178P Spinal muscular atrophy type II skeletal muscle treated with Nusinersen and Risdiplam shows SMN restoration but mitochondrial deficiency

• Published in: Neuromuscular disorders : NMD Vol. 43; p. 104441
• Main Authors: Grandi, F., Astord, S., Pezet, S., Gidaja, E., Mazzucchi, S., Chapart, M., Vasseur, S., Mamchaoui, K., Smeriglio, P.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2024
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.622

Spinal muscular atrophy (SMA) is a rare autosomal recessive developmental disorder caused by the genetic loss or mutation of the SMN1 gene (Survival of Spinal Motor Neuron 1). The disordered is classically characterized by neuromuscular symptoms, including muscular atrophy, weakness of the proximal muscles, especially those of the lower extremities, and hypotonia. Although originally thought of as a purely motor neuron disease, current research has shown that most, if not all, tissues are affected, including the muscle. Several years ago, SMA treatment underwent a radical transformation, with the approval of three different SMN-dependent disease modifying therapies. This includes two SMN2 splicing therapies which can be administered by Type II patients that have symptom onset later in age. Among one of the main challenges for Type II SMA patients treated with Risdiplam and Nusinersen is ongoing muscle fatigue, limited mobility, and other skeletal problems, including hip dysplasia and scoliosis. Until recently, muscle problems in SMA were predominantly considered a consequence of denervation due to the MN death. However, recent work using muscle-specific mouse models of SMN loss, as well as skeletal stem cell specific models have shown that there are tissue specific problems in muscle due to SMN deficiency. To date, few molecular studies have been conducted on SMA-patient derived tissues after treatment, limiting our understanding how different organ systems react to the therapies, and what additional combination therapies may be beneficial. With this goal in mind, we collected paravertebral muscle from the surgical discard in a cohort of 8 SMA Type II patients undergoing spinal surgery for scoliosis, as well as 7 non- SMA controls with scoliosis and used RNA-sequencing and epigenetic profiling (5hmC-sequencing) to characterize their molecular profiles. We observed that despite a restoration of the SMN mRNA and protein levels in these patients – at levels at or above the controls – a subset of patients continued to have alterations in mitochondrial metabolism and other markers of cellular stress. Using the epigenetic and transcriptomic profiling, we were able to generate two molecular subtypes with different signatures, which we termed SMAII-A and SMAII-B. In the SMAII-A, we observed activation of P53 target genes, including GADD45A, and a decrease in mitochondrial biomass and mitochondrial function. The second group was more similar to control samples, put had some changes in cytoskeletal pathways and extracellular matrix genes. Both groups had marked differences in the histological characterization of the muscle, including increase fiber size in the SMA patients compared to controls. his work presents, to our knowledge, the largest analysis of RNA-sequencing of Type II SMA muscles samples after treatment and provides a molecular roadmap of the state of SMA muscle after treatment. Our findings validated previous findings about the role of mitochondrial dysfunction in SMA pathology. Work is ongoing to determine that molecular reasons – be they genetic, epigenetic, or clinical- for the heterogenous response to Nusinersen injection, and to test drug candidates to improve mitochondrial function and decrease DNA damage in skeletal muscle.