Variable Outcome of Immunotherapy in Advanced Multiple Cutaneous Squamous Cell Carcinomas in Two Patients with Recessive Dystrophic Epidermolysis Bullosa
Cutaneous squamous cell carcinoma (cSCC) is a major complication of recessive dystrophic epidermolysis bullosa (RDEB) that has high morbidity and mortality rates and unmet therapeutic needs. The aim of this study was to evaluate the molecular pattern of cSCC and the clinical course of immunotherapy in 2 RDEB patients with multiple advanced cSCC. Clinical course and disease staging were evaluated retrospectively. The tumour tissues were subjected to immunohistochemical staining. DNA from the blood and cSCC samples was subjected to massive parallel sequencing, and somatic mutations were determined. Patient 1 survived for over 2 years as disease control was achieved with cemiplimab and intralesional interleukin-2. The target advanced cSCC demonstrated a high rate of somatic mutations and strong expression of the immune markers, indoleamine 2,3-dioxygenase, programmed cell death protein ligand 1, and lymphocyte-activation gene 3. The patient ultimately succumbed to complications of oesophageal carcinoma. Patient 2 had an undifferentiated cSCC on the foot, which displayed a low mutational burden and did not express immune markers. The tumour progressed quickly even with cemiplimab therapy. These 2 cases underscore the challenges of cSCC treatment for RDEB. Multiple tumours with different molecular and immune profiles occur concomitantly or sequentially, and surgical excision is not always possible because of the anatomical and tissue constraints imposed by the disease itself. In conclusion, programmed cell death protein 1 inhibitors are approved and effective in treating metastatic and locally advanced cSCC. Our experience and the literature suggest that cemiplimab is an option in patients with RDEB if surgery is not. Somatic mutations and the immune microenvironment should be characterized to predict therapeutic response, particularly in aggressive undifferentiated tumours.
2023-03-14 | COL7A1 Editing via RNA Trans-Splicing in RDEB-Derived Skin Equivalents.
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.
2022-11-18 | 302 Availability of mRNA Obtained from Peripheral Blood Mononuclear Cells for Mutational Analysis in Dystrophic Epidermolysis Bullosa
Dystrophic epidermolysis bullosa (DEB) is an inheritable blistering disease caused by mutations in COL7A1, which encodes type VII collagen. To address the issue of genotype-phenotype correlations in DEB, analyzing the consequences of COL7A1 mutations using mRNA is indispensable. Herein we established a novel method for testing the effect of mutations in DEB using COL7A1 mRNA extracted from peripheral blood mononuclear cells (PBMCs). We investigated the consequences of four COL7A1 mutations (c.6573 + 1G > C, c.6216 + 5G > T, c.7270C > T and c.2527C > T) in three Japanese individuals with recessive DEB. The novel method detected the consequences of two recurrent COL7A1 mutations (c.6573 + 1G > C, c.6216 + 5G > T) and a novel COL7A1 mutation (c.7270C > T) accurately. In addition, it detected aberrant splicing resulting from a COL7A1 mutation (c.2527C > T) which was previously reported as a nonsense mutation. Furthermore, we revealed that type VII collagen-expressing cells in PBMCs have similar cell surface markers as mesenchymal stem cells; they were CD105+, CD29+, CD45-, and CD34-, suggesting that a small number of mesenchymal stem cells or mesenchymal stromal cells are circulating in the peripheral blood, which enables us to detect COL7A1 mRNA in PBMCs. Taken together, our novel method for analyzing mutation consequences using mRNA obtained from PBMCs in DEB will significantly contribute to genetic diagnoses and novel therapies for DEB.
2021-04-13 | Treatment with immunotherapy and other systemic therapies for patients with recessive dystrophic epidermolysis bullosa and cutaneous squamous cell carcinoma. A single institution experience.
Abstract Purpose. Cutaneous squamous cell carcinoma (CSCC) is a frequent complication in patients with recessive dystrophic epidermolysis bullosa (RDEB). Immunotherapy is a novel treatment approach for CSCC, however there is little experience in patients with RDEB. Methods. We included all the patients with a molecular-confirmed diagnosis of RDEB and advanced CSCC treated with systemic therapy between November 1988 and January 2021. Results . Five patients were treated with immunotherapy (n = 2), other systemic therapies (n = 2), or both (n = 1). The tolerability of immunotherapy was overall acceptable with no treatment-related serious adverse events. Radiological tumor response observed in one patient. The other patients were treated with a combination of chemotherapy and targeted therapy (EGFR inhibitors), with mixed tumor response. Median OS was 3 months (range, 1 to 11). Conclusions : Patients with RDEB and advanced CSCC benefit from immunotherapy and do not experience unexpected toxicity.
proteins
2026-09-18 | Disrupted Skin-Nerve Homeostasis in Recessive Dystrophic Epidermolysis Bullosa: a Neurocutaneous Unit Perspective on Pain.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited disorder characterised by type VII collagen impairment, leading to dermo-epidermal junction (DEJ) instability and chronic skin fragility. Pain is a near-universal and quality-of-life-limiting feature; however, explanations centred solely on tissue injury and inflammation do not fully account for its persistence or treatment resistance. Increasing evidence supports a broader framework in which disrupted skin-nerve homeostasis within the neurocutaneous unit (NCU) contributes to pain generation. This narrative, hypothesis-driven review integrates clinical, experimental and translational evidence to examine the role of the NCU, the functional interface between keratinocytes and intraepidermal sensory fibres, in RDEB pain. Chronic injury, persistent inflammation and DEJ disruption create a microenvironment that is unfavourable for sensory nerve maintenance and repair. Clinical and experimental findings support the presence of small-fibre pathology, reflected by reduced intraepidermal nerve fibre density, altered sensory thresholds and neuropathic pain descriptors. Mechanistically, repeated injury appears to impair reinnervation and contribute to progressive distal sensory fibre loss within a hostile cutaneous microenvironment. Keratinocyte dysfunction drives this process through impaired neurotrophic support and the sustained release of pro-inflammatory mediators that directly sensitise nociceptors. In parallel, dermal fibrosis and extracellular matrix remodelling may constrain axonal regeneration. Molecular studies further demonstrate a persistent inflammatory and pro-fibrotic signature in RDEB skin, including clinically non-lesional areas. These converging abnormalities suggest that disrupted skin-nerve homeostasis is an important contributor to disease-associated pain. Translational evidence suggests partial reversibility, with pain reduction observed following therapies targeting neuropathic mechanisms or restoring DEJ integrity. Together, these findings support a framework in which altered neurocutaneous interactions contribute substantially to pain in RDEB, underscoring the need for mechanism-based and potentially early neuroprotective strategies.
