Dystrophic Epidermolysis Bullosa Research Articles

Epidermolysis Bullosa: Two rare case reports of COL7A1 and EBS-GEN SEV KRT14 variants with review of literature

EpidermolysisBullosa is a rare hereditary skin condition that causes blisters. Genes encoding structural proteins at or near the dermal-epidermal junction are mutated recessively or dominantly, and this is the primary cause of EB. Herein, two Chinese boys were diagnosed with the condition, each with a different variant in a gene that serves as a reference for EB genetic counseling. Skincare significantly impacted their prognosis and quality of life.Case presentationTwo Chinese boys, with phenotypically normal parents, have been diagnosed with distinct blister symptoms, one with Dominant Dystrophic Epidermolysis Bullosa and the other with a severe form of Epidermolysis Bullosa Simplex. The first patient had a G-to-A variant in the COL7A1 allele, at nucleotide position 6163 which was named “G2055A”. The proband is heterozygous for Dystrophic Epidermolysis Bullosa due to a COL7A1 allele with a glycine substitution at the triple helix domain. A similar variant has been discovered in his mother, indicating its potential transmission to future generations. Another patient had severe Epidermolysis Bullosa Simplex with a rare c.377T > A  variant resulting in substitution of amino acid p.Leu126Arg (NM_000526.5 (c.377T > G, p.Leu126Arg) in the Keratin 14 gene. In prior literature, Keratin 14 has been associated with an excellent prognosis. However, our patient with this infrequent variant tragically died from sepsis at 21 days old. There has been a reported occurrence of the variant only once.ConclusionOur study reveals that Epidermolysis Bullosa patients with COL7A1 c.6163G > A and KRT14 c.377T>A variants have different clinical presentations, with dominant forms of Dystrophic EB having milder phenotypes than recessive ones. Thus, the better prognosis in the c.6163G > A patient. Furthermore, c.377T>A patient was more prone to infection than the patient with c.6163G>A gene variant. Genetic testing is crucial for identifying the specific variant responsible and improving treatment options.

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.

Dipeptidyl Peptidase-4–Mediated Fibronectin Processing Evokes a Profibrotic Extracellular Matrix

Fibronectin serves as a platform to guide and facilitate deposition of collagen and fibrillin microfibrils. During development of fibrotic diseases, altered fibronectin deposition in the extracellular matrix (ECM) is generally an early event. Following this, dysregulated organization of fibrillins and fibrillar collagens occurs. Because fibronectin is an essential orchestrator of healthy ECM, perturbation of its ECM-organizational capacity may be involved in development of fibrosis. To investigate this, we employed recessive dystrophic epidermolysis bullosa (RDEB) as a disease model with progressive, severe dermal fibrosis. Fibroblasts from RDEB donors in 2D and 3D cultures displayed dysregulated fibronectin deposition. Our analyses revealed that increase of pro-fibrotic DPP4+ fibroblasts coincides with altered fibronectin deposition. DPP4 inhibitors normalized deposition of fibronectin and subsequently of fibrillin microfibrils and collagen I. Intriguingly, proteomics, inhibitor and mutagenesis studies disclosed that DPP4 modulates ECM deposition through proteolysis of the fibronectin N-terminus. Our study provides mechanistic insights to the observed pro-fibrotic activities of DPP4 and extends the understanding of fibronectin-guided ECM assembly in health and disease.

Lipid nanoparticles efficiently deliver the base editor ABE8e for COL7A1 correction in dystrophic epidermolysis bullosa fibroblasts in vitro.

Lipid nanoparticles efficiently deliver the base editor ABE8e for COL7A1 correction in dystrophic epidermolysis bullosa fibroblasts in vitro.

Abstract 2102: Understanding the mechanism of action of rigosertib in recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma through single cellanalysis

