Targeting lysosomal damage is a new therapeutic perspective for Duchenne Muscular Dystrophy

Abstract Duchenne Muscular Dystrophy (DMD), a muscle degenerative disease affecting young boys, arises from the loss of dystrophin. Current gene therapy approaches aim to restore a shortened form of dystrophin (microdystrophin) via Adeno-Associated Vector (AAV) delivery, but clinical studies show limited efficacy, emphasizing the need for improved strategies such as combined therapies. In this study, we identified lysosomal perturbations in the myofibers of DMD patients and animal models, an overlooked mechanism of cellular damage in muscular dystrophies. These were notably marked by the upregulation and recruitment of Galectin-3, a known biomarker of lysosomal membrane permeabilization, to damaged lysosomes, alongside alterations in lysosome number, morphology, and activation of endolysosomal damage response. Importantly, microdystrophin therapy in Dmdmdx mice fails to fully correct these damages. However, combining it with trehalose, a lysosome-protective disaccharide, significantly improves outcome, enhancing muscle function, histology and transcriptome. These findings highlight lysosomal damage as a novel mechanism in DMD pathogenesis and suggest that combining trehalose with gene therapy could enhance therapeutic efficacy. Teaser Lysosomal damage contributes to DMD pathology and is an interesting therapeutic target worth considering for current and future approaches. Competing Interest Statement The authors have declared no competing interest.