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

Georgiadis, C; Syed, F; Petrova, A; Abdul-Wahab, A; Lwin, SM; Farzaneh, F; Chan, L; ... Qasim, W; + view all (2016) Lentiviral Engineered Fibroblasts Expressing Codon Optimized COL7A1 Restore Anchoring Fibrils in RDEB. Journal of Investigative Dermatology , 136 (1) pp. 284-292. 10.1038/jid.2015.364. Green open access

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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.

Type: Article
Title: Lentiviral Engineered Fibroblasts Expressing Codon Optimized COL7A1 Restore Anchoring Fibrils in RDEB
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/jid.2015.364
Publisher version: http://dx.doi.org/10.1038/jid.2015.364
Language: English
Additional information: Copyright © 2015 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1475231
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