Speaker Dr Piera Smeriglio, Team Leader - Biotherapies for Motor Neuron Disorders, Sorbonne Université, Paris

Title Unveiling the Molecular Secrets of Skeletal Muscle Dysfunction in SMA: Pathogenesis and Therapeutic targets

Host Massimo Ganassi

 

Abstract Spinal Muscular Atrophy (SMA) is traditionally considered a disease of the motor neurons, however, increasingly the systemic role of the SMN protein is being underscored. In particular, the role of the muscle as both an axis of pathology and driver of overall disease, is being appreciated. However, few datasets are available from SMA patients, especially that of Type II and III patients. With the objective to obtaining a better molecular understanding of the SMA Type II muscle and its response to treatment, we collected paravertebral muscle from SMA Type II patients treated with Nusinersen.

RNA-seq analysis of these samples revealed a variable molecular profile of patients’ muscle suggesting a variable response to treatment. Based on their gene expression profile, we clustered the samples into 2 groups. The first group, which we will call SMAII-A, had an overall transcriptional landscape that was like that of their age matched controls (5/8 samples). The second, which we will call SMAII-B (3/8 samples), had a transcriptional profile that was highly different from the controls. After differential expression and pathway analysis on the SMAII-B we observed that pathways related to mitochondrial metabolism and oxidative phosphorylation were downregulated.

In contrast, while overall they did not carry the signature of the SMA-B group, a small subset of genes distinguished the SMAII-A samples from the controls related to p53 activation and DNA damage and also activated in the SMAII-A, showing that this signature is not exclusive to the SMAII-A group. Interestingly, full-length SMN expression was not correlated with sample grouping into SMAII-A or SMAII-B subgroups. Additional correlations with clinical variables are being tested.

This work presents, provides a molecular roadmap of the state of SMA muscle after treatment suggesting a lack of rescue in mitochondrial metabolism after treatment. 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.