Limb-Girdle Muscular Dystrophies (LGMDs) are hereditary neuromuscular diseases characterized by progressive damage to proximal muscles. Among these, calpainopathy (LGMDR1) is caused by mutations in the CAPN3 gene, leading to a defect in plasticity and repair. Currently, no curative treatment is available, but gene therapies using adeno-associated viral (AAV) vectors represent a promising approach. However, major challenges remain, particularly concerning the dose administered and the efficiency of muscle transduction and expression.
We wondered whether well-controlled physical exercises, depending on their intensity and the mechanical constraints they impose, could play a key role in optimizing gene therapy by modifying the muscle to enhance transgene expression and functional outcomes.
Preliminary results from mouse models of these limb-girdle dystrophies showed that non-damaging swimming exercises, depending on their intensity, can positively modulate the viral efficiency of AAVs and transgene expression. We observed that the mechanisms governing transduction and transcription are oppositional, cellular and molecular mechanisms that we aim to decipher.
We will lead a comparative analysis of the muscular transcriptomics of mouse models of Calpainopathy trained or not with our adapted swimming protocols and injected with AAV-CAPN3
This project aims to optimize the efficacy of gene therapies for LGMDs. It holds strong translational potential and could open new therapeutic perspectives.
