Unveiling the value of C-reactive protein as a severity biomarker and the IL4/IL13 pathway as a therapeutic target in recessive dystrophic epidermolysis bullosa: A multiparametric cross-sectional study.

Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience numerous complications, which are exacerbated by inflammatory dysregulation and infection. Understanding the immunological mechanisms is crucial for selecting medications that balance inflammation control and immunocompetence. In this cross-sectional study, aiming to identify potential immunotherapeutic targets and inflammatory biomarkers, we delved into the interrelationship between clinical severity and systemic inflammatory parameters in a representative RDEB cohort. Encompassing 84 patients aged 1-67 and spanning all three Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) severity categories, we analysed the interrelationship of infection history, standard inflammatory markers, systemic cytokines and Ig levels to elucidate their roles in RDEB pathophysiology. Our findings identify C-reactive protein as an excellent biomarker for disease severity in RDEB. A type 2 inflammatory profile prevails among moderate and severe RDEB patients, correlating with dysregulated circulating IgA and IgG. These results underscore the IL4/IL13 pathways as potential evidence-based therapeutic targets. Moreover, the complete inflammatory scenario aligns with Staphylococcus aureus virulence mechanisms. Concurrently, abnormalities in IgG, IgE and IgM levels suggest an immunodeficiency state in a substantial number of the cohort's patients. Our results provide new insights into the interplay of infection and immunological factors in the pathogenesis of RDEB.

Functional genotype-phenotype associations in recessive dystrophic epidermolysis bullosa.

BACKGROUND: Genotype-phenotype associations in recessive dystrophic epidermolysis bullosa (RDEB) have been difficult to elucidate. OBJECTIVE: To investigate RDEB genotype-phenotype associations and explore a functional approach to genotype classification. METHODS: Clinical examination and genetic testing of RDEB subjects, including assessment of clinical disease by RDEB subtype and extent of blistering. Genotypes were evaluated according to each variant's effect on type VII collagen function per updated literature and subsequently categorized by degree of impact on VII collagen function as low-impact (splice/missense, missense/missense), medium-impact (premature termination codon [PTC]/missense, splice/splice), and high-impact (PTC/PTC, PTC/splice). Genotype-phenotype associations were investigated using Kruskal-Wallis and Fisher's exact tests, and age-adjusted regressions. RESULTS: Eighty-three participants were included. High-impact variants were associated with worse RDEB subtype and clinical disease, including increased prevalence of generalized blistering (55.6% for low-impact vs 72.7% medium-impact vs 90.4% high-impact variants, P = .002). In age-adjusted regressions, participants with high-impact variants had 40.8-fold greater odds of squamous cell carcinoma compared to low-impact variants (P = .02), and 5.7-fold greater odds of death compared to medium-impact variants (P = .05). LIMITATIONS: Cross-sectional design. CONCLUSION: Functional genotype categories may stratify RDEB severity; high-impact variants correlated with worse clinical outcomes. Further validation in larger cohorts is needed.

Bone marrow transplantation and bone marrow-derived mesenchymal stem cell therapy in epidermolysis bullosa: A systematic review.

Epidermolysis bullosa (EB) is a genodermatosis that lacks effective treatments and requires supportive care for its severe, life-threatening manifestations. Bone marrow transplantation (BMT) and its derived cells have been suggested to improve clinical symptoms and quality of life. A comprehensive search was conducted for publications evaluating BMT and bone marrow-derived mesenchymal stem cell (BM-MSC) therapy for EB in PubMed/MEDLINE, Google Scholar, and Cochrane databases from inception until June 2023. A total of 55 participants with severe forms of EB had BMT and/or BM-MSCs, with recessive dystrophic EB as the most common EB type; 53 (96.4%) patients had better wound healing, and 3 (5.5%) patients died of sepsis. The most common adverse events reported were graft failure, sepsis, graft-versus-host disease, and renal insufficiency. Allogeneic BMT is a high-risk procedure with possible benefits and adverse events. BM-MSCs revealed favorable outcomes to improve the safety of EB cell-based therapy by minimizing the risk of serious adverse events, reducing blisters, and accelerating wound healing. Further studies are needed to assess the treatment's long-term effects and clarify the risk/benefit ratio of procedure versus conventional therapy.