Abstract The allosteric inhibitor rigosertib (an experimental therapeutic) was previously identified as an effective inducer of G2M arrest and apoptosis in squamous cell carcinoma (SCC) keratinocytes isolated from patients with the rare genetic disease recessive dystrophic epidermolysis bullosa (RDEB), both in vitro and in vivo. Early clinical trial data treating RDEB-associated SCC with rigosertib has shown remarkable efficacy in a sub-set of patients and understanding the mechanism of action of rigosertib in this lethal cancer would provide rationale for patient stratification. Multiple mechanisms of action were previously attributed to rigosertib, including polo-like kinase-1 (PLK1), PI3-kinase, activated RAS and microtubule polymerization inhibition. Our published data comparing PLK1 siRNA with PI3-Kinase inhibitors, MAPK inhibitors and microtubule disruption favored PLK1 as a mechanism of action without definitive conclusion. We therefore sought to determine the mechanism of action using transcriptomic profiling. Flow cytometry experiments identified three main categories of time to increase G2M in nine separate RDEB SCC keratinocyte populations in culture ranging from 1 to 6 hours after exposure to 1uM rigosertib. Bulk-RNA sequencing of representative populations from time to G2M groupings failed to identify consistent transcriptional change after exposure to rigosertib. However, single cell sequencing was able to identify increases in sub-populations of cells associated with G2M as well as transient emergence of unique populations that were specific to individual patient populations after exposure to rigosertib in culture. Of note a transient population of RDEB SCC keratinocytes only present after 1 hour of exposure to rigosertib was characterized by increased expression of the potassium regulator KCNRG which has previously been associated with apoptosis in chronic lymphocytic leukemia. Ongoing work is determining the role this gene may play in the mechanism of apoptosis induction in RDEB SCC keratinocytes after exposure to rigosertib. Citation Format: Andrew P. South, Suhao Han, Paolo Fortina. Understanding the mechanism of action of rigosertib in recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma through single cellanalysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2102.

Abstract 2033: Rigosertib promotes anti-tumor activity of cancer cells via CETSA revealed novel targets and activates NLRP3-dependent inflammatory responses

Abstract Background: Rigosertib (ON 01910.Na) is considered a promising anticancer agent due to its ability to inhibit multiple disease signaling pathways, including RAS-MAPK signaling. Rigosertib is in a Phase 2 program in advanced squamous cell carcinoma complicating recessive dystrophic epidermolysis bullosa (RDEB-associated SCC) (NCT03786237, NCT04177498), and a Phase 2 trial in combination with pembrolizumab in patients with metastatic melanoma (NCT05764395). The aim of our study was to further elucidate the mechanism of action and to identify potential novel targets engaged by rigosertib. Methods: A variety of biochemical, molecular and cell biological assays were performed to characterize the binding of rigosertib to previously proposed targets and its effect on RAS-MAPK signaling and tumor cell survival. A mass spectrometry-based Cellular Thermal Shift Assay (CETSA-MS) was conducted to identify potential new protein targets of rigosertib. Time-lapse microscopy was used for detection of ROS levels and tubulin polymerization in rigosertib treated lung cancer cells. Bone Marrow Derived Macrophages (BMDM) collected from C57/BL6 mice and human lung cancer organoids were treated with rigosertib and the cell death was determined by flow cytometry. Results: Comparative CETSA profiling of rigosertib and colchicine, a classical tubulin depolymerizing agent, reveals unique targets of rigosertib in multiple tumor cell types. We identify two ROS-related proteins, ERO1A and NQO2 that potentially contribute to the induction of ROS-dependent JNK activation. Fluorescence live-cell imaging confirms the effect of ERO1A and NQO2 on rigosertib induced ROS generation. NEK7, a relevant protein for microtubule organization, is another potential target for rigosertib. NEK7 knock-down reveals reduced microtubule depolymerization in rigosertib treated lung cancer cells. While we confirm that rigosertib might affect microtubules at higher concentrations, the main cellular target(s) responsible for the induction of stress and JNK-mediated inhibition of RAS-RAF-MEK signaling needs to be further characterized. Rigosertib affects the tumor immune environment by activating NLRP3-dependent inflammatory responses and Caspase-1 to trigger IL-1β and IL-18 secretion in THP1 cells, as well as in human cancer organoids, and in wild-type, Casp1/11−/−, Asc−/− and Nlrp3−/− BMDMs. Conclusion: These findings indicate that rigosertib may represent an effective compound for inhibition of RAS-MAPK signaling through ROS-mediated JNK activation. The rigosertib-dependent mechanism for NLRP3 activation suggests a reprogramming of the tumor immune environment which may contribute to the synergistic effect seen with immune checkpoint inhibitors pre-clinically and clinically. Clinical trials in several difficult-to-treat cancers continue. Citation Format: Petros Kechagioglou, Camille Dupont, Hajime Yurugi, Alexey Chernobrovkin, Rossana Romero, Rebecca Tweedell, Thirumala-Devi Kanneganti, Stephen Cosenza, Steven M. Fruchtman, Krishnaraj Rajalingam. Rigosertib promotes anti-tumor activity of cancer cells via CETSA revealed novel targets and activates NLRP3-dependent inflammatory responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2033.

Dominant dystrophic epidermolysis bullosa is associated with glycolytically active GATA3+ Th2 cells which may contribute to pruritus in lesional skin.

