Objective
We aim to develop ex vivo gene therapy of recessive dystrophic epidermolysis bullosa RDEB. It is caused by loss of function mutations in the collagen VII gene (COL7A1) encoding anchoring fibrils. Patients suffer from skin blistering since birth, and from severe local and systemic complications resulting in poor prognosis. We lack a specific treatment for RDEB, but ex vivo gene transfer to epidermal stem cells shows therapeutic potential. in vitro correction of primary RDEB keratinocytes and fibroblasts by retroviral and lentiviral COL7A1 cDNA vectors was reported. Reports of leukemia caused by retroviral insertional mutagenesis in gene therapy of X-SCID steered us toward safer SIN vectors. In Step I of this project, we will design safe SIN retroviral and lentiviral COL7A1 vectors. Different promoters and viral envelope proteins will be tested for efficient gene delivery and expression in cultured primary keratinocytes and fibroblasts. We will study the proliferative capacity of transduced cells and assess long-term expression of recombinant collagen VII. We will analyse synthesis, folding and secretion of recombinant collagen VII, and its ability to form anchoring fibres in a skin equivalent model and in skin grafts on mice. Vectors will be structed and produced form to GLP standards. In Step II, cell clones producing the highest titres of the selected SIN retroviral or lentiviral vector (mini-cell bank) will be expanded, evaluated, and a unique GMP master cell bank will be established. This MCB will be tested for safety, to be used in the production of clinical grade viral particles. Step III will be a pilot clinical trial (Phase I/II) of genetically corrected autologous skin grafts in selected patients. This project, which combines the complementary expertise of several international groups, will serve as proof of principle for the treatment of RDEB, and as a model for the treatment of severe dermatological genetic disorders by ex vivo gene therapy.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health sciencesclinical medicineoncologyskin cancer
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesbasic medicineimmunology
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesclinical medicinesurgerysurgical procedures
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Call for proposal
FP6-2003-LIFESCIHEALTH-I
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Funding Scheme
STIP - Specific Targeted Innovation ProjectCoordinator
PARIS
France