Splicing Modulation via Antisense Oligonucleotides in Recessive Dystrophic Epidermolysis Bullosa.

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

ABCB5+ mesenchymal stromal cells facilitate complete and durable wound closure in recessive dystrophic epidermolysis bullosa.

BACKGROUND AND AIMS: Recessive dystrophic epidermolysis bullosa (RDEB) is a hereditary, rare, devastating and life-threatening skin fragility disorder with a high unmet medical need. In a recent international, single-arm clinical trial, treatment of 16 patients (aged 6-36 years) with three intravenous infusions of 2 × 106 immunomodulatory ABCB5+ dermal mesenchymal stromal cells (MSCs)/kg on days 0, 17 and 35 reduced disease activity, itch and pain. A post-hoc analysis was undertaken to assess the potential effects of treatment with ABCB5+ MSCs on the overall skin wound healing in patients suffering from RDEB. METHODS: Documentary photographs of the affected body regions taken on days 0, 17, 35 and at 12 weeks were evaluated regarding proportion, temporal course and durability of wound closure as well as development of new wounds. RESULTS: Of 168 baseline wounds in 14 patients, 109 (64.9%) wounds had closed at week 12, of which 63.3% (69 wounds) had closed already by day 35 or day 17. Conversely, 74.2% of the baseline wounds that had closed by day 17 or day 35 remained closed until week 12. First-closure ratio within 12 weeks was 75.6%. The median rate of newly developing wounds decreased significantly (P = 0.001) by 79.3%. CONCLUSIONS: Comparison of the findings with published data from placebo arms and vehicle-treated wounds in controlled clinical trials suggests potential capability of ABCB5+ MSCs to facilitate wound closure, prolongate wound recurrence and decelerate formation of new wounds in RDEB. Beyond suggesting therapeutic efficacy for ABCB5+ MSCs, the analysis might stimulate researchers who develop therapies for RDEB and other skin fragility disorders to not only assess closure of preselected target wounds but pay attention to the patients' dynamic and diverse overall wound presentation as well as to the durability of achieved wound closure and the development of new wounds. TRIAL REGISTRATION: Clinicaltrials.gov NCT03529877; EudraCT 2018-001009-98.

Therapeutic base editing and prime editing of COL7A1 mutations in recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by loss-of-function mutations in the COL7A1 gene, which encodes type VII collagen (C7), a protein that functions in skin adherence. From 36 Korean RDEB patients, we identified a total of 69 pathogenic mutations (40 variants without recurrence), including point mutations (72.5%) and insertion/deletion mutations (27.5%). For fibroblasts from two patients (Pat1 and Pat2), we applied adenine base editors (ABEs) to correct the pathogenic mutation of COL7A1 or to bypass a premature stop codon in Pat1-derived primary fibroblasts. To expand the targeting scope, we also utilized prime editors (PEs) to correct the COL7A1 mutations in Pat1- and Pat2-derived fibroblasts. Ultimately, we found that transfer of edited patient-derived skin equivalents (i.e., RDEB keratinocytes and PE-corrected RDEB fibroblasts from the RDEB patient) into the skin of immunodeficient mice led to C7 deposition and anchoring fibril formation within the dermal-epidermal junction, suggesting that base editing and prime editing could be feasible strategies for ex vivo gene editing to treat RDEB.

Maintenance of chronicity signatures in fibroblasts isolated from recessive dystrophic epidermolysis bullosa chronic wound dressings under culture conditions.

