Résumé :
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Dystrophin, with its modular structure, and in particular its central domain made up of 24 spectrin-like repeat motifs, is a protein that can support the deletion of certain internal areas provided that the final reading frame is preserved. Taking into account the organization of the DMD gene, its pre-mRNA processing can be modulated with high specificity by antisense oligoribonucleotides (AON) that mask key determinants of splicing through Watson-Crick pairing. This approach has been used to counteract the deleterious effect of many mutations in mouse, dog and man by using either synthetic DNA or RNA analogues or engineered snRNAs as antisense carriers delivered by AAV gene vectors. In this case, the practical application of a clinically relevant gene therapy would require the treatment of the whole skeletal and cardiac musculature through a unique exposition to the vector since treated individuals raise rapidly a robust immune response jamming further treatments. Whole body transduction using systemic delivery for AAV gene vectors has been successfully achieved in mouse. However, its translation in dog was not trivial and disclosed a number of problems which still need to be solved to guarantee efficacy and safety of this approach in human patients.
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