GDF5 modulation of MuSC pool as a potential therapeutic benefit for DMD

Duchenne muscular dystrophy (DMD) is a fatal disease characterized by the absence of dystrophin, leading to degeneration of the entire musculature. With the aim of improving muscle pathophysiology and gene therapy for DMD, we investigated the potential of growth differentiation factor 5 (GDF5) in the DMD mdx mouse model. We showed that the overexpression of GDF5 in the muscle improved its histology, reduced inflammation, modulated regeneration and induced the appearance of de novo fibers. We demonstrated that muscle satellite cells (MuSCs) are targeted by GDF5 which enhanced their proliferation and slowed down their myogenic commitment and finally their fusion. Next, we combined GDF5 overexpression with AAV-mediated microdystrophin gene therapy, the most promising treatment for DMD, and showed an increased number of microdystrophin-positive myofibers compared with gene therapy alone. Overall, we reveal here the potential role of GDF5 in improving DMD pathophysiology and provide a first proof of concept of a synergistic effect of the combination of GDF5-based treatment and AAV-microdystrophin.