Résumé :
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Limb-girdle muscular dystrophies (LGMD) are a group of genetically heterogeneous muscular dystrophies grouped together on the basis of common clinical features: they all primarily and predominantly affect proximal muscles. Gene transfer to the muscle in animal models using recombinant adeno-associated virus (rAAV) vectors has proven to be an effective option for the treatment of several LGMD. However, hurdles linked to the nature of the transgene can be observed in some instance. For example, whereas for most of the LGMD, the size of the corresponding cDNA is compatible with the encapsidation capacity of rAAV, there are two notable exceptions: dysferlin and titin. To obtain correction of the genetic defects, we are applying strategies based on the capacity of AAV to concatemerize to transfer the dysferlin gene using head and tail vectors and spliceosome-mediated RNA trans-splicing to exchange exons in the titin gene. In addition, biosafety issues related to the generation of an immune response against the transgene in _-sarcoglycan gene transfer or to the toxicity of ectopic expression in calpain 3 gene transfer were identified. To circumvent these problems, restriction of transcription of transgenes to the target tissue by constructing cassettes carrying regulatory elements such as endogenous promoters and/or specific miRNA target are explored. In this presentation, results obtained with these different strategies will be presented.
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