Dystrophic Epidermolysis Bullosa Research Articles

IL-6 levels dominate the serum cytokine signature of severe epidermolysis bullosa: A prospective cohort study.

Systemic inflammation is considered a major player in the pathogenesis of epidermolysis bullosa (EB), but its pattern has only been described in small heterogeneous cohorts. There is controversy if and how systemic inflammation should be therapeutically targeted. We examined serum proinflammatory, anti-inflammatory, and itch related cytokines in a paediatric cohort of 29 patients with junctional and dystrophic EB. The cytokine that emerged as the most relevant was measured in a validation cohort of 42 patients during follow-up visits over 2 years. IL-6 showed the most consistent and highest aberration dominating systemic inflammation. IL-6 correlated with wound body surface area (BSA) in both, finding and validation cohorts. Patients with less than 3% wound BSA had normal IL-6, while IL-6 levels significantly increased at more than 5% and 10% of wound BSA. TGF-β was only marginally elevated in patients with severe recessive dystrophic EB, while TNF-α, IFN-γ and IL-1β varied inconsistently. Patients reporting itch showed elevations in type 2 immunity (IgE, TSLP, IL4 and/or IL-31, respectively). Our data suggest a dominant skin barrier and wound healing inflammatory pattern in junctional and dystrophic EB that depends on the wound area and not on the EB type. In EB, itch mediators may be similar to other pruritic disorders.

Intravenous gentamicin therapy induces functional type VII collagen in patients with recessive dystrophic epidermolysis bullosa: an open-label clinical trial.

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable widespread blistering skin disorder caused by mutations in the gene encoding for type VII collagen (C7), the major component of anchoring fibrils. To evaluate the efficacy and safety of intravenous (IV) gentamicin readthrough therapy in patients with RDEB harbouring nonsense mutations. The primary outcomes were increased expression of C7 in patients' skin and safety assessments (ototoxicity, nephrotoxicity, autoimmune response); secondary outcomes included measuring wound healing in target wounds and assessment by a validated Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) scoring system. An open-label pilot trial to assess two different IV gentamicin regimens between August 2018 and March 2020 with follow-up through to 180 days post-treatment was carried out. Three patients with RDEB with confirmed nonsense mutations in COL7A1 in either one or two alleles and decreased baseline expression of C7 at the dermal-epidermal junction (DEJ) of their skin participated in the study. Three patients received gentamicin 7.5 mg kg-1 daily for 14 days and two of the three patients further received 7.5 mg kg-1 IV gentamicin twice weekly for 12 weeks. Patients who had pre-existing auditory or renal impairment, were currently using ototoxic or nephrotoxic medications, or had allergies to aminoglycosides or sulfate compounds were excluded. After gentamicin treatment, skin biopsies from all three patients (age range 18-28 years) exhibited increased C7 in their DEJ. With both regimens, the new C7 persisted for at least 6 months post-treatment. At 1 and 3 months post-treatment, 100% of the monitored wounds exhibited > 85% closure. Both IV gentamicin infusion regimens decreased EBDASI total activity scores. Of the patients assessed with the EBDASI, all exhibited decreased total activity scores 3 months post-treatment. All three patients completed the study; no adverse effects or anti-C7 antibodies were detected. IV gentamicin induced the readthrough of nonsense mutations in patients with RDEB and restored functional C7 in their skin, enhanced wound healing and improved clinical parameters. IV gentamicin may be a safe, efficacious, low-cost and readily available treatment for this population of patients with RDEB.

Ocular Gene Therapy in a Patient with Dystrophic Epidermolysis Bullosa

SummaryDystrophic epidermolysis bullosa is a rare genetic disease caused by damaging variants in COL7A1, which encodes type VII collagen. Blistering and scarring of the ocular surface develop, potentially leading to blindness. Beremagene geperpavec (B-VEC) is a replication-deficient herpes simplex virus type 1–based gene therapy engineered to deliver functional human type VII collagen. Here, we report the case of a patient with cicatrizing conjunctivitis in both eyes caused by dystrophic epidermolysis bullosa who received ophthalmic administration of B-VEC, which was associated with improved visual acuity after surgery.

Increased healthcare burden and comorbidity risks of pediatric patients with dystrophic epidermolysis bullosa: Analysis of Nationwide Emergency Department Sample 2015-2019.