BACKGROUND: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare inherited skin disease caused by variants in the COL7A1 gene, coding for type VII collagen (C7), an important component of anchoring fibrils in the basement membrane of the epidermis. RDEB patients suffer from skin fragility starting with blister formation and evolving into chronic wounds, inflammation and skin fibrosis, with a high risk of developing aggressive skin carcinomas. Restricted therapeutic options are limited by the lack of in vitro models of defective wound healing in RDEB patients. RESULTS: In order to explore a more efficient, non-invasive in vitro model for RDEB studies, we obtained patient fibroblasts derived from discarded dressings) and examined their phenotypic features compared with fibroblasts derived from non-injured skin of RDEB and healthy-donor skin biopsies. Our results demonstrate that fibroblasts derived from RDEB chronic wounds (RDEB-CW) displayed characteristics of senescent cells, increased myofibroblast differentiation, and augmented levels of TGF-ß1 signaling components compared to fibroblasts derived from RDEB acute wounds and unaffected RDEB skin as well as skin from healthy-donors. Furthermore, RDEB-CW fibroblasts exhibited an increased pattern of inflammatory cytokine secretion (IL-1ß and IL-6) when compared with RDEB and control fibroblasts. Interestingly, these aberrant patterns were found specifically in RDEB-CW fibroblasts independent of the culturing method, since fibroblasts obtained from dressing of acute wounds displayed a phenotype more similar to fibroblasts obtained from RDEB normal skin biopsies. CONCLUSIONS: Our results show that in vitro cultured RDEB-CW fibroblasts maintain distinctive cellular and molecular characteristics resembling the inflammatory and fibrotic microenvironment observed in RDEB patients' chronic wounds. This work describes a novel, non-invasive and painless strategy to obtain human fibroblasts chronically subjected to an inflammatory and fibrotic environment, supporting their use as an accessible model for in vitro studies of RDEB wound healing pathogenesis. As such, this approach is well suited to testing new therapeutic strategies under controlled laboratory conditions.

The clinical efficacy and safety of anti-IgE therapy in recessive dystrophic epidermolysis bullosa.

The treatment of recessive dystrophic epidermolysis bullosa (RDEB) remains challenging. Elevated IgE levels have previously been reported in several RDEB patients. In this prospective, single-centre, open intervention study, elevated IgE levels were seen in 11 out of 12 patients with intense pruritus, and the patients with elevated IgE levels received anti-IgE therapy every 4 weeks for at least three cycles. Compared with the baseline, 10 patients with RDEB had good clinical outcomes with enhanced wound healing, a reduction in Birmingham (epidermolysis bullosa) EB severity score by 15%, a reduction in affected body surface area by 23.3%, amelioration of skin inflammation, and an increase in type VII collagen deposition by 13.1-fold. All the patients had a good tolerance to anti-IgE therapy. Furthermore, patients with higher IgE levels tended to have higher disease severity and more favorable clinical outcomes. Our report also suggested the potential role of IgE in the pathogenesis of inflammatory conditions associated with RDEB. (ChiCTR1900021437).

Losartan treatment improves recessive dystrophic epidermolysis bullosa: A case series.

Recessive dystrophic epidermolysis bullosa (RDEB) manifests with blistering and erosions of the skin and mucous membranes due to mutations in COL7A1. The repetitive wound healing processes lead to extensive cutaneous scarring. The scarring is driven by inflammatory processes, particularly the TGF-ß signaling pathways, resulting in excess synthesis and deposition of the extracellular matrix, especially collagen. There is currently no effective or specific treatment for RDEB. Losartan, an angiotensin II type 1 receptor antagonist, is an inhibitor of TGF-ß activity. Previous preclinical studies with hypomorphic Col7a1 mice recapitulating features of RDEB have suggested that losartan may improve the clinical features of RDEB. In this case series, we assessed the effects of losartan on the clinical and histopathologic features in seven patients with RDEB; three females and four males; aged 18.1 ± 9.1 years. The diagnosis was based on characteristic clinical features and the presence of biallelic loss-of-function mutations in COL7A1. Daily oral administration of losartan (0.7 mg/kg) for six weeks resulted in subjective improvement of the clinical features, as judged by the treating physicians and the patients, and the severity of the disease objectively improved based on Birmingham Epidermolysis Bullosa Severity (BEBS) score (30.1 ± 12.8 versus 23.3 ± 10.4, before and after treatment, p = 0.018), accompanied by improvement of quality of life, as determined by the EB-QoL questionnaire (24.0 ± 8.1 versus 17.7 ± 5.5, p = 0.018). Histopathology of the selected lesions revealed after treatment increased number of mast cells, and enhanced microvasculature in the mid and lower dermis. The width of collagen bundles in dermis was suggested to be decreased in four samples and changed from dense to loose in appearance. In summary, this case series reports beneficial effects of losartan on RDEB as a potentially novel treatment.

