Sustained phenotypic reversion of junctional epidermolysis bullosa dog keratinocytes: Establishment of an immunocompetent animal model for cutaneous gene therapy

Journal Article · Fri Jan 20 00:00:00 EST 2006 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/j.bbrc.2005.10.216· OSTI ID:20798753

Spirito, Flavia ^[1]; Capt, Annabelle ^[1]; Rio, Marcela Del ^[2]; Larcher, Fernando ^[2]; Guaguere, Eric ^[3]; Danos, Olivier ^[4]; Meneguzzi, Guerrino ^[1]

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1. INSERM U634, Faculty of Medicine, Nice (France)
2. Centro de Investigaciones Energeticas Medioambientales y Tecnologicas (CIEMAT), 28040 Madrid (Spain)
3. Clinique Veterinaire St Bernard, Lomme (France)
4. Genethon III-CNRS UMR 8115, Evry (France)

Gene transfer represents the unique therapeutic issue for a number of inherited skin disorders including junctional epidermolysis bullosa (JEB), an untreatable genodermatose caused by mutations in the adhesion ligand laminin 5 ({alpha}3{beta}3{gamma}2) that is secreted in the extracellular matrix by the epidermal basal keratinocytes. Because gene therapy protocols require validation in animal models, we have phenotypically reverted by oncoretroviral transfer of the curative gene the keratinocytes isolated from dogs with a spontaneous form of JEB associated with a genetic mutation in the {alpha}3 chain of laminin 5. We show that the transduced dog JEB keratinocytes: (1) display a sustained secretion of laminin 5 in the extracellular matrix; (2) recover the adhesion, proliferation, and clonogenic capacity of wild-type keratinocytes; (3) generate fully differentiated stratified epithelia that after grafting on immunocompromised mice produce phenotypically normal skin and sustain permanent expression of the transgene. We validate an animal model that appears particularly suitable to demonstrate feasibility, efficacy, and safety of genetic therapeutic strategies for cutaneous disorders before undertaking human clinical trials.

• OSTI ID: 20798753
• Journal Information: Biochemical and Biophysical Research Communications, Vol. 339, Issue 3; Other Information: DOI: 10.1016/j.bbrc.2005.10.216; PII: S0006-291X(05)02580-5; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CLINICAL TRIALS
DISEASE VECTORS
DOGS
GENE THERAPY
LIGANDS
MICE
MUTATIONS
SECRETION
SKIN DISEASES
VIRUSES