Dystrophic epidermolysis bullosa (DEB) describes a rare genetic blistering disorder characterized by fragile skin. This study aimed to classify the frequency, demographics, cost, and comorbidities associated with emergency department (ED) visits due to DEB. The Nationwide Emergency Department Sample (NEDS) was analyzed for pediatric (age <18) ED visits from 2015 to 2019. DEB was identified with ICD-10-CM code Q81.2. Weighted frequency, prevalence, and 95% confidence intervals (CIs) of comorbidities were determined among ED visits with and without a DEB diagnosis. From 2015 to 2019, 53 (weighted 242) cases of DEB among 27,223,220 pediatric ED visits were captured. Patients with DEB were more likely to visit the ED in summer compared with those without a diagnosis of DEB (35.7% vs. 21.4%, P < .05). More than half of patients with DEB were admitted to the hospital (56.2%, 95% CI: 39.3-72.5, P < .001) versus only 3.4% (95% CI: 3.1-3.7) of other patients. For ED visits with a secondary DEB diagnosis, the top three primary diagnoses were fever, constipation, and bone marrow transplant aftercare. Patients with DEB had higher rates of hypertension, cellulitis, sepsis, acute and chronic kidney injury, esophageal obstruction, gastroesophageal reflux disease, cardiomyopathy, and anxiety, compared to patients without DEB (all P < .001). DEB is a complex blistering disorder with multisystemic manifestations. Patients with DEB have significantly higher admission rates and commonly present with infectious or gastrointestinal complications. Understanding the features of ED visits due to DEB can better prepare healthcare teams and improve patient outcomes.

Patients suffering from dystrophic epidermolysis bullosa are prone to developing autoantibodies against skin proteins: A longitudinal confirmational study.

Epidermolysis bullosa (EB) is a heritable skin blistering disease caused by variants in genes coding for proteins that secure cell-cell adhesion and attachment of the epidermis to the dermis. Interestingly, several proteins involved in inherited EB are also associated with autoimmune blistering diseases (AIBD). In this study, we present a long-term follow-up of 15 patients suffering from recessive dystrophic or junctional EB. From these patients, 62 sera were analysed for the presence of autoantibodies associated with AIBD. We show that patients suffering from recessive dystrophic EB (RDEB) are more susceptible to developing autoantibodies against skin proteins than patients suffering from junctional EB (70% vs. 20%, respectively). Interestingly, no correlation with age was observed. Most patients showed reactivity to Type XVII collagen/linear IgA bullous dermatosis autoantigen (n = 5; 33%), followed by BP230 (n = 4; 27%), Type VII collagen (n = 4; 27%) and laminin-332 (n = 1; 7%). The pathogenicity of these autoantibodies remains a subject for future experiments.

Modulation of Inflammation By Unrestricted Somatic Stem Cells (USSCs) to Suppress Fibrosis in Mice with Dystrophic Epidermolysis Bullosa

Modulation of Inflammation By Unrestricted Somatic Stem Cells (USSCs) to Suppress Fibrosis in Mice with Dystrophic Epidermolysis Bullosa

Pruritus Anesis in Dystrophic Epidermolysis Bullosa Pruriginosa with Dupilumab.

Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a rare subtype of dystrophic epidermolysis bullosa, and traditional treatments have limited efficacy. Dupilumab has demonstrated remarkable efficacy in relieving pruritus. In this case study, after traditional treatment failed, providers recommended the patient begin dupilumab to treat his pruritus. The patient was administrated a loading dose of 600 mg of dupilumab and a dose of 300 mg every 2 weeks. The Dermatology Life Quality Index and Pruritic Numeric Rating Scale were used to assess the patient's situation. After several months, the patient's DEB-Pr was considered in remission. Dupilumab may be a better choice than immunosuppressants for the treatment of pruritus in patients with DEB-Pr.

Estimated Spending on Beremagene Geperpavec for Dystrophic Epidermolysis Bullosa

New gene therapies can offer substantial benefits to patients, particularly those with rare diseases who have few therapeutic options. In May 2023, the US Food and Drug Administration (FDA) approved the first topical gene therapy, beremagene geperpavec (B-VEC), for treating both autosomal recessive and autosomal dominant dystrophic epidermolysis bullosa (DEB). However, FDA approval was based on limited data in patients with autosomal dominant disease, even though they comprise approximately 50% of all DEB cases. To estimate projected spending in the US on B-VEC therapy for treating autosomal recessive and autosomal dominant DEB. This economic evaluation used data from the National Epidermolysis Bullosa Registry to estimate the current population of US patients with autosomal dominant and autosomal recessive DEB, with the aim of estimating US spending on B-VEC therapy from an all-payers perspective during 1- and 3-year periods after FDA approval. A base-case cost of $300 000 per patient per year was assumed based on a report from the manufacturer (Krystal Biotech). Treatment with B-VEC. Estimated overall spending on B-VEC in the first year and over a 3-year period after FDA approval. Several prespecified sensitivity analyses with different assumptions about the eligible patient population and the cost of therapy were performed, and lifetime total costs of treatment per patient were estimated. The estimated number of US patients with DEB who were eligible for treatment with B-VEC in the first year after FDA approval was 894. The estimated total expenditure for B-VEC therapy was $268 million (range, $179 million-$357 million). Over a 3-year period, estimated spending was $805 million (range, $537 million-$1.1 billion). Estimated lifetime total costs per patient were $15 million (range, $10 million-$20 million) per patient with autosomal recessive DEB and $17 million (range, $11 million-$22 million) for patients with autosomal dominant DEB. Results of this economic evaluation suggest that the FDA's broad indication for the use of B-VEC in treating both autosomal recessive and autosomal dominant DEB will have significant implications for payers.

Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy.

Cutaneous squamous cell carcinomas (SCCs) are a major complication of some subtypes of epidermolysis bullosa (EB), with high morbidity and mortality rates and unmet therapeutic needs. The high rate of endogenous mutations and the fibrotic stroma are considered to contribute to the pathogenesis. Patients with dystrophic EB (DEB) and Kindler EB (KEB) have the highest propensity for developing SCCs. Another patient group that develops high-risk SCCs is immunosuppressed (IS) patients, especially after organ transplantation. Herein, we interrogate whether immune checkpoint proteins and immunosuppressive enzymes are dysregulated in EB-associated SCCs as an immune resistance mechanism and compare the expression patterns with those in SCCs from IS patients, who frequently develop high-risk tumors and sporadic SCCs, and immunocompetent (IC) individuals. The expression of indoleamine 2,3-dioxygenase (IDO), programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), T cell immunoglobulin and mucin-domain-containing protein-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and inflammatory infiltrates (CD4, CD8, and CD68) was assessed via immunohistochemistry and semi-quantitative analysis in 30 DEB-SCCs, 22 KEB-SCCs, 106 IS-SCCs, and 100 sporadic IC-SCCs. DEB-SCCs expressed significantly higher levels of IDO and PD-L1 in tumor cells and PD-1 in the tumor microenvironment (TME) compared with SCCs from IC and IS individuals. The number of CD4-positive T cells per mm2 was significantly lower in DEB-SCCs compared with IC-SCCs. KEB-SCCs showed the lowest expression of the exhaustion markers TIM-3 and LAG-3 compared with all other groups. These findings identify IDO, PD-1, and PD-L1 to be increased in EB-SCCs and candidate targets for combinatory treatments, especially in DEB-SCCs.

Gamma-Secretase Inhibitors Downregulate the Profibrotic NOTCH Signaling Pathway in Recessive Dystrophic Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare skin fragility disorder caused by mutations in COL7A1. RDEB is hallmarked by trauma-induced unremitting blistering, chronic wounds with inflammation, and progressive fibrosis, leading to severe disease complications. There is currently no cure for RDEB-associated fibrosis. Our previous studies and increasing evidence highlighted the profibrotic role of NOTCH pathway in different skin disorders, including RDEB. In this study, we further investigated the role of NOTCH signaling in RDEB pathogenesis and explored the effects of its inhibition by γ-secretase inhibitors DAPT and PF-03084014 (nirogacestat). Our analyses demonstrated that JAG1 and cleaved NOTCH1 are upregulated in primary RDEB fibroblasts (ie, RDEB-derived fibroblasts) compared with controls, and their protein levels are further increased by TGF-β1 stimulation. Functional assays unveiled the involvement of JAG1/NOTCH1 axis in RDEB fibrosis and demonstrated that its blockade counteracts a variety of fibrotic traits. In particular, RDEB-derived fibroblasts treated with PF-03084014 showed (i) a significant reduction of contractility, (ii) a diminished secretion of TGF-β1 and collagens, and (iii) the downregulation of several fibrotic proteins. Although less marked than PF-03084014-treated cells, RDEB-derived fibroblasts exhibited a reduction of fibrotic traits also upon DAPT treatment. This study provides potential therapeutic strategies to antagonize RDEB fibrosis onset and progression.

Highly efficient CRISPR/Cas9-mediated exon skipping for recessive dystrophic epidermolysis bullosa.

Gene therapy based on the CRISPR/Cas9 system has emerged as a promising strategy for treating the monogenic fragile skin disorder recessive dystrophic epidermolysis bullosa (RDEB). With this approach problematic wounds could be grafted with gene edited, patient-specificskin equivalents. Precise gene editing using homology-directed repair (HDR) is the ultimate goal, however low efficiencies have hindered progress. Reframing strategies based on highly efficient non-homologous end joining (NHEJ) repair aimed at excising dispensable, mutation-harboring exons offer a promising alternative approach for restoring the COL7A1 open reading frame. To this end, we employed an exon skipping strategy using dual single guide RNA (sgRNA)/Cas9 ribonucleoproteins (RNPs) targeted at three novel COL7A1 exons (31, 68, and 109) containing pathogenic heterozygous mutations, and achieved exon deletion rates of up to 95%. Deletion of exon 31 in both primary human RDEB keratinocytes and fibroblasts resulted in the restoration of type VII collagen (C7), leading to increased cellular adhesion in vitro and accurate C7 deposition at the dermal-epidermal junction in a 3D skin model. Taken together, we extend the list of COL7A1 exons amenable to therapeutic deletion. As an incidental finding, we find that long-read Nanopore sequencing detected large on-target structural variants comprised of deletions up to >5 kb at a frequency of ~10%. Although this frequency may be acceptable given the high rates of intended editing outcomes, our data demonstrate that standard short-read sequencing may underestimate the full range of unexpected Cas9-mediated editing events.

Clinical-grade human skin-derived ABCB5+ mesenchymal stromal cells exert anti-apoptotic and anti-inflammatory effects in vitro and modulate mRNA expression in a cisplatin-induced kidney injury murine model.

Acute kidney injury (AKI) is characterized by a rapid reduction in renal function and glomerular filtration rate (GFR). The broadly used anti-cancer chemotherapeutic agent cisplatin often induces AKI as an adverse drug side effect. Therapies targeted at the reversal of AKI and its potential progression to chronic kidney disease or end-stage renal disease are currently insufficiently effective. Mesenchymal stromal cells (MSCs) possess diverse immunomodulatory properties that confer upon them significant therapeutic potential for the treatment of diverse inflammatory disorders. Human dermal MSCs expressing ATP-Binding Cassette member B5 (ABCB5) have shown therapeutic efficacy in clinical trials in chronic skin wounds or recessive dystrophic epidermolysis bullosa. In preclinical studies, ABCB5+ MSCs have also shown to reverse metabolic reprogramming in polycystic kidney cells, suggesting a capacity for this cell subset to improve also organ function in kidney diseases. Here, we aimed to explore the therapeutic capacity of ABCB5+ MSCs to improve renal function in a preclinical rat model of cisplatin-induced AKI. First, the anti-apoptotic and immunomodulatory capacity was compared against research-grade adipose stromal cells (ASCs). Then, cross-species immunomodulatory capacity was checked, testing first inhibition of mitogen-driven peripheral blood mononuclear cells and then modulation of macrophage function. Finally, therapeutic efficacy was evaluated in a cisplatin AKI model. First, ABCB5+ MSCs suppressed cisplatin-induced apoptosis of human conditionally-immortalized proximal tubular epithelial cells in vitro, most likely by reducing oxidative stress. Second, ABCB5+ MSCs inhibited the proliferation of either human or rat peripheral blood mononuclear cells, in the human system via the Indoleamine/kynurenine axis and in the murine context via nitric oxide/nitrite. Third, ABCB5+ MSCs decreased TNF-α secretion after lipopolysaccharide stimulation and modulated phagocytosis and in both human and rat macrophages, involving prostaglandin E2 and TGF-β1, respectively. Fourth, clinical-grade ABCB5+ MSCs grafted intravenously and intraperitoneally to a cisplatin-induced AKI murine model exerted modulatory effects on mRNA expression patterns toward an anti-inflammatory and pro-regenerative state despite an apparent lack of amelioration of renal damage at physiologic, metabolic, and histologic levels. Our results demonstrate anti-inflammatory and pro-regenerative effects of clinical grade ABCB5+ MSCs in vitro and in vivo and suggest potential therapeutic utility of this cell population for treatment or prevention of cisplatin chemotherapy-induced tissue toxicity.

