BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation. METHODS. In this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 10 6 cells/cm 2 of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin. RESULTS. Gene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P < 0.05) 1.26-fold to 26.10-fold increase in C7 mean fluorescence intensity in the injected skin compared with noninjected skin in 3 of 4 subjects, with a sustained increase up to 12 months in 2 of 4 subjects. The presence of transgene (codon-optimized COL7A1 cDNA) was demonstrated in the injected skin at month 12 in 1 subject, but no new mature AFs were detected. CONCLUSION. To our knowledge, this is the first human study demonstrating safety and potential efficacy of lentiviral fibroblast gene therapy with the presence of COL7A1 transgene and subsequent C7 restoration in vivo in treated skin at 1 year after gene therapy. These data provide a rationale for insight.jci.org

This series is the largest reported to date and highlights that individuals with different forms of epidermolysis bullosa are at risk of developing squamous cell carcinomas of the skin. Patients often develop multiple primary tumours that tend to behave aggressively despite wide local excision and have poor response to conventional chemotherapy. The prognosis in severe recessive dystrophic epidermolysis bullosa is worse than previously reported, with median survival from diagnosis of first squamous cell carcinoma of only 2.4 years.Epidermolysis bullosa (EB), notably severe recessive dystrophic EB (RDEB-S), is associated with increased risk of aggressive mucocutaneous squamous cell carcinomas, the major cause of mortality in early adulthood. This observational, retrospective case review describes a series of EB patients with cutaneous squamous cell carcinomas over a 28-year period. Forty-four EB patients with squamous cell carcinomas were identified with a total of 221 primary tumours. They comprised: 31 (70%) with RDEB-S, 4 (9%) with other RDEB subtypes, 5 (11.4%) with dominant dystrophic EB, 3 (6.8%) with intermediate junctional EB and 1 (2.3%) with Kindler EB. Squamous cell carcinomas occurred earlier in RDEB-S (median age 29.5 years; age range 13-52 years) than other groups collectively (median age 47.1 years; age range 30-89 years) and most had multiple tumours (mean 5.8; range 1-44). Squamous cell carcinoma-associated mortality was high in RDEB-S (64.5%), with median survival after first squamous cell carcinoma of 2.4 years (range 0.5-12.6 years), significantly lower than previous reports, highlighting the need for early surveillance and better treatments.

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Epidermolysis bullosa (EB) is a rare inherited disease that causes epidermal fragility, blistering, and erosions. EB results from a variety of mutations in proteins of the skin and mucous membranes of the body. Mutations in plectin a protein involved in hemidesmosome integrity and function, are associated with subtypes of EB, including EB with pyloric atresia and EB with muscular dystrophy. We present two cases of EB with significant urologic involvement resulting from mutations in plectin.