Longitudinal Transcriptomic Analysis Reveals Systemic Effects of Risdiplam in Adults with Spinal Muscular Atrophy

Background: Spinal Muscular Atrophy (SMA) is a neurodegenerative disease caused by reduced survival motor neuron (SMN) protein levels due to SMN1 gene mutations. The natural history of SMA has dramatically changed since innovative therapies were approved; among them, Risdiplam (an oral molecule) increases the peripheral levels of SMN by modifying the pre-mRNA slicing of the paralogous SMN2 that also codes for the protein. Methods: We performed longitudinal RNA sequencing on peripheral blood samples from 16 adult SMA patients (types II and III) before and after 12 months of Risdiplam treatment to assess transcriptomic changes. Results: During Risdiplam treatment, increased SMN2 transcript levels were observed, which was coherent with the clinical condition of the investigated SMA cohort. Upregulated mitochondria genes or pseudogenes (i.e., MT-ATP8 and MTND1P11) and downregulated autophagy-related pathways were also found. Baseline differences in gene expression between SMA type II and type III involved neurodegenerative (i.e., MS4A3, C4BPA, and NEILS3) and immune-related (B2M) genes. Conclusions: These findings support Risdiplam’s systemic impact in adult SMA subjects and reveal molecular distinctions between SMA phenotypes (types II and III), which may be of some relevance for future clinical and therapeutic strategies.