TY - JOUR AU - Lwin, Su M. AU - Syed, Farhatullah AU - Di, Wei-Li AU - Kadiyirire, Tendai AU - Liu, Lu AU - Guy, Alyson AU - Petrova, Anastasia AU - Abdul-Wahab, Alya AU - Reid, Fiona AU - Phillips, Rachel AU - Elstad, Maria AU - Georgiadis, Christos AU - Aristodemou, Sophia AU - Lovell, Patricia A. AU - McMillan, James R. AU - Mee, John AU - Miskinyte, Snaigune AU - Titeux, Matthias AU - Ozoemena, Linda AU - Pramanik, Rashida AU - Serrano, Sonia AU - Rowles, Racheal AU - Maurin, Clarisse AU - Orrin, Elizabeth AU - Martinez-Queipo, Magdalena AU - Rashidghamat, Ellie AU - Tziotzios, Christos AU - Onoufriadis, Alexandros AU - Chen, Mei AU - Chan, Lucas AU - Farzaneh, Farzin AU - Del Rio, Marcela AU - Tolar, Jakub AU - Bauer, Johann W. AU - Larcher, Fernando AU - Antoniou, Michael N. AU - Hovnanian, Alain AU - Thrasher, Adrian J. AU - Mellerio, Jemima E. AU - Qasim, Waseem AU - McGrath, John A. T1 - Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa PY - 2019/06/06/ AB - 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 × 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.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 phase II studies for further clinical evaluation.TRIAL REGISTRATION ClincalTrials.gov NCT02493816.FUNDING Cure 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.126243 VL - 4 IS - 11 UR - https://doi.org/10.1172/jci.insight.126243 PB - The American Society for Clinical Investigation ER -