Contribution of Skeletal Muscle-resident progenitor cells to the physiopathology and the long-term treatment of Spinal Muscular Atrophy – CSMART

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by a selective loss of motor neurons (MN) due to a deficiency of the SMN protein encoded by SMN1 gene. Recently approved therapeutic approaches, namely AAV-mediated replacement of the SMN1 gene (Onasemnogene abeparvovec) or modulation of splicing of SMN2 paralogous gene transcripts by antisense oligonucleotides (Nusinersen)or by oral administration of a small molecule (Risdiplam), have shown unprecedented therapeutic benefits and brought great hope for the treatment of this devastating disease. However, with these first therapeutic successes, uncertainties emerge concerning the role of peripheral tissues, and in particular skeletal muscle tissue and resident progenitor cells (Mucle Stem Cells [MuSC] and Fibro-Adipogenic ProgenitorS [FAPS]), in the pathophysiology of SMA and the long-term effects of these therapies. We observed that the number of quiescent PAX7+ MuSCs is reduced in the muscles of SMA type 2 patients. Using a Pax7CreERT2/+;Smn floxed mouse model, we demonstrated that a high level of SMN is required to maintain the pool of quiescent MuSC in adult muscle, and that the depletion of SMN-deficient MuSC was sufficient to induce a destabilization of the neuromuscular junctions (NMJ) and a selective loss of alpha MN in the long term. Our findings demonstrate that SMN deficiency in quiescent MuSC could induce a non-cell autonomous loss of MN and that MuSC are therefore crucial therapeutic targets to ensure long-term neuromuscular system preservation in treated patients. However, to date, no monitoring of the integrity of the MuSC pool during the different existing treatments has been conducted. By combining the complementary expertise of 2 partners, the CMSART project aims to Therefore, the objectives of this project are to: (1) Clarify the role of SMN in MuSC and the contribution of these cells to the course of the disease, by identifying the molecular signals underlying the relationship between the MuSC, the NMJ and the MN using omics approaches, (2) To conduct an in-depth study of the targeting of skeletal muscle-resident progenitor cells (MuSC and FAPS) by risdiplam, a small molecule recently approved for the treatment of SMA, (3) To characterize the fate of these cells during the natural history of the disease and under risdiplam treatment. We anticipate that this project will have significant outcomes for the understanding of the pathophysiology of SMA and the development of next generation therapeutic strategies.