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

Su M. Lwin, Farhatullah Syed, Wei Li Di, Tendai Kadiyirire, Lu Liu, Alyson Guy, Anastasia Petrova, Alya Abdul-Wahab, Fiona Reid, Rachel Phillips, Maria Elstad, Christos Georgiadis, Sophia Aristodemou, Patricia A. Lovell, James R. McMillan, John Mee, Snaigune Miskinyte, Matthias Titeux, Linda Ozoemena, Rashida PramanikSonia Serrano, Racheal Rowles, Clarisse Maurin, Elizabeth Orrin, Magdalena Martinez-Queipo, Ellie Rashidghamat, Christos Tziotzios, Alexandros Onoufriadis, Mei Chen, Lucas Chan, Farzin Farzaneh, Marcela Del Rio, Jakub Tolar, Johann W. Bauer, Fernando Larcher, Michael N. Antoniou, Alain Hovnanian, Adrian J. Thrasher, Jemima E. Mellerio, Waseem Qasim, John A. McGrath

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63 Scopus citations


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.

Original languageEnglish (US)
Article number:e126243
JournalJCI Insight
Issue number11
StatePublished - Jun 6 2019

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Copyright: © 2019 American Society for Clinical Investigation


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