Lysosomal damage is a therapeutic target in Duchenne muscular dystrophy
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 delivery. While recent clinical studies show promise, therapeutic efficacy remains incomplete, emphasizing the need for improved approaches. Here, we identified lysosomal perturbations in myofibers of patients with DMD and animal models, an overlooked mechanism of cellular damage in muscular dystrophies. These were notably marked by the up-regulation and recruitment of Galectin-3, a biomarker of lysosomal membrane permeabilization, to lysosomes, alongside alterations in lysosome number, morphology, and function. Microdystrophin therapy in <i>Dmd<sup>mdx</sup></i> mice fails to fully correct these damages. However, combining it with trehalose, a lysosome-protective disaccharide, substantially improves the outcome, enhancing muscle function, myopathology, and transcriptome. These findings highlight lysosomal damage as an important pathomechanism in DMD and suggest that combining trehalose with gene therapy could enhance therapeutic efficacy.
Authors
- Bagwan Das
- Nathalie Bourg
- Teresinha Evangelista (ORCID: https://orcid.org/0000-0002-1329-9131)
- Nathalie Danièle (ORCID: https://orcid.org/0000-0002-7985-2788)
- Laetitia van Wittenberghe
- Stéphane Blot (ORCID: https://orcid.org/0000-0002-8982-0317)
- Inès Barthélémy (ORCID: https://orcid.org/0000-0002-4747-5893)
- Guillaume Tanniou (ORCID: https://orcid.org/0000-0002-9642-7839)
- David Israeli (ORCID: https://orcid.org/0000-0003-2762-2195)
- Daniel Stockholm (ORCID: https://orcid.org/0000-0002-5069-5256)
- Laura Palmieri (ORCID: https://orcid.org/0009-0006-4275-278X)
- Isabelle Richard (ORCID: https://orcid.org/0000-0002-6505-446X)
- Sonia Albini (ORCID: https://orcid.org/0000-0001-9502-1004)
- Adeline Miranda
- Ai Vu Hong (ORCID: https://orcid.org/0000-0002-0872-4295)
- Abbass Jaber
- Jérôme Poupiot
- Mai Thao Bui (ORCID: https://orcid.org/0009-0002-5128-5694)
- Edoardo Malfatti (ORCID: https://orcid.org/0000-0001-5485-9521)
- Rania Bakour
- Carinne Roudaut
- Elise Lachiver
Institutions
- Inserm (FR)
- École Pratique des Hautes Études (FR)
- École Nationale Vétérinaire d'Alfort (FR)
- Université Paris-Est Créteil (FR)
- Université Paris-Saclay (FR)
- Sorbonne Université (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Institut de Myologie (FR)
- Genethon (France) (FR)
- Hôpitaux Universitaires Henri-Mondor (FR)
- Institut Mondor de Recherche Biomédicale (FR)
- Université d'Évry Val-d'Essonne (FR)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-22
- DOI
- https://doi.org/10.1126/sciadv.adv6805
- Citations
- 6
- Primary Topic
- Muscle Physiology and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 4.84