15 | GDF5 therapeutic potential for Duchenne muscular dystrophy

C. Gentil, A. Bourguiba, A. Vergnol, B. Cadot, Z. Guesmia, L. Saillard, P. Meunier, S. Falcone, L. Giordani, France Pietri-Rouxel | Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France.

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 muscle overexpression of GDF5 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 fusion. Next, we combined GDF5 overexpression with AAV-microdystrophin, the key gene therapy treatment for DMD, and showed an increased number of microdystrophinpositive myofibers compared with gene therapy alone. Overall, we decipher here the role of GDF5 in improving DMD pathophysiology and provide a first proof of concept of a synergistic effect of the combination of AAV-GDF5 and AAV-microdystrophin.