2025-12-27 | First experience of the application of beremagene geperpavec genetically engineered drug for treatment of congenital dystrophic epidermolysis bullosa in the Russian Federation
Congenital epidermolysis bullosa (CEB) is a group of heterogenous, hereditary genetic diseases. Emergence of blisters and erosions on the skin, slight vulnerability of the skin cover, formation of disabling deformities and aggressive skin cancer development are the main clinical manifestations of this pathology. The disease is based on a hereditary genetic defect caused by one or several mutations in the COL7A gene, leading to an insufficient synthesis of type VII collagen functional protein (COL7), which contributes to the occurrence of persistent skin wounds and their infection. Generalized recessive dystrophic epidermolysis bullosa (RDEB) leading to death of patients at a young age is the most severe form of the disease. In the Russian Federation, symptomatic methods aimed at accelerating the healing of erosive and ulcerative skin defects and preventing the development of secondary infection and correcting complications are currently being used to treat patients with CEB, including RDEB. The article presents the first experience of treatment of a patient with RDEB with beremagene geperpavec genetically engineered drug in the Russian Federation. A male patient, 14 years old, with a verified congenital dystrophic epidermolysis bullosa, recessive type, Q81.1 diagnosis was under follow-up. Treatment was carried out at the North-East Clinic with the Children’s Center of the Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology (MSPCDC). Beremagene geperpavec gel was applied to the open wounds located on the skin of the back, right axillary region, inguinal folds, lower extremities. In total, 8 applications were done during 2 months. The treatment had a pronounced therapeutic effect, which manifested itself in complete epithelialization of the wound surfaces.
2019-08-01 | Decorin counteracts disease progression in mice with recessive dystrophic epidermolysis bullosa
Loss-of-function mutations in the gene encoding type VII collagen underlie recessive dystrophic epidermolysis bullosa (RDEB), a disease characterized by skin and mucosal blistering, impaired wound healing, and diffuse dermal inflammation and fibrosis. Transforming growth factor-β signaling plays a crucial role in determining RDEB fibrotic microenvironment that leads to the development of disabling secondary disease manifestations, including hand and foot deformities. Experimental findings indicate that expression levels of decorin, a small leucine-rich proteoglycan and an endogenous TGF-β inhibitor, can modulate RDEB disease phenotype by contrasting dermal fibroblast fibrotic behavior. In this study, the ability of decorin to modify RDEB course was investigated by systemically treating RDEB mice with a lentivirus expressing human decorin. Overexpressed decorin was able to enhance survival, and to limit digit contraction and the development of paw deformities. These effects were associated with decreased TGF-β1 levels and TGF-β signaling activation. Fibrotic traits were strongly reduced in paw skin and also attenuated in the non-chronically injured back skin. However, the expression of pro-inflammatory proteins was not decreased in both paw and back skin. Our findings confirm TGF-β role in promoting fibrosis and disease progression in RDEB, and show that decorin counteracts disease manifestations by inhibiting TGF-β activation. More generally, our data indicate that modifying extracellular matrix composition is an option to improve RDEB disease course.
2017-10-01 | 192 Loss of keratinocyte type VII collagen induces increased DNA damage in vitro and in vivo
Epidermolysis Bullosa is a severe blistering disease caused by mutations in basement membrane genes and is characterised by severe blistering of the skin and increased predisposition to cancer. To investigate the function of the skin basement membrane, siRNA knockdown of type IV, VII (Col7) and XVII (Col17) collagens was performed in primary neonatal foreskin keratinocytes. Global transcriptomic analysis was carried out using RNA-Seq. Pathway analysis revealed dysregulation of genes involved in DNA damage and cell cycle control in cells with Col7 and Col17 knockdown predicting reduced proliferation of siCol7 cells and increased proliferation of siCol17 cells which was confirmed in in vitro proliferation assays. Rescue experiments involving addition of recombinant Col7 or knockdown of TGFβ receptor 1 resulted in normalisation of c-Myc and cyclin expression in siCol7 cells. Primary keratinocytes transfected with siC (non-targeting control), siCol7 or siCol17 were treated with UV or mitomycin-C to induce DNA damage. The siCol7 cells have markedly decreased phosphorylation of Chk1 and Chk2 suggesting an inability to recognise DNA damage. Increased g-H2A.X expression was observed in siCol7 cells suggesting the presence of DNA double-strand breaks. Increased g-H2A.X and 53BP1 nuclear foci and decreased Ki-67 were observed in neonatal skin from a mouse model of RDEB indicating increased DNA damage, and injection with human recombinant type VII collagen was sufficient to reduce DNA damage, but not proliferation, to wild type control levels. Our findings suggest that aberrant TGF-beta signalling in RDEB with loss of type VII collagen results in loss of keratinocyte ability to repair DNA, decreased keratinocyte proliferation and genomic instability resulting in early SCC development.