Dominant dystrophic epidermolysis bullosa (DDEB) is characterized by trauma-induced blisters and, in some individuals, intense pruritus. Precisely what causes itch in DDEB and optimal ways to reduce it have not been fully determined. To characterize DDEB skin transcriptomes to identify therapeutic targets to reduce pruritus in patients. We evaluated affected and unaffected skin biopsy samples from 6 DDEB subjects (all with the very itchy pruriginosa subtype), and 4 healthy individuals using bulk RNA-seq. Single-cell transcriptomes of affected (n=2) and unaffected (n=1) DDEB and healthy skin (n=2) were obtained. Dupilumab treatment was provided for three patients. The skin bulk transcriptome showed significant enrichment of Th1/2 and Th17 pathways in affected DDEB skin compared with non-lesional DDEB and healthy skin. Single-cell transcriptomics showed an association of glycolytically active GATA3+ Th2 cells in affected DDEB skin. Treatment with dupilumab in three people with DDEB led to significantly reduced VAS itch scores after 12 weeks (mean VAS=3.83) compared to pre-treatment (mean VAS=7.83). Bulk RNA-seq and qPCR showed that healthy skin and dupilumab-treated epidermolysis bullosa (EB) pruriginosa skin show very similar transcriptomic profiles, and reduced Th1/2 and Th17 pathway enrichment. Single-cell RNA-seq helps define an enhanced DDEB-associated Th2 profile and rationalizes drug repurposing of anti-Th2 drugs in treating DDEB pruritus.

Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin disease characterized by defects in type VII collagen leading to a range of fibrotic pathologies resulting from skin fragility, aberrant wound healing, and altered dermal fibroblast physiology. Using a novel in vitro model of fibrosis based on endogenously produced extracellular matrix, we screened an FDA-approved compound library and identified antivirals as a class of drug not previously associated with anti-fibrotic action. Preclinical validation of our lead hit, daclatasvir, in a mouse model of RDEB demonstrated significant improvement in fibrosis as well as overall quality of life with increased survival, weight gain and activity, and a decrease in pruritus-induced hair loss. Immunohistochemical assessment of daclatasvir-treated RDEB mouse skin showed a reduction in fibrotic markers, which was supported by in vitro data demonstrating TGFβ pathway targeting and a reduction of total collagen retained in the extracellular matrix. Our data support the clinical development of antivirals for the treatment of patients with RDEB and potentially other fibrotic diseases.

Cyclization-enhanced poly(β-amino ester)s vectors for efficient CRISPR gene editing therapy

Among non-viral gene delivery vectors, poly(β-amino ester)s (PAEs) are one of the most versatile candidates because of their wide monomer availability, high polymer flexibility, and superior gene transfection performance both in vitro and in vivo. Over two decades, PAEs have evolved from linear to highly branched structures, significantly enhancing gene delivery efficacy. Building on the proven efficient sets of monomers in highly branched PAEs (HPAEs), this work introduced a new class of cyclic PAEs (CPAEs) constructed via an A2 + B4 + C2 cyclization synthesis strategy and identified their markedly improved gene transfection capabilities in gene delivery applications. Two sets of cyclic PAEs (CPAEs) with rings of different sizes and topologies were obtained. Their chemical structures were confirmed via two-dimensional nuclear magnetic resonance and the photoluminescence phenomena, and their DNA delivery behaviours were investigated and compared with the HPAE counterparts. In vitro assessments demonstrated that the CPAEs with a macrocyclic architecture (MCPAEs), significantly enhanced DNA intracellular uptake and facilitated efficient gene expression while maintaining perfect biocompatibility. The top-performance MCPAEs have been further employed to deliver a plasmid coding dual single guide RNA-guided CRISPR-Cas9 machinery to delete COL7A1 exon 80 containing the c.6527dupC mutation. In recessive dystrophic epidermolysis bullosa (RDEB) patient-derived epidermal keratinocytes, MCPAEs facilitated the CRISPR plasmid delivery and achieved efficient targeted gene editing in multiple colonies.

Advances in Treatments for Epidermolysis Bullosa (EB): Emphasis on Stem Cell-Based Therapy.

Epidermolysis bullosa (EB) is a rare genetic dermatosis characterized by skin fragility and blister formation. With a wide phenotypic spectrum and potential extracutaneous manifestations, EB poses significant morbidity and mortality risks. Currently classified into four main subtypes based on the level of skin cleavage, EB is caused by genetic mutations affecting proteins crucial for maintaining skin integrity. The management of EB primarily focuses on preventing complications and treating symptoms through wound care, pain management, and other supportive measures. However, recent advancements in the fields of stem cell therapy, tissue engineering, and gene therapy have shown promise as potential treatments for EB. Stem cells capable of differentiating into skin cells, have demonstrated positive outcomes in preclinical and early clinical trials by promoting wound healing and reducing inflammation. Gene therapy, on the other hand, aims to correct the underlying genetic defects responsible for EB by introducing functional copies of mutated genes or modifying existing genes to restore protein function. Particularly for severe subtypes like Recessive Dystrophic Epidermolysis Bullosa (RDEB), gene therapy holds significant potential. This review aims to evaluate the role of new therapeutic approaches in the treatment of EB. The review includes findings from studies conducted on humans. While early studies and clinical trials have shown promising results, further research and trials are necessary to establish the safety and efficacy of these innovative approaches for EB treatment.

