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JCI Insight. 2019 Jun 6;4(11). pii: 126243. doi: 10.1172/jci.insight.126243. eCollection 2019 Jun 6.

Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa.

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St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, United Kingdom.
Infection, Immunity and Inflammation Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
The Robin Eady National Diagnostic Epidermolysis Bullosa Laboratory, Viapath, St Thomas' Hospital, London, United Kingdom.
School of Population Health and Environmental Sciences, King's College London, London, United Kingdom.
Immunodermatology Laboratory, Viapath, St Thomas' Hospital, London, United Kingdom.
INSERM UMR 1163, Imagine Institute, Université Paris Descartes Sorbonne Cite, Paris, France.
National Institute for Health Research (NIHR) Biomedical Research Centre, Guy's and St Thomas' Hospitals, London, United Kingdom.
Department of Dermatology, University of Southern California, Los Angeles, California, USA.
Department of Haematological Medicine, King's College London, The Rayne Institute, London, United Kingdom.
Epithelial Biomedicine Division, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT); Department of Biomedical Engineering, Carlos III University (UC3M); Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER) U714, Madrid, Spain.
Department of Pediatric Oncology, Hematology and Bone Marrow Transplant, University of Minnesota, Minneapolis, Minnesota, USA.
Department of Dermatology and EB House Austria, University Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria.
Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.


BACKGROUNDRecessive 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.METHODSIn this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 106 cells/cm2 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.RESULTSGene-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.CONCLUSIONTo 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 phase II studies for further clinical evaluation.TRIAL NCT02493816.FUNDINGCure EB, Dystrophic Epidermolysis Bullosa Research Association (UK), UK NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London, and Fondation René Touraine Short-Exchange Award.


Dermatology; Gene therapy; Genetic diseases; Genetics; Skin

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