2017-09-08 | 568 Investigation of the role of type VII collagen in the HIF1α induced pro-angiogenic pathway
Type VII collagen (Col7) is the main component of anchoring fibrils in the basement membrane of skin. Loss of function mutations in the COL7A1 gene lead to recessive dystrophic epidermolysis bullosa (RDEB) with severe congenital blistering, scarring and later development of aggressive squamous cell carcinomas (SCCs). A recent study from our group has shown an increase in angiogenesis with loss of Col7 in RDEB. One of the main regulators of tumour angiogenesis is hypoxia. The most important regulator of the cellular response to hypoxia is the transcription factor HIF-1 and its subunit HIF-1α. In this study, we investigated the effect of hypoxia on SCC cell lines with loss of Col7 on HIF-1α, VEGFR1 and other angiogenic factors. SCC cells with stable knock down (KD) of Col7 established using lentiviral shRNA were grown in normoxia (20% oxygen) or hypoxia (0.2% oxygen). RNA and protein lysates were prepared and analysed using RT-PCR and western blotting. Findings were confirmed in vivo in mouse xenograft tumours generated using Col7 knockdown cells. Increased HIF-1α mRNA and protein expression were observed with knock down of Col7 (shCol7) compared to control (shC). Global expression profiling identified a number of angiogenesis related genes differentially regulated with loss of Col7 that were further investigated. Increased expression of VEGFR1, Amphiregulin, UPA and Ephrin A1 were all observed with loss of Col7. These changes were amplified by hypoxia and could be reversed in vivo by treatment with human recombinant Col7 (hrCol7). These data demonstrate that loss of Col7 enhances hypoxic signals and the expression of pro-angiogenic factors which are reversed by hrCol7. This work improves our understanding of angiogenesis in RDEB and could lead to new therapeutic strategies for RDEB wounds and SCC targeting angiogenic pathways and the adaptive hypoxic response activated by loss of Col7.
small molecules
2026-09-24 | Minimally Invasive Caries Arrest and Oral Rehabilitation for a Patient With Severe Recessive Dystrophic Epidermolysis Bullosa.
To describe the stepwise, atraumatic dental management of a pediatric patient with severe recessive dystrophic epidermolysis bullosa (RDEB), emphasizing conservative caries arrest, the challenges of restorative care within a severely microstomia-limited oral opening, and coordinated multidisciplinary care. A male patient with severe RDEB was followed at a university pediatric dental clinic from Age 13 to 14 years within a dental home maintained since infancy. Serial silver diamine fluoride applications arrested multiple occlusal carious lesions. Glass ionomer sealants were placed on seven teeth without retraction or mirror use. At Age 14, comprehensive restorative care under general anesthesia included stainless-steel crown placement on a mandibular first molar and glass ionomer restorations on two additional teeth, all accomplished through a maximum interincisal opening of approximately 30 mm. Fiber-optic nasal intubation required multiple attempts. Six-month follow-up confirmed caries-free status and intact restorations. A guideline-driven, stepwise protocol combining conservative caries arrest, glass ionomer sealants and restorations, and targeted general anesthesia care preserved oral function while minimizing mucosal trauma. Multidisciplinary coordination supported the care episode, with anesthesiology managing the difficult airway, dermatology advising on the treatment setting and mucosal protection, and hematology optimizing the patient's baseline iron-deficiency anemia.
2026-06-30 | Clinical outcomes of gentamicin therapy in dystrophic Epidermolysis Bullosa: a case-based literature review
Introduction: Epidermolysis bullosa (EB) comprises a group of inherited disorders characterized by skin fragility and blister formation resulting from mutations in proteins essential for dermoepidermal adhesion. Dystrophic EB (DEB), particularly its recessive form (RDEB), is caused by mutations in the COL7A1 gene, leading to defective type VII collagen and impaired anchoring fibrils. Clinically, severe forms are associated with chronic wounds, scarring, pseudosyndactyly, mucosal involvement, and increased risk of cutaneous squamous cell carcinoma. Current therapeutic options remain limited and largely supportive. Gentamicin has emerged as a potential disease-modifying therapy due to its ability to induce translational readthrough of nonsense mutations, restoring partial production of functional collagen VII. This study aims to analyze published cases of EB treated with gentamicin and identify patterns in clinical response and therapeutic outcomes. Methodology: A case-based literature review was conducted, including studies published between 2020 and 2026, retrieved from the PubMed and SciELO databases, in English, Portuguese, and Spanish. Patients with severe generalized dystrophic epidermolysis bullosa treated with gentamicin were included. Extracted variables comprised age, sex, EB subtype, genetic mutation, route of administration (topical or intravenous), treatment duration, methods used to assess response (including immunofluorescence, quality of life scales, and pain scores), collagen VII expression before and after treatment, clinical improvement, adverse effects, and follow-up duration. Data from four studies were compiled into a comparative table to identify trends in therapeutic response and safety outcomes. Discussion: Across the analyzed cases, gentamicin therapy was consistently associated with increased expression of type VII collagen and corresponding clinical improvement, including enhanced wound healing and reduction of mucocutaneous lesions. These findings support its mechanism of action as a readthrough agent that partially restores protein synthesis in patients with nonsense mutations in COL7A1. Both topical and intravenous routes demonstrated therapeutic benefit, although with different clinical profiles. Topical administration was predominantly associated with localized improvement, particularly in oral and cutaneous lesions, reflecting its direct action on treated areas. In contrast, intravenous administration was associated with more systemic effects. Despite these promising findings, variability in treatment response was observed, likely influenced by mutation type, disease severity, and differences in treatment protocols. Additionally, methodological heterogeneity across studies, such as variation in biopsy sites, outcome measures, and duration of therapy, limits direct comparability. Importantly, no significant adverse effects were reported across the included studies, suggesting a favorable short-term safety profile. Some studies also demonstrated maintenance of collagen VII expression after treatment discontinuation, although without evidence of progressive improvement over time. Conclusion: Gentamicin appears to be a promising therapeutic strategy for patients with dystrophic epidermolysis bullosa, particularly those with nonsense mutations in COL7A1. The available evidence demonstrates increased collagen VII expression and associated clinical improvement, regardless of the route of administration. The absence of significant adverse effects supports its short-term safety. However, further large-scale and controlled studies are needed to establish standardized treatment protocols and confirm long-term efficacy.
