Proteomic alterations in cerebrospinal fluid of spinal muscular atrophy patients undergoing nusinersen therapy: a systematic review and meta-analysis of potential biomarkers of treatment response.

This systematic review and meta-analysis synthesizes evidence on cerebrospinal fluid (CSF) proteomic alterations in patients with spinal muscular atrophy (SMA) treated with nusinersen. Across 21 studies, consistent post-treatment decreases were observed in neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNF-H), and tau protein, which correlated with motor improvement, particularly in younger patients. Synaptic stress markers (e.g., α-synuclein, DJ-1) and metabolic proteins (e.g., apolipoprotein A1, transthyretin) demonstrated dynamic responses, suggesting systemic effects of therapy, while inflammatory cytokines and glial markers showed inconsistent trends. Extracellular matrix proteins and muscle-specific microRNAs emerged as promising indicators of musculoskeletal remodeling and treatment response. To evaluate clinical outcomes, a meta-analysis of 12 studies (n = 195 pre-treatment; n = 175 post-treatment) revealed a statistically significant mean improvement of 3.33 points in Hammersmith Functional Motor Scale Expanded (HFMSE) scores following nusinersen therapy (95% CI: –6.22 to –0.43; p = 0.02), with no heterogeneity (I² = 0%), indicating consistent functional gains across SMA populations. Overall, these findings suