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J Invest Dermatol. 2016 Jul;136(7):1346-1354. doi: 10.1016/j.jid.2016.02.811. Epub 2016 Mar 16.

Gene-Corrected Fibroblast Therapy for Recessive Dystrophic Epidermolysis Bullosa using a Self-Inactivating COL7A1 Retroviral Vector.

Author information

1
Laboratory of Genetic Skin Diseases, Inserm UMR1163 and Imagine Institute of Genetic Diseases, Paris, France; University Paris Descartes-Sorbonne Paris Cite, Paris, France.
2
Laboratory of Genetic Skin Diseases, Inserm UMR1163 and Imagine Institute of Genetic Diseases, Paris, France; University Paris Descartes-Sorbonne Paris Cite, Paris, France; Department of General Surgery, Plastic Surgery, and Ambulatory Surgery, AP-HP, HUPC, Cochin Hospital, Paris, France.
3
Laboratory of Genetic Skin Diseases, Inserm UMR1163 and Imagine Institute of Genetic Diseases, Paris, France; University Paris Descartes-Sorbonne Paris Cite, Paris, France; Department of Genetics, Necker Hospital, Paris, France. Electronic address: alain.hovnanian@inserm.fr.

Abstract

Patients with recessive dystrophic epidermolysis bullosa (RDEB) lack type VII collagen and therefore have severely impaired dermal-epidermal stability causing recurrent skin and mucosal blistering. There is currently no specific approved treatment for RDEB. We present preclinical data showing that intradermal injections of genetically corrected patient-derived RDEB fibroblasts using a Good Manufacturing Practices grade self-inactivating COL7A1 retroviral vector reverse the disease phenotype in a xenograft model in nude mice. We obtained 50% transduction efficiency in primary human RDEB fibroblasts with an average low copy number (range = 1-2) of integrated provirus. Transduced fibroblasts showed strong type VII collagen re-expression, improved adhesion properties, normal proliferative capabilities, and viability in vitro. We show that a single intradermal injection of 3 × 10(6) genetically corrected RDEB fibroblasts beneath RDEB skin equivalents grafted onto mice allows type VII collagen deposition, anchoring fibril formation at the dermal-epidermal junction, and improved dermal-epidermal adherence 2 months after treatment, supporting functional correction in vivo. Gene-corrected fibroblasts previously showed no tumorigenicity. These data show the efficacy and safety of gene-corrected fibroblast therapy using a self-inactivating vector that has now been good manufacturing grade-certified and pave the way for clinical translation to treat nonhealing wounds in RDEB patients.

PMID:
26994967
DOI:
10.1016/j.jid.2016.02.811
[Indexed for MEDLINE]
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