Elevated expression of interleukin-6 (IL-6) and serum amyloid A (SAA) in the skin and the serum of recessive dystrophic epidermolysis bullosa: Skin as a possible source of IL-6 through Toll-like receptor ligands and SAA.

The effect of persistent skin inflammation on extracutaneous organs and blood is not well studied. Patients with recessive dystrophic epidermolysis bullosa (RDEB), a severe form of the inherited blistering skin disorder, have widespread and persistent skin ulcers, and they develop various complications including anaemia, hyperglobulinaemia, hypoalbuminaemia and secondary amyloidosis. These complications are associated with the bioactivities of IL-6, and the development of secondary amyloidosis requires the persistent elevation of serum amyloid A (SAA) level. We found that patients with RDEB had significantly higher serum levels of IL-6 and SAA compared to healthy volunteers and patients with psoriasis or atopic dermatitis. Both IL-6 and SAA were highly expressed in epidermal keratinocytes and dermal fibroblasts of the skin ulcer lesions. Keratinocytes and fibroblasts surrounding the ulcer lesions are continuously exposed to Toll-like receptor (TLR) ligands, pathogen-associated and damage-associated molecular pattern molecules. Invitro, TLR ligands induced IL-6 expression via NF-κB in normal human epidermal keratinocytes (NHEKs) and dermal fibroblasts (NHDFs). SAA further induced the expression of IL-6 via TLR1/2 and NF-κB in NHEKs and NHDFs. The limitation of this study is that NHEKs and NHDFs were not derived from RDEB patients. These observations suggest that TLR-mediated persistent skin inflammation might increase the risk of IL-6-related systemic complications, including RDEB.

Th2 response drives itch in dystrophic epidermolysis bullosa pruriginosa: a case-control study

Th2 response drives itch in dystrophic epidermolysis bullosa pruriginosa: a case-control study

Self-improving dystrophic epidermolysis bullosa with a novel heterozygous missense variant in the COL7A1 gene in a Taiwanese family.

Self-improving dystrophic epidermolysis bullosa (DEB) is a genodermatosis that is inherited autosomal dominantly or recessively, and its clinical symptoms may improve or subside spontaneously. Herein, we report a case of self-improving DEB with COL7A1 p.Gly2025Asp variant. The diagnosis was made through histopathological, electron microscopic examination, and genetic testing. The same variant is also noted on his father, who presents with dystrophic toenails without any blisters. This study highlights that idiopathic nail dystrophy could be linked to congenital or hereditary disease. Furthermore, we conducted a review of the literature on the characteristics of reported cases of self-improving DEB with a personal or family history of nail dystrophy. The results supported our findings that nail dystrophy may be the sole manifestation in some family members. We suggest that individuals suffering from idiopathic nail dystrophy may seek genetic counselling when planning pregnancy to early evaluate the potential risk of hereditary diseases.

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 recessive dystrophic epidermolysis bullosa patients: 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 harboring nonsense mutations. Primary outcomes were increased expression of C7 in patients' skin and assessments for safety (ototoxicity, nephrotoxicity, autoimmune response). Secondary outcomes included measuring wound healing in target wounds and assessment by a validated Epidermolysis Bullosa Disease and Activity Scarring Index (EBDASI) scoring system. An open-label pilot trial assessing two different regimens of IV gentamicin between August 2018 and March 2020 with follow-up through 180 days post-treatment. Three RDEB patients 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 at 7.5 mg/kg daily for 14 days and two of three patients further received 7.5 mg/kg 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 (ages ranging 18-28 years) exhibited increased C7 in their DEJ. With both regimens, the new C7 persisted at least six months post-treatment. At one and three-months post-treatment, 100% of the monitored wounds exhibited greater than 85% closure. Both IV gentamicin infusion regimens decreased EBDASI total activity scores. Of all patients assessed with the EBDASI, all patients exhibited decreased total activity scores three-month post-treatment. All three patients completed the study, and no adverse effects or anti-C7 antibodies were detected. IV gentamicin induced readthrough of nonsense mutations in RDEB patients 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 therapy in this population of RDEB patients. Clinicaltrials.gov Identifiers: NCT03392909.

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.

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.