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Risultati finali
By transfer of a curative transgene, we have achieved the full phenotypic reversion of primary keratinocytes of patients with a mild form of junctional epidermolysis bullosa (JEB) associated with genetic point mutations in the laminin beta3 gene. These findings confirm the feasibility of phenotypic reversion of adhesion-defective epithelial cells expressing a recombinant basement membrane protein, and pave the way to the gene therapy of genetic skin diseases.
Specifically, we have permanently transduced epidermal stem cells with replication-defective retroviral constructs carrying an exogenous cDNA. We have achieved a long-term expression of curative transgene in vivo following grafting onto athymic animals. We have demonstrated the stable gene correction in the epidermal stem cells isolated from JEB-patients and the possibility of cultivating large amount of genetically engineered epidermis in the GMP conditions. By long-term evaluation of cultured graphs, we have showed that the transplanted epithelia are indistinguishable from the normal epithelium.
This result comprises protocols and methods allowing correction of diseased skin keratinocytes by genetic manipulations. Methods for the reconstruction of skin and corneal epithelia have also been perfected.
The molecular bases underlying the clinical observations that define the clinical variants of severe and mild junctional epidermolysis bullosa (JEB) have been clarified. The identification of new candidate genes in the clinical variants of JEB, and the identification of novel mutations in the genes associated with the disease have led to the establishment of DNA-based prenatal diagnosis of pregnancies at risk for recurrence.
Elucidation of the anatomy of ITGB4 and LAMA3 has served to delineate mutation detection strategies for each gene devoted to the identification of pathogenic mutations associated with JEB. A new candidate gene in the disease (CD151) has been identified. Genetic mutations associated with EB have been identified in dog breeds. This result comprises number of protocols allowing detection of genetic mutations in the population suffering of blistering diseases
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