CRISPR/Cas9-based targeted genome editing for correction of recessive dystrophic epidermolysis bullosa using iPS cells.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited skin disorder caused by mutations in the COL7A1 gene encoding type VII collagen (C7). The spectrum of severity depends on the type of mutation in the COL7A1 gene. C7 is the major constituent of anchoring fibrils (AFs) at the basement membrane zone (BMZ). Patients with RDEB lack functional C7 and have severely impaired dermal-epidermal stability, resulting in extensive blistering and open wounds on the skin that greatly affect the patient's quality of life. There are currently no therapies approved for the treatment of RDEB. Here, we demonstrated the correction of mutations in exon 19 (c.2470insG) and exon 32 (c.3948insT) in the COL7A1 gene through homology-directed repair (HDR). We used the clustered regulatory interspaced short palindromic repeats (CRISPR) Cas9-gRNAs system to modify induced pluripotent stem cells (iPSCs) derived from patients with RDEB in both the heterozygous and homozygous states. Three-dimensional human skin equivalents (HSEs) were generated from gene-corrected iPSCs, differentiated into keratinocytes (KCs) and fibroblasts (FBs), and grafted onto immunodeficient mice, which showed normal expression of C7 at the BMZ as well as restored AFs 2 mo postgrafting. Safety assessment for potential off-target Cas9 cleavage activity did not reveal any unintended nuclease activity. Our findings represent a crucial advance for clinical applications of innovative autologous stem cell-based therapies for RDEB.

[Oral microbiome in children with dystrophic recessive epidermolysis bullosa]. / Mikrobiota slizistoi obolochki rta u detei s retsessivnym distroficheskim bulleznym epidermolizom.

THE AIM OF THE STUDY: Was to assess bacterial load in oral wounds in children with recessive dystrophic epidermolysis bullosa (RDEB). MATERIALS AND METHODS: The study comprised 77 RDEB children aged 3-18 years (mean age 9.5±3.6 years) and 27 healthy children aged 4-18 years (mean age 9.8±4.1 years) who served as controls. Swabs for bacteriological study were taken from the oral wounds in RDEB patients and non-affected corresponding oral mucosa areas in controls. The microorganism growth was assessed after 24, 48 and 72 hours of incubation (37 °C and 30 °C) with subsequent identification in automatic bacteriological analyzer MicroScan Walk Away (Simens, USA). Results. The study revealed high prevalence and concentrations of Candida albicans (in 40.3% children), Staphilococcus aureus (23.4%), Enterobacter cloacae (9.1%), and Enterobacteria (10.4%) in RDEB children. From these species, only Candida albicans was present in controls (26%). The prevalence and concentration of commensal and pathogenic species correlated positively with age and significant difference was revealed between children at the age of 3-6 and 7-10 years (p=0.001). Thus, bacterial load in oral wounds correlates with the RDEB natural history and fibrosis progression. Delayed oral wound healing was associated with microbiome shift towards biofilm-producing bacteria Staphilococcus aureus and Enterobacter cloacae. CONCLUSION: Oral wounds microbiome may be an indicator of RDEB severity and tendency to oral fibrosis. The decrease of bacterial load in the oral wounds may remove one of the healing obstacles and serve as fibrosis prevention measure.

Patient-reported outcomes and quality of life in recessive dystrophic epidermolysis bullosa: A global cross-sectional survey.

BACKGROUND: A spectrum of skin disease severity exists in patients with recessive dystrophic epidermolysis bullosa (RDEB). OBJECTIVE: To characterize the patient-reported outcomes and quality of life (QOL) in patients with RDEB. METHODS: A cross-sectional study of patients with RDEB surveyed through the global EBCare Registry. Patient-reported outcomes included skin disease severity, wound characteristics, pain, itch, extracutaneous symptoms, and medications. QOL was measured by using the validated Quality of Life in Epidermolysis Bullosa instrument. RESULTS: A total of 85 patients with RDEB reported 1226 wounds (937 recurrent wounds and 289 chronic open wounds). Overall skin disease severity was self-reported as mild (26%; 22/83), moderate (48%; 40/83), or severe (25%; 21/83). Worsening skin disease severity was significantly associated with larger wounds, increased opiate use, anemia, gastrostomy tube use, infections, osteoporosis, and squamous cell carcinoma. Larger wound size was associated with worse quality of life scores. LIMITATIONS: All data were self-reported from an online epidermolysis bullosa patient registry. CONCLUSIONS: This study shows a significant correlation between larger wound size with worsening skin disease severity and quality of life in participants with RDEB. Worsening skin disease severity significantly correlated with key clinical manifestations. These results show that patients with RDEB are able to self-report their skin disease severity and wounds.