2025-11-25 | Assessment of Growth Hormone and Insulin-Like Growth Factor 1 in Children With Epidermolysis Bullosa Dystrophica.
Epidermolysis bullosa dystrophica (EBD) is characterized by mucocutaneous fragility with blistering, scarring and severe growth retardation attributed to many factors. This cross-sectional study included 51 patients aged 1-12 years with recessive dystrophic EB (RDEB). Weight and height were measured, with the calculation of weight standard deviation (SD), height SD, and body mass index (BMI), followed by plotting them on Egyptian growth curves. Serum levels of basal growth hormone (GH), insulin-like growth factor 1 (IGF-1), hemoglobin (Hb) level, erythrocyte sedimentation rate (ESR), and thyroid functions (TSH and free T4) were measured. Growth hormone stimulation test was performed in 11 patients. Weight SD and height SD were lower than normal measurements (p < 0.05*). Growth hormone, growth hormone stimulation, and IGF-1 were lower than the normal range (p < 0.05*). Hb levels were lower than normal, whereas ESR levels were elevated (p < 0.001*). A negative correlation was found between ESR and basal GH, and a positive correlation between ESR and IGF-1. Children with generalized RDEB have poor growth and low circulating GH and IGF-1 levels, likely due not only to malnutrition and anemia, but possibly also as a consequence of inflammation that suppresses the GH/IGF-1 axis. Future treatments targeting the correction of GH and IGF-1 levels as well as the chronic inflammatory state should be considered. ClinicalTrials.gov identifier: NCT05390073.
2025-09-03 | Safety and Efficacy of Angiotensin Receptor Antagonists in Recessive Dystrophic Epidermolysis Bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited progressive blistering skin disorder caused by mutations in the COL7A1 gene. Chronic wounds lead to cycles of scarring and healing, causing severe functional deformities. Losartan is an angiotensin II type 1 receptor (AT1R) antagonist that has been shown to have antifibrotic activity via inhibiting the production of transforming growth factor beta (TGF-B) and has a favourable safety profile in children. In this systematic review, there were five studies found, with a total of 59 patients including case series, case-control and an open label phase 2 clinical trial. These studies have demonstrated the safety of losartan with no significant adverse effects such as hypotension, hyperkalaemia and hypersensitivity. They have also demonstrated evidence of efficacy utilising subjective assessments and objective criteria such as the Birmingham Epidermolysis Bullosa Severity score (BEBS) and Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI). Although safe and effective, further clinical trials are required to fully elucidate the role of this treatment; whether this approach should be standardised across the RDEB patient cohort is yet to be determined from the current evidence. Trial Registration: PROSPERO ID: CRD42024557126.
2025-01-24 | Repurposing diacerein for the treatment of chronic wounds in recessive-dystrophic epidermolysis bullosa patients by modulating matrix metalloproteinase-9 expression.
Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in COL7A1, leading to loss or dysfunction of type-VII collagen (C7), a protein essential for skin stability. Clinically, patients suffer from severe skin blistering, chronic or recurrent wounds, and scarring, which predispose to early onset of aggressive squamous cell carcinoma. Previous studies showed that RDEB-keratinocytes (RDEB-KC) express high levels of matrix-metalloproteinase 9 (MMP-9), a molecule known to play a crucial role in wound chronification if dysregulated. We investigated the potential of diacerein, a small molecule that interferes with the MMP-9 regulatory pathway, to improve wound healing in a 5-year old RDEB patient presenting with chronic, generalized skin involvement unresponsive to previous treatment approaches. Upon 4 weeks of topical therapy applied to the patient's back, parents reported a nearly complete wound closure and a significant increase in quality of life. We also provide evidence that diacerein treatment of patient keratinocytes results in a downregulation of MMP-9 expression, accompanied by a reduction in their ability to degrade a fibrinogen matrix. These data characterize diacerein as a potential candidate for improving wound healing in RDEB through its impact on inflammatory as well as epithelial cells.
