430P The damaged lysosome is a therapeutic target for combined therapy in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a muscle degenerative disease that affects mainly boys, which is caused by the loss or drastic reduction in the expression of dystrophin. Gene therapy for the restoration of a functional shortened form of dystrophin (µ-dystrophin) have provided encouraging results in animal models. Nevertheless, in treated DMD patients the therapeutic benefit of this approach is still questionable, and therefore there is an urgent need for improved approach. Recently, we performed a non-supervised omics study (plasma miRNA profiling) of a large DMD cohort and found that cholesterol metabolism is a therapeutic target. In lysosomal storage diseases, lysosomal damage is often linked to cholesterol excess, and interestingly, previous and more recent investigations identified lysosomal perturbations in DMD. Taken together, these observations support the possible link in DMD between cholesterol excess and lysosomal perturbation. In the present work, we observed upregulation of the lysosomal damage biomarker Galectin-3 (Gal-3) in dystrophic muscle, thus confirmed Gal-3 as a lysosomal damage biomarker. We then treated mdx mice with Adeno Associated Virus (AAV) expressing µ-dystrophin and found that Gal-3 expression pattern was only partially normalized, supporting an incomplete correction of lysosomal damage by µ-dystrophin gene therapy. Consequently, we treated the mdx mouse by the combination of Trehalose, a safe dietary supplement disaccharide to alleviate lysosomal damage, and AAV µ-dystrophin to restore dystrophin expression, as compared to mice treated by only one of these treatments. We found that correction of lysosomal damage by trehalose exceeded lysosomal correction by µ-dystrophin. Importantly, the best correction of lysosomal damage and muscle function parameters was achieved by the combined treatment. Lysosomal damage may play a key role in the pathology of DMD and is therefore a potential therapeutic target. Trehalose and µ-dystrophin combined therapy for DMD holds the potential for improved therapeutic outcome. [ABSTRACT FROM AUTHOR]