The utility of dermal fibroblasts in treatment of skin disorders: A paradigm of recessive dystrophic epidermolysis bullosa.

Dermal fibroblasts are the most accessible cells in the skin that have gained significant attention in cell therapy. Applying dermal fibroblasts' regenerative capacity can introduce new patterns to develop cell-based therapies to treat skin disorders. Dermal fibroblasts originate from mesenchymal cells and are located within the dermis. These cells are mainly responsible for synthesizing glycosaminoglycans, collagens, and components of extracellular matrix supporting skin's structural integrity. Preclinical studies suggested that allogeneic and autologous dermal fibroblasts provide widespread and beneficial applications for wound healing, burn ulcers, and inherited skin disorders. In this regard, generating induced pluripotent stem cells (iPSCs) from fibroblasts and gene-edited fibroblasts are promising approaches for treating skin disorders. Here, we aimed to review literature about ongoing and completed clinical trials that applied fibroblasts and bioengineered fibroblasts as therapeutic agents for various skin disorders. This review explores cell therapy protocols from the earliest phase of allogeneic and autologous fibroblasts development in different benches to translating them into bedside-level treatment for skin disorders, particularly recessive dystrophic epidermolysis bullosa.

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa.

Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB), a skin fragility disorder that, unexpectedly, manifests also with elevated colonization of commensal bacteria and frequent wound infections. Here, we describe an unprecedented systemic function of collagen VII as a member of a unique innate immune-supporting multiprotein complex in spleen and lymph nodes. In this complex, collagen VII specifically binds and sequesters the innate immune activator cochlin in the lumen of lymphoid conduits. In genetic mouse models, loss of collagen VII increased bacterial colonization by diminishing levels of circulating cochlin LCCL domain. Intraperitoneal injection of collagen VII, which restored cochlin in the spleen, but not in the skin, reactivated peripheral innate immune cells via cochlin and reduced bacterial skin colonization. Systemic administration of the cochlin LCCL domain was alone sufficient to diminish bacterial supercolonization of RDEB mouse skin. Human validation demonstrated that RDEB patients displayed lower levels of systemic cochlin LCCL domain with subsequently impaired macrophage response in infected wounds. This study identifies an intrinsic innate immune dysfunction in RDEB and uncovers a unique role of the lymphoid extracellular matrix in systemic defense against bacteria.

Impaired Wound Healing, Fibrosis, and Cancer: The Paradigm of Recessive Dystrophic Epidermolysis Bullosa.

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a devastating skin blistering disease caused by mutations in the gene encoding type VII collagen (C7), leading to epidermal fragility, trauma-induced blistering, and long term, hard-to-heal wounds. Fibrosis develops rapidly in RDEB skin and contributes to both chronic wounds, which emerge after cycles of repetitive wound and scar formation, and squamous cell carcinoma-the single biggest cause of death in this patient group. The molecular pathways disrupted in a broad spectrum of fibrotic disease are also disrupted in RDEB, and squamous cell carcinomas arising in RDEB are thus far molecularly indistinct from other sub-types of aggressive squamous cell carcinoma (SCC). Collectively these data demonstrate RDEB is a model for understanding the molecular basis of both fibrosis and rapidly developing aggressive cancer. A number of studies have shown that RDEB pathogenesis is driven by a radical change in extracellular matrix (ECM) composition and increased transforming growth factor-beta (TGFß) signaling that is a direct result of C7 loss-of-function in dermal fibroblasts. However, the exact mechanism of how C7 loss results in extensive fibrosis is unclear, particularly how TGFß signaling is activated and then sustained through complex networks of cell-cell interaction not limited to the traditional fibrotic protagonist, the dermal fibroblast. Continued study of this rare disease will likely yield paradigms relevant to more common pathologies.

