IMPORTANCERecessive dystrophic epidermolysis bullosa (RDEB) is a devastating, often fatal, inherited blistering disorder caused by mutations in the COL7A1 gene encoding type VII collagen. Support and palliation are the only current therapies.OBJECTIVE To evaluate the safety and wound outcomes following genetically corrected autologous epidermal grafts in patients with RDEB.DESIGN, SETTING, AND PARTICIPANTS Single-center phase 1 clinical trial conducted in the United States of 4 patients with severe RDEB with a measured area of wounds suitable for grafting of at least 100 cm 2 . Patients with undetectable type VII collagen keratinocyte expression were excluded.INTERVENTIONS Autologous keratinocytes isolated from biopsy samples collected from 4 patients with RDEB were transduced with good manufacturing practice-grade retrovirus carrying full-length human COL7A1 and assembled into epidermal sheet grafts. Type VII collagen gene-corrected grafts (approximately 35 cm 2 ) were transplanted onto 6 wounds in each of the patients (n = 24 grafts). MAIN OUTCOMES AND MEASURESThe primary safety outcomes were recombination competent retrovirus, cancer, and autoimmune reaction. Molecular correction was assessed as type VII collagen expression measured by immunofluorescence and immunoelectron microscopy. Wound healing was assessed using serial photographs taken at 3, 6, and 12 months after grafting. RESULTSThe 4 patients (mean age, 23 years [range, 18-32 years]) were all male with an estimated body surface area affected with RDEB of 4% to 30%. All 24 grafts were well tolerated without serious adverse events. Type VII collagen expression at the dermal-epidermal junction was demonstrated on the graft sites by immunofluorescence microscopy in 9 of 10 biopsy samples (90%) at 3 months, in 8 of 12 samples (66%) at 6 months, and in 5 of 12 samples (42%) at 12 months, including correct type VII collagen localization to anchoring fibrils. Wounds with recombinant type VII collagen graft sites displayed 75% or greater healing at 3 months (21 intact graft sites of 24 wound sites; 87%), 6 months (16/24; 67%), and 12 months (12/24; 50%) compared with baseline wound sites. CONCLUSIONS AND RELEVANCEIn this preliminary study of 4 patients with RDEB, there was wound healing in some type VII collagen gene-corrected grafts, but the response was variable among patients and among grafted sites and generally declined over 1 year. Long-term follow-up is necessary for these patients, and controlled trials are needed with a broader range of patients to better understand the potential long-term efficacy of genetically corrected autologous epidermal grafts.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, life-threatening bullous genodermatosis (1, 2). Genetic mutations in the COL7A1 gene lead to lack of functional type VII collagen (C7), a large triple-helical protein found beneath the lamina densa (2-4). C7 contains 2 noncollagenous domains (NC1 and NC2) and a central collagenous domain, forming anchoring fibrils (AFs) that are critical to dermal-epidermal basement cohesion (2, 4). Mutations in COL7A1 lead to disruptions in keratinocyte adhesion, reducing mucocu-BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) patients have mutations in the COL7A1 gene and thus lack functional type VII collagen (C7) protein; they have marked skin fragility and blistering. This single-center phase 1/2a open-label study evaluated the long-term efficacy, safety, and patient-reported outcomes in RDEB patients treated with gene-corrected autologous cell therapy. METHODS. Autologous keratinocytes were isolated from participant skin biopsies. Epidermal sheets were prepared from cells transduced with a retrovirus carrying the full-length human COL7A1 gene. These gene-corrected autologous epidermal sheets measured 5 × 7 cm (35 cm 2) and were transplanted onto 6 wound sites in each of 7 adult participants (n = 42 sites total) from 2013 to 2017. Participants were followed for 2 to 5 years. RESULTS. No participants experienced any serious related adverse events. Wound healing of 50% or greater by Investigator Global Assessment was present in 95% (36 of 38) of treated wounds versus 0% (0 of 6) of untreated control wounds at 6 months (P < 0.0001). At year 1, 68% (26 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.025). At year 2, 71% (27 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.019). CONCLUSION. C7 expression persisted up to 2 years after treatment in 2 participants. Treated wounds with 50% or greater healing demonstrated improvement in patient-reported pain, itch, and wound durability. This study provides additional data to support the clinically meaningful benefit of treating chronic RDEB wounds with ex vivo, C7 gene-corrected autologous cell therapy. This approach was safe and promoted wound healing that was associated with improved patientreported outcomes. TRIAL REGISTRATION. Clinicaltrials.gov identifier: NCT01263379.

Background Qualitative data suggest that pruritus is a burdensome symptom in patients with epidermolysis bullosa (EB), but the prevalence of pruritus in children and adults with EB, as well as factors that contribute to pruritus are unknown. Objective To quantitatively identify and to characterize pruritus experienced by EB patients using a comprehensive online questionnaire. Methods A questionnaire was developed to evaluate pruritus in all ages and types of EB. Questions that characterize pruritus were included, and factors that aggravate symptoms were investigated. Patients from seven North American EB centers were invited to participate. Results A total of 146 out of 216 questionnaires were completed (response rate=68%) (73 males, 73 females; median age, 20.0). Using a 5-point Likert scale (1=never, 2=rarely, 3=sometimes, 4=often, 5=always), itchiness was the most bothersome EB complication (mean=3.3). The average daily frequency of pruritus increased with self-reported EB severity. Pruritus was most frequent at bedtime (mean=3.8) and interfered with sleep. Factors that aggravated pruritus included healing wounds, dry skin, infected wounds, stress, heat, dryness, and humidity. Conclusions Pruritus is common in EB patients and can be very bothersome. Future studies will need to investigate the most effective treatments given to EB patients for pruritus.

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