Costs of UK community care for individuals with recessive dystrophic epidermolysis bullosa: Findings of the Prospective Epidermolysis Bullosa Longitudinal Evaluation Study.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin fragility disorder requiring multidisciplinary management. Information regarding costs of current standard treatment is scant. As part of a longitudinal natural history study, we explored the community care costs of UK patients with different forms of RDEB. Fifty-nine individuals with RDEB provided detailed information on multiple facets of RDEB including disease severity scores (iscorEB, BEBS) and patient reported outcomes (quality of life evaluation in epidermolysis bullosa, iscorEB patient questionnaire). Costs data included time spent doing dressings, frequency of dressing changes, details of materials used, and paid and unpaid care. Overall costs of dressing materials and associated care were high in RDEB. Median annual costs across all subtypes for those using dressings (n=51) were over £26000. For severe RDEB (RDEB-S), median costs were almost £90000 per annum, with a median of 18h per week spent on dressing changes. Half of working-age adults with RDEB were unemployed and 39% of carers were unable to take on full-time or part-time paid employment, adding to indirect costs and the financial burden from RDEB on families and society. The findings demonstrate the high costs of care of RDEB, particularly for RDEB-S. The current expense supports the drive to develop new therapies which accelerate wound healing and diminish total wound burden, thereby reducing costs of dressings and care. While costly to bring to market, these might ultimately reduce the overall cost of treatment and also the impact on individuals living with this rare disease. The data also highlight the need for adequate reimbursement for EB care which can place significant financial strain on families.

EFFICACY OF TETRAHYDROCANNABINOL-RICH CANNABIS OINTMENT IN A CHILD WITH RECCESSIVE DYSTROPHIC EPIDERMOLYSIS BULLOSA: CASE REPORT

Epidermolysis Bullosa (EB) is characterized by epithelial fragility with blistering and the presence of pain and chronic pruritus. Studies demonstrate the potential of cannabinoids in the treatment of dermatological disorders, presenting anti-inflammatory action, pruritus control, and analgesic effect. In addition, two case series of patients with EB demonstrated positive results with both topical and systemic use of cannabinoids. OBJECTIVES: to evaluate the therapeutic efficacy of the topical use of a tetrahydrocannabinol-rich (THC) Cannabis sativa ointment in a patient with EB. METHODS: this is the case report of a 4-year-old female patient with recessive dystrophic EB. Two similar chronic wounds were chosen, in which one was treated with the placebo and the other treated with the THC-rich Cannabis ointment. The influence on healing and on pain and pruritus symptoms was evaluated for 28 days. After this period, the blinding status was removed and, due to the results achieved, it was decided to continue the application of the THC-rich Cannabis ointment in both lesions. RESULTS: The THC-rich Cannabis sativa ointment improved the wound healing process and the control of pain and pruritus when compared to placebo. CONCLUSIONS: The use of the THC-rich Cannabis ointment was effective in the healing process of the chronic wounds presented by the patient. A positive effect was also observed in relation to pain, pruritus, and improvement in the overall quality of life.

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).

Simple and affordable soft brace application in dystrophic epidermolysis bullosa patients.

Dystrophic epidermolysis bullosa (DEB) is a hereditary disease characterized by increased fragility of the epidermis and mucosa and is accompanied by blister formation following minor trauma. Repeated injuries cause contracture and scar formation, which can further result in hand deformity, leading to a decline in hand ability and a lower quality of life. In this study, after the scar release of patients' hands, we developed a new and practical portable soft support, and evaluated its efficacy in delaying the scar contracture of hands after operation. According to the hand function scores, the patients were divided into two groups. Those with excellent and good grades were assigned to the open hand function group, and those with poor grades were allocated to the restricted hand function group. The primary conditions, the use of a postoperative soft brace, and some common factors in the two groups were compared to determine whether these parameters influence postoperative hand function. There were no significant differences in age, gender, body mass index, ADL assessment index, albumin concentration, hemoglobin concentration, fasting blood glucose level, prothrombin time, and activated partial thromboplastin time between the two groups (p > 0.05). In contrast, there was a significant difference between the two groups in the use of soft braces following the operation (p < 0.05). The odds ratio of patients fixed with a brace compared with patients not fixed with soft braces was 11.01. Soft brace is a critical factor impacting the hand function of patients with dystrophic epidermolysis bullosa after scar contracture release in both hands. Indeed, a hand brace worn after the operation can delay the recurrence of scar contracture in both hands and offer patients a longer time to use their hands effectively. In addition, by restoring the appearance of patients' hands and some hand functions, patients' mental state and quality of life have been greatly improved.