cell therapies
2026-06-28 | Identification of a long-term surviving human mesenchymal stromal cell subpopulation and implications for recessive dystrophic epidermolysis bullosa treatment.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by loss-of-function pathogenic variants in COL7A1 encoding type VII collagen (C7). Patients with RDEB suffer since birth from skin and mucosal blistering and develop severe local and systemic complications resulting in poor prognosis. Mesenchymal stromal cells (MSCs) have demonstrated their potential to enhance wound healing and reduce skin inflammation in RDEB patients due to their anti-inflammatory properties and capacity to express C7. We aim to optimize in vitro conditioning of human bone marrow-derived MSCs (BM-MSCs) to improve their limited survival following local injection in a murine model. BM-MSCs from healthy human donors were transduced with a lentiviral vector encoding firefly luciferase and mCherry reporter proteins and then subjected to various culture conditions: monolayer on plastic or spheroid culture, either in hypoxia (5% O2) or in normoxia (21% O2). These cells were subsequently injected intradermally (ID) in immunodeficient mice and their survival was assessed by in vivo imaging. BM-MSCs populations were analyzed prior to injection by single-cell RNA sequencing (scRNAseq). Murine skin injected with BM-MSCs were sampled two months post-injection and the surviving subpopulations were characterized by spatial transcriptomic. scRNAseq analysis revealed marked variations between monolayer and spheroid conditions, which were significantly impacted by oxygen level. Although most injected cells gradually died within the first 2 months in all tested conditions, 1% of live bioluminescent cells persisted for 54 up to 61 weeks post-injection. Spatial transcriptomics data analysis demonstrated that all surviving cells, regardless of their in vitro preconditioning, retained the expression of the MSC markers THY1, ENG, and NT5E, shared features with fibroblasts, and exhibited enriched expression in genes related to extracellular matrix and collagen fibril organization, which are key processes in wound healing. Spatial transcriptomic and scRNAseq data integration suggested that surviving BM-MSCs were initially present in the injected population, regardless of their culture condition. Remarkably, none of the in vitro preconditioning strategies appeared to affect their survival capacity or functional properties following local injection. The identification and characterization of a BM-MSC subpopulation capable of long-term survival following ID injection hold promise for the development of improved cell therapy protocols for RDEB.
2026-05-21 | MesenSistem-EB: systemic haploidentical mesenchymal stem cell therapy in recessive dystrophic epidermolysis bullosa associated with clinical benefits and correlated with MCP1 and sCD40L dynamics.
Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating genodermatosis caused by biallelic COL7A1 mutations, where chronic inflammation drives disabling complications affecting quality of life and survival. Effective inflammatory control remains a major unmet need. While systemic administration of mesenchymal stromal cells (MSC) from various sources has proven safe with transient benefits yet only one recent placebo-controlled study in RDEB. Consistent type VII collagen (C7) deposition is lacking, and therapeutic mechanisms and predictive biomarkers remain undefined. The MesenSistem-EB trial evaluated for the first time the use of haploidentical BM-MSC and extensively explored their anti-inflammatory potential as a monotherapy in RDEB. Phase I/II, single-center, open-label trial, in which nine children with severe RDEB were recruited and eight completed the study after three intravenous infusions of haploidentical BM-MSC (2-3×106 cells/kg) at 21-day intervals. Safety, clinical and patient-reported outcomes, systemic inflammatory mediators and peripheral blood immune profiles were assessed over 12 months. MSC therapy was well-tolerated without serious adverse events. Long-term pruritus, sleep and fatigue were globally reduced. In 7/8 patients at least one key domain significantly improved (disease severity, pruritus, or inflammation) with five classified as good responders. Global median CRP and fibrinogen levels remained stable throughout the study period. Responses correlated with sCD40L and MCP1 dynamics. Flow cytometry revealed altered circulating myeloid and lymphoid compartments at baseline. Post-infusion, immune cell subset changes did not consistently distinguish responders while typically including increased CLA expression on monocytes, partial recovery of memory CD8+ T cells and disappearance of an aberrant granulocyte population, potentially linked to immature myeloid mobilization driven by chronic inflammation. Haploidentical MSC did not consistently confer durable engraftment or sustained C7 deposition. BM-MSC is a safe and potentially effective anti-inflammatory intervention that mitigates the expected escalation of systemic inflammatory markers during a critical phase of RDEB progression. MCP1 and sCD40L modulation, with both potentially serving as predictive biomarkers. MSC appear to exert both shared and patient-specific immunomodulatory effects depending on baseline inflammatory cues. Findings provide insights into individual variability, underlying mechanisms and potential therapeutic responsiveness, supporting their use also as a complementary strategy. ClinicalTrials.gov, identifier NCT04153630.
2026-05-13 | Amniotic Membrane Transplantation Preserves Vision in Pediatric Recessive Dystrophic Epidermolysis Bullosa: Case Series.
Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited disorder characterized by extreme epithelial fragility and progressive cicatrization, frequently leading to severe ocular surface disease and early visual impairment. Surgical interventions such as ocular surface reconstruction (OSR) in childhood are often delayed because of anesthetic risks and concerns regarding recurrence. Consequently, the effectiveness of OSR, including amniotic membrane transplantation (AMT), and its impact on visual development remain poorly documented. Methods: We report a case series of two pediatric patients (three eyes) with genetically confirmed RDEB who underwent single-step OSR using AMT. Clinical outcomes, long-term visual acuity, perioperative management, and histopathological findings were evaluated. Results: Ocular manifestations included corneal epithelial damage, symblepharon, and pseudopterygium extending over the cornea. One patient underwent symblepharon lysis, superficial keratectomy, and AMT onto the bare sclera in the right eye at age 4 and in the left eye at age 8, both under intubated general anesthesia. The other patient underwent the same procedure in the right eye at age 6. Best spectacle-corrected visual acuity improved from ≤20/300 to 20/30 in all eyes, and pupillary zone clarity was maintained during the follow-up period (up to 6 years). Histopathology confirmed pseudopterygium with squamous metaplasia, goblet cell loss, and fibrovascular stroma. Safe general anesthesia was achieved through meticulous multidisciplinary perioperative planning involving anesthesiologists, dermatologists, and pediatricians. No systemic complications related to anesthesia or perioperative management were observed. Conclusions: Single-step OSR with on-lay AMT can restore and preserve visual function in pediatric RDEB. Early surgical intervention may prevent profound amblyopia and provide durable ocular surface stability. A multidisciplinary approach enables safe general anesthesia and perioperative management.
2025-12-04 | IPSC-derived organoid-sourced skin cells enable functional 3D skin modeling of recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited skin disorder caused by mutations in COL7A1. Patient-derived induced pluripotent stem cells (iPSCs) enable the personalized study of RDEB pathogenesis and potential therapies. However, current skin cell differentiation protocols via 2D culture perform suboptimally when applied to engineered 3D skin constructs (ESC). Here, we present an approach to source fibroblasts (iFBs) and keratinocytes (iKCs) from iPSC-derived skin organoids using an optimized differentiation protocol, and utilize them to engineer ESCs modeling wild-type and RDEB phenotypes. The resulting iPSC-derived skin cells display marker expression consistent with primary counterparts and produce ESCs exhibiting significant extracellular matrix remodeling, protein deposition, and epidermal differentiation. RDEB constructs recapitulated hallmark disease features, including absence of collagen VII and reduced iFB proliferation. This work establishes a robust and scalable strategy for generating physiologically-relevant, iPSC-derived skin constructs, offering a powerful model for studying RDEB mechanisms and advancing personalized regenerative medicine.
2025-05-22 | Mesenchymal intravenous stromal cell infusions in children with recessive dystrophic epidermolysis bullosa: MissionEB protocol for a randomised, double-blinded, placebo-controlled, two-centre, crossover trial with an internal phase I dose de-escalation phase and open-label extension.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic mucocutaneous fragility disorder characterised by chronic blistering, slow wound healing and increased risk of squamous cell carcinoma. Current management options are very limited. This is a randomised (1:1), placebo-controlled, double-blinded crossover (A/B) trial with an internal phase I dose de-escalation (4+5 design) in the first 3 months and a 12-month continued treatment follow-on open-label study if 3-month outcome data from the crossover trial indicate safe and beneficial effects. RDEB is a rare condition, so we expect to recruit a maximum of 36 participants based on feasibility and not formal power considerations. Participants aged>6 months and <16 years will be recruited at Great Ormond Street Hospital and Birmingham Children's Hospital. They will receive 2-3×106 cells/kg intravenous infusion of umbilical cord-derived mesenchymal stem cells or placebo at the start of each crossover period (day 0) and 14 days later. The dose will be de-escalated to 1-1.5×106 cells/kg depending on observed toxicity. For the main crossover trial, the primary outcome is the change in disease severity as measured by the Epidermolysis Bullosa Disease Activity and Scarring Index at 3 months from day 0 infusion. Secondary outcomes measured at 3 and 6 months from day 0 infusion include changes in general clinical appearance of skin disease, pain and itch, and quality of life. Adverse events and serious adverse events will be monitored throughout the trial. North East-York Research Ethics Committee approved the protocol (ref: 21/NE/0016) on 16 March 2021. Findings will be published in peer-reviewed scientific journals, presented at relevant national and international conferences, and an open-access final report submitted to the funder. ISRCTN14409785. Protocol V. 8.0, 14 November 2022.
gene therapies
2026-08-11 | Topical gene therapy for severe recessive dystrophic epidermolysis bullosa: clinical outcomes and multidisciplinary management in three patients treated with beremagene geperpavec (B-VEC) in Italy - a case series.
Recessive dystrophic epidermolysis bullosa is a severe inherited blistering disorder characterized by chronic wounds, fibrosis and systemic complications. Beremagene geperpavec (B-VEC), a topical HSV1-based gene therapy delivering full-length COL7A1, has shown efficacy in clinical trials; however, real-world data remain limited. This retrospective, descriptive case series reports on three patients with genetically confirmed recessive dystrophic epidermolysis bullosa - two children and one young adult - treated between 2024 and 2026 at two Italian tertiary centres. All patients had extensive chronic skin involvement and received weekly topical B-VEC. Clinical data included wound characteristics, response to therapy, supportive care and adverse events. All patients showed clinically meaningful improvement in target wound healing. One child achieved ~70% reduction in the wound area needing treatment; the second had ~50% with shallower morphology and reduced bleeding. The adult, previously enrolled in the GEM-3 trial, achieved over 60% wound closure after reinitiating B-VEC via Italy's 5% Italian Medicines Agency (AIFA) access programme. No treatment-related adverse events occurred. Adjunctive care included wound hygiene optimization, nutritional and iron support, and pain control. In this small descriptive case series, B-VEC was well tolerated and associated with clinically meaningful improvement in wound healing though outcomes were more variable and, in some cases, less pronounced than those reported in pivotal trials, nevertheless supporting its integration into a comprehensive care model that addresses infection risk, anaemia, nutrition, and wound management.
2025-11-19 | Base edited skin equivalents with clinical potential for ex vivo correction of recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic disorder caused by bi-allelic null mutations in the COL7A1 gene. Among various therapeutic genome editing (GE) strategies, adenine base editors (ABEs) have demonstrated particular efficacy in nonsense mutations. Previous studies have predominantly focused on RDEB fibroblasts, which produce significantly less type VII collagen (C7) than keratinocytes. This study evaluates the efficacy and safety of ABE8e, via mRNA electroporation, to correct three different COL7A1 nonsense mutations (one homozygous and two heterozygous [patients 1, 2, and 3]), and a cryptic splice site mutation (patient 4) in primary cells from RDEB patients. Sanger and next-generation sequencing revealed high efficiency (>90%) at the intended mutation-causing nucleotides. Bystander effects were observed in two of the four loci analyzed. Deeper off-target study was performed in the first two patients. A safe off-target profile was observed in the homozygous patient (P1), while off-target effects were identified in the heterozygous patient (P2). The restoration of C7 expression in treated cells was consistent with genotypic correction. Additionally, functional assessments, including transplantation of skin equivalents formed by both base-edited keratinocytes and fibroblasts, demonstrated sustained in vivo skin regeneration and proper C7 deposition at the basement membrane. ABE8e-mediated base editing shows high efficacy and safety correcting COL7A1 mutations in the two cell types, broadening the scope of this GE therapeutic modality for RDEB treatment.
2025-05-28 | Safe and Efficacious Permanent Removal of Large COL7A1 Exons for Gene Reframing as a Reliable Therapeutic Strategy for Recessive Dystrophic Epidermolysis Bullosa.
Mutations leading to premature termination codons in COL7A1 are commonly associated with severe generalized recessive dystrophic epidermolysis bullosa (RDEB). Previous research, including our own, has indicated that removing mutated COL7A1 exons along with the consequent reframing of COL7A1 may not pose noticeable impact on protein function, offering a potential therapeutic strategy. However, investigations into the long-term in vivo effects of genome editing-mediated removal of mutant exons have only focused on the small exon 80 thus far. Hence, this study focuses on exons 73 and 105 of COL7A1 to explore whether targeted exon removal, through a CRISPR/Cas9-assisted, Non-homologous end joining (NHEJ)-mediated approach, could be extended to other larger exons. Introducing ribonucleoprotein complexes carrying Cas9 and optimized sgRNA guide pairs for each exon (73 and 105) through electroporation efficiently led to their removal, consequently restoring type VII collagen (C7) synthesis in RDEB primary patient cells carrying frameshift mutations in these exons. In vitro tests indicated the normal stability of the resulting C7 variants expressed at physiological levels, while in vivo analyses of regenerated skin grafted onto immunodeficient mice using E73 or E105 RDEB edited cells demonstrated the proper deposition of C7 at the basement membrane zone, thereby restoring normal dermo-epidermal adherence. This study enhances the broader potential of the exon deletion approach in the treatment of RDEB.
2023-06-01 | Innovations in the Treatment of Dystrophic Epidermolysis Bullosa (DEB): Current Landscape and Prospects
Abstract: Dystrophic epidermolysis bullosa (DEB) is one of the major types of EB, a rare hereditary group of trauma-induced blistering skin disorders. DEB is caused by inherited pathogenic variants in the COL7A1 gene, which encodes type VII collagen, the major component of anchoring fibrils which maintain adhesion between the outer epidermis and underlying dermis. DEB can be subclassified into dominant (DDEB) and recessive (RDEB) forms. Generally, DDEB has a milder phenotype, while RDEB patients often have more extensive blistering, chronic inflammation, skin fibrosis, and a propensity for squamous cell carcinoma development, collectively impacting on daily activities and life expectancy. At present, best practice treatments are mostly supportive, and thus there is a considerable burden of disease with unmet therapeutic need. Over the last 20 years, considerable translational research efforts have focused on either trying to cure DEB by direct correction of the COL7A1 gene pathology, or by modifying secondary inflammation to lessen phenotypic severity and improve patient symptoms such as poor wound healing, itch, and pain. In this review, we provide an overview and update on various therapeutic innovations for DEB, including gene therapy, cell-based therapy, protein therapy, and disease-modifying and symptomatic control agents. We outline the progress and challenges for each treatment modality and identify likely prospects for future clinical impact. Keywords: skin, blister, gene therapy, cell therapy, inflammation, fibrosis
2022-10-17 | Long-term safety and efficacy of gene-corrected autologous keratinocyte grafts for recessive dystrophic epidermolysis bullosa
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating blistering genodermatosis caused by mutations in the COL7A1 gene, which encodes for type VII collagen and is necessary for dermal-epidermal adhesion and integrity. Disease manifestations include severe and debilitating wounds, aggressive squamous cell carcinomas, and premature death; however, there are currently no approved therapies. This Phase 1/2a, open-label study evaluated the long-term efficacy and safety of gene-corrected autologous keratinocyte grafts (EB-101) for chronic RDEB wounds.Autologous keratinocytes were harvested from participants with severe RDEB, transduced with a retrovirus containing the full-length COL7A1 gene, and grown into 5 × 7 cm (35 cm2) sheets. Gene-corrected keratinocyte sheets were then transplanted onto chronic RDEB wounds present for ≥ 12 weeks.Seven adult participants with severe RDEB were grafted with six sheets each (42 total sheets) onto wounds and followed for a mean of 5.9 years (range 4-8 years). Long-term improvements in wound healing and symptoms were observed. At year five, 70% (21/30) of treated sites demonstrated ≥ 50% wound healing compared to baseline by investigator global assessment. No sites with ≥ 50% wound healing were painful or pruritic, compared to 67% (6/9) of sites with < 50% wound healing (p < 0.001) at year five. Grafts were well-tolerated throughout long-term follow-up. No serious adverse events related to treatment were reported over a mean of 5.9 years of follow-up. No persistent systemic autoimmunity against type VII collagen or replication-competent retrovirus infections were identified, and no participants developed squamous cell carcinomas related to treatment during long-term follow-up.Treatment with EB-101 appears safe and efficacious, and produces long-term improvements in wound healing, pain, and itch for RDEB patients. Results from the Phase 3 randomized controlled trial are forthcoming.ClinicalTrials.gov, NCT01263379. Registered December 15, 2010. https://clinicaltrials.gov/ct2/show/NCT01263379.
other
2024-08-19 | Splice modulation strategy applied to deep intronic variants in COL7A1 causing recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and most often severe genetic disease characterized by recurrent blistering and erosions of the skin and mucous membranes after minor trauma, leading to major local and systemic complications. The disease is caused by loss-of-function variants in COL7A1 encoding type VII collagen (C7), the main component of anchoring fibrils, which form attachment structures stabilizing the cutaneous basement membrane zone. Alterations in C7 protein structure and/or expression lead to abnormal, rare or absent anchoring fibrils resulting in loss of dermal-epidermal adherence and skin blistering. To date, more than 1,200 distinct COL7A1 deleterious variants have been reported and 19% are splice variants. Here, we describe two RDEB patients for whom we identified two pathogenic deep intronic pathogenic variants in COL7A1. One of these variants (c.7795-97C > G) promotes the inclusion of a pseudoexon between exons 104 and 105 in the COL7A1 transcript, while the other causes partial or complete retention of intron 51. We used antisense oligonucleotide (ASO) mediated exon skipping to correct these aberrant splicing events in vitro. This led to increased normal mRNA splicing above 94% and restoration of C7 protein expression at a level (up to 56%) that should be sufficient to reverse the phenotype. This first report of exon skipping applied to counteract deep intronic variants in COL7A1 represents a promising therapeutic strategy for personalized medicine directed at patients with intronic variants at a distance of consensus splice sites.
2023-06-20 | Variable Outcome of Immunotherapy in Advanced Multiple Cutaneous Squamous Cell Carcinomas in Two Patients with Recessive Dystrophic Epidermolysis Bullosa
Cutaneous squamous cell carcinoma (cSCC) is a major complication of recessive dystrophic epidermolysis bullosa (RDEB) that has high morbidity and mortality rates and unmet therapeutic needs. The aim of this study was to evaluate the molecular pattern of cSCC and the clinical course of immunotherapy in 2 RDEB patients with multiple advanced cSCC. Clinical course and disease staging were evaluated retrospectively. The tumour tissues were subjected to immunohistochemical staining. DNA from the blood and cSCC samples was subjected to massive parallel sequencing, and somatic mutations were determined. Patient 1 survived for over 2 years as disease control was achieved with cemiplimab and intralesional interleukin-2. The target advanced cSCC demonstrated a high rate of somatic mutations and strong expression of the immune markers, indoleamine 2,3-dioxygenase, programmed cell death protein ligand 1, and lymphocyte-activation gene 3. The patient ultimately succumbed to complications of oesophageal carcinoma. Patient 2 had an undifferentiated cSCC on the foot, which displayed a low mutational burden and did not express immune markers. The tumour progressed quickly even with cemiplimab therapy. These 2 cases underscore the challenges of cSCC treatment for RDEB. Multiple tumours with different molecular and immune profiles occur concomitantly or sequentially, and surgical excision is not always possible because of the anatomical and tissue constraints imposed by the disease itself. In conclusion, programmed cell death protein 1 inhibitors are approved and effective in treating metastatic and locally advanced cSCC. Our experience and the literature suggest that cemiplimab is an option in patients with RDEB if surgery is not. Somatic mutations and the immune microenvironment should be characterized to predict therapeutic response, particularly in aggressive undifferentiated tumours.
2023-03-14 | COL7A1 Editing via RNA Trans-Splicing in RDEB-Derived Skin Equivalents.
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.
2022-11-18 | 302 Availability of mRNA Obtained from Peripheral Blood Mononuclear Cells for Mutational Analysis in Dystrophic Epidermolysis Bullosa
Dystrophic epidermolysis bullosa (DEB) is an inheritable blistering disease caused by mutations in COL7A1, which encodes type VII collagen. To address the issue of genotype-phenotype correlations in DEB, analyzing the consequences of COL7A1 mutations using mRNA is indispensable. Herein we established a novel method for testing the effect of mutations in DEB using COL7A1 mRNA extracted from peripheral blood mononuclear cells (PBMCs). We investigated the consequences of four COL7A1 mutations (c.6573 + 1G > C, c.6216 + 5G > T, c.7270C > T and c.2527C > T) in three Japanese individuals with recessive DEB. The novel method detected the consequences of two recurrent COL7A1 mutations (c.6573 + 1G > C, c.6216 + 5G > T) and a novel COL7A1 mutation (c.7270C > T) accurately. In addition, it detected aberrant splicing resulting from a COL7A1 mutation (c.2527C > T) which was previously reported as a nonsense mutation. Furthermore, we revealed that type VII collagen-expressing cells in PBMCs have similar cell surface markers as mesenchymal stem cells; they were CD105+, CD29+, CD45-, and CD34-, suggesting that a small number of mesenchymal stem cells or mesenchymal stromal cells are circulating in the peripheral blood, which enables us to detect COL7A1 mRNA in PBMCs. Taken together, our novel method for analyzing mutation consequences using mRNA obtained from PBMCs in DEB will significantly contribute to genetic diagnoses and novel therapies for DEB.
2021-04-13 | Treatment with immunotherapy and other systemic therapies for patients with recessive dystrophic epidermolysis bullosa and cutaneous squamous cell carcinoma. A single institution experience.
Abstract Purpose. Cutaneous squamous cell carcinoma (CSCC) is a frequent complication in patients with recessive dystrophic epidermolysis bullosa (RDEB). Immunotherapy is a novel treatment approach for CSCC, however there is little experience in patients with RDEB. Methods. We included all the patients with a molecular-confirmed diagnosis of RDEB and advanced CSCC treated with systemic therapy between November 1988 and January 2021. Results . Five patients were treated with immunotherapy (n = 2), other systemic therapies (n = 2), or both (n = 1). The tolerability of immunotherapy was overall acceptable with no treatment-related serious adverse events. Radiological tumor response observed in one patient. The other patients were treated with a combination of chemotherapy and targeted therapy (EGFR inhibitors), with mixed tumor response. Median OS was 3 months (range, 1 to 11). Conclusions : Patients with RDEB and advanced CSCC benefit from immunotherapy and do not experience unexpected toxicity.
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Drug Discovery Landscape
1 orphan drug designation for Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form.
1 orphan drug designation for Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Angiotensin (1-7) | peptides | FDA | — | Constant Therapeutics LLC |
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