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Lentiviral Engineered Fibroblasts Expressing Codon Optimized COL7A1 Restore Anchoring Fibrils in RDEB

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Christos Georgiadis, Farhatullah Syed, Anastasia Petrova, Alya Abdul-Wahab, Su M Lwin, Farzin Farzaneh, Lucas Chan, Sumera Ghani, Roland A Fleck, Leanne Glover, James R McMillan, Mei Chen, Adrian J Thrasher, John A McGrath, Wei-Li Di, Waseem Qasim

Original languageEnglish
JournalJournal of Investigative Dermatology
Early online date22 Sep 2015
DOIs
Accepted/In press3 Aug 2015
E-pub ahead of print22 Sep 2015

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Abstract

Cells therapies, engineered to secrete replacement proteins, are being developed to ameliorate otherwise debilitating diseases. Recessive dystrophic epidermolysis bullosa (RDEB) is caused by defects of type VII collagen (C7), a protein essential for anchoring fibril formation at the dermal-epidermal junction (DEJ). Whilst allogeneic fibroblasts injected directly into the dermis can mediate transient disease modulation, autologous gene-modified fibroblasts should evade immunological rejection and support sustained delivery of C7 at the DEJ. We demonstrate the feasibility of such an approach using a therapeutic grade, self-inactivating-lentiviral vector, encoding codon optimized COL7A1, to transduce RDEB fibroblasts under conditions suitable for clinical application. Expression and secretion of C7 was confirmed, with transduced cells exhibiting supra-normal levels of protein expression and ex vivo migration of fibroblasts was restored in functional assays. Gene modified RDEB fibroblasts also deposited C7 at the DEJ of human RDEB skin xenografts placed on NOD-scid IL2Rgamma(null) recipients, with reconstruction of human epidermal structure and regeneration of anchoring fibrils at the DEJ. Fibroblast mediated restoration of protein and structural defects in this RDEB model strongly supports proposed therapeutic applications in man.Journal of Investigative Dermatology accepted article preview online, 22 September 2015. doi:10.1038/jid.2015.364.

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