Exploring the Impact of Epidermolysis Bullosa on Parents and Caregivers: A Cross-Cultural Validation of the Epidermolysis Bullosa Burden of Disease Questionnaire.

Epidermolysis bullosa (EB) is a heterogeneous group of genetically inherited skin and mucosal fragility disorders. EB may have a profound impact on parental physical and psychosocial health. This study was designed to evaluate the disease burden in parents of patients with EB and identify out-of-pocket (OOP) expenditures for EB care in Saudi Arabia. Thirty-eight caregivers of patients with EB were recruited from the Saudi EB registry to participate. All participants completed the EB Burden of Disease (EB-BoD) questionnaire. Data were collected between May 2020 and December 2020. The sample included 10 patients with EB simplex (EBS), 10 with junctional EB (JEB), 14 with dystrophic EB (DEB), and 4 with an unknown type. Mothers were the primary caregivers in 89.5% of cases. The mean EB-BoD score was 53 ± 21.5. The family-life and child's life dimensions had the higher burden. The mean EB-BoD score observed in patients with DEB was 62.4±16.8 versus 45.7 ± 19.42 for EBS. The EB-BoD score was correlated with the patient's family income. Most caregivers (97.4%) reported OOP expenditure, with a mean monthly OOP expenditure of $575.5± $701.1. OOP expenses increased with the severity of the condition. This study highlights the need for support services for parents caring for patients with EB.

Good clinical response to cemiplimab in a young patient with locally advanced cutaneous squamous cell carcinoma on preexisting recessive dystrophic epidermolysis bullosa

Good clinical response to cemiplimab in a young patient with locally advanced cutaneous squamous cell carcinoma on preexisting recessive dystrophic epidermolysis bullosa

Highly efficient biallelic correction of homozygous COL7A1 mutation using ABE8e adenine base editor.

Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic skin disorder characterized by severe skin blistering. With no cure at present, we have pursued a gene repair approach using base editing of COL7A1. Following on from our previous report of highly efficient base editing using the novel base editor, ABE8e, here we explore the use of lipid nanoparticle (LNP)-based delivery systems instead of electroporation to effect base editing in RDEB fibroblasts and correct a missense G &amp;gt; A mutation. We demonstrate increasingly high editing efficiencies, averaging 90%, which vary with the ABE8e dosage. We then demonstrate the viability of topical delivery of mRNA encapsulated in an LNP. Our work underscores the translational potential of this therapeutic route for DEB.

Efficacy of oral JAK1 or JAK1/2 inhibitor for treating refractory pruritus in dystrophic epidermolysis bullosa: A retrospective case series.

Refractory pruritus is the most distressing, disease-related symptom in patients with dystrophic epidermolysis bullosa (DEB), inducing an itch-scratch-blister cycle. Chronic inflammation is a hallmark of DEB, thus upregulation of inflammatory cytokines and Janus kinase (JAK) signaling may play a role in DEB-related pruritus. We retrospectively reviewed the medical records of DEB patients with refractory pruritus who were treated with either baricitinib, a JAK1/2 inhibitor, or upadacitinib, a selective JAK1 inhibitor. Patients received baricitinib (4 mg) or upadacitinib (15 mg) once a day for 2-32 weeks. A total of 12 DEB patients (six recessive DEB and six dominant DEB) were included in this study. The mean±SD baseline pruritus visual analog scale (VAS) score was 7.5 ± 1.7. Upadacitinib or baricitinib treatment resulted in a rapid and sustained decrease in itch. Four out of 12 patients (33.3%) and seven out of 10 patients (70%) showed a decrease of at least 3 points in the pruritus VAS score from baseline at weeks 2 and 4, respectively. The mean percentage changes from baseline in pruritus VAS scores at weeks 2 and 4 were -42.9% and -52.7%, respectively. Subgroup analysis showed greater reductions in the pruritus VAS score in the baricitinib group (n = 5) compared to the upadacitinib group (n = 7), and in patients with epidermolysis bullosa pruriginosa (n = 3) compared to other subtypes of DEB (n = 9); however, these differences did not reach statistical significance. Three out of 10 (33.3%) patients showed at least a 2-point reduction in pain intensity from baseline at week 4. Eight out of 12 patients (66.7%) also showed a reduction in the number of new blisters, which correlated with a reduction in the pruritus score. No patient discontinued treatment because of serious adverse events. Our results suggest that JAK1 or JAK1/2 inhibitors could be a promising treatment option for DEB-related pruritus. Long-term safety should be assessed in future studies.