Résumé
Duchenne muscular dystrophy (DMD) is a rare, progressive muscular dystrophy that affects mainly young boys. It is caused by mutations in the DMD gene coding for the dystrophin protein. To date, there is no cure for DMD. The most promising therapeutic approach is gene therapy, which consists of delivering a shortened version of dystrophin (μ-dys) using recombinant adeno-associated viruses (rAAV). However, μ-dys gene therapy showed limited efficacy in patients and toxicity issues linked to high doses of injected vectors. The aim of the work presented here is to first improve our understanding of the metabolic and cellular perturbations in DMD, and secondly to develop combined therapies approaches, associating gene therapy to treatments of identified dysregulations. We have identified that cholesterol metabolism is dysregulated in DMD muscle, which correlated with a high cholesterol accumulation in the endolysosomal compartment. An overexpression and recruitment of galectine-3 (LGALS3) to lysosomes indicated significant lysosome damage in DMD muscle. Moreover, we have identified a drug (Drug X) capable of removing lysosomal cholesterol from muscle. This drug corrected lysosome damage in a mouse model of DMD (Dmdmdx) and reduced some of the dystrophic features. The combination of this drug to μ-dys gene therapy improved the efficacy of gene therapy, which did not correct lysosome damage alone. The identification of lysosomal damage in DMD offers new therapeutic approaches for DMD.