Development of Minicircle Vectors Encoding COL7A1 Gene with Human Promoters for Non-Viral Gene Therapy for Recessive Dystrophic Epidermolysis Bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare autosomal inherited skin disorder caused by mutations in the COL7A1 gene that encodes type VII collagen (C7). The development of an efficient gene replacement strategy for RDEB is mainly hindered by the lack of vectors able to encapsulate and transfect the large cDNA size of this gene. To address this problem, our group has opted to use polymeric-based non-viral delivery systems and minicircle DNA. With this approach, safety is improved by avoiding the usage of viruses, the absence of bacterial backbone, and the replacement of the control viral cytomegalovirus (CMV) promoter of the gene with human promoters. All the promoters showed impressive C7 expression in RDEB skin cells, with eukaryotic translation elongation factor 1 α (EF1α) promoter producing higher C7 expression levels than CMV following minicircle induction, and COL7A1 tissue-specific promoter (C7P) generating C7 levels similar to normal human epidermal keratinocytes. The improved system developed here has a high potential for use as a non-viral topical treatment to restore C7 in RDEB patients efficiently and safely, and to be adapted to other genetic conditions.

Efficacy of gentamicin 0.3% solution of oral erosions healing in patients with severe generalized recessive dystrophic epidermolysis bullosa and its impact on the expression of type VII collagen.

INTRODUCTION: Epidermolysis bullosa (EB) is a rare genetic skin disorder inherited either in autosomal recessive (AR) or autosomal dominant (AD) manner and characterized by blistering of the skin and mucous membranes. According to a subtype of EB, the oral manifestations and dental involvement vary in frequency and in severity. The most severe dental problems occur in patients with junctional epidermolysis bullosa (JEB) and severe generalized dystrophic epidermolysis bullosa (RDEB) and involve enamel erosion and development of blisters followed by painful oral wounds. Oral mucosa lesions decrease patients' quality of life and may contribute to difficulties in nutrition leading to cachexia. AIM: Assessment of efficacy of gentamicin 0.3% solution in the healing and preventing of oral erosions in patients with RDEB and evaluating its impact on the expression of type VII collagen. MATERIAL AND METHODS: The study included four female patients with RDEB, aged 16-42 who show different mutations in the COL7A1 gene and were administered the mouth rinse two times daily with a solution of 0.3% gentamycin for 4 consecutive weeks. Prior to and at the end of the study, the samples from oral mucosa were collected to estimate the expression of type VII collagen by immunofluorescence test. RESULTS: The clinical improvement of oral wounds healing and reduced number of new blisters and mucous membrane soreness as well as partial re-expression of type VII collagen was observed in all studied patients. CONCLUSIONS: Topical gentamicin therapy of oral cavity in RDEB patients resulted in clinical improvement of mucosal lesions and re-expression of collagen type VII.

Losartan as disease modulating therapy for recessive dystrophic epidermolysis bullosa.

A 6-year-old child with recessive dystrophic epidermolysis bullosa, confirmed by history, clinical exam, and antigen mapping, was treated with losartan with reduction in the blistering and better quality of life.

Reprogramming and Differentiation of Cutaneous Squamous Cell Carcinoma Cells in Recessive Dystrophic Epidermolysis Bullosa.

The early onset and rapid progression of cutaneous squamous cell carcinoma (cSCC) leads to high mortality rates in individuals with recessive dystrophic epidermolysis bullosa (RDEB). Currently, the molecular mechanisms underlying cSCC development in RDEB are not well understood and there are limited therapeutic options. RDEB-cSCC arises through the accumulation of genetic mutations; however, previous work analyzing gene expression profiles have not been able to explain its aggressive nature. Therefore, we generated a model to study RDEB-cSCC development using cellular reprograming and re-differentiation technology. We compared RDEB-cSCC to cSCC that were first reprogrammed into induced pluripotent stem cells (RDEB-cSCC-iPSC) and then differentiated back to keratinocytes (RDEB-cSCC-iKC). The RDEB-cSCC-iKC cell population had reduced proliferative capacities in vitro and in vivo, suggesting that reprogramming and re-differentiation leads to functional changes. Finally, we performed RNA-seq analysis for RDEB-cSCC, RDEB-cSCC-iPSC, and RDEB-cSCC-iKC and identified different gene expression signatures between these cell populations. Taken together, this cell culture model offers a valuable tool to study cSCC and provides a novel way to identify potential therapeutic targets for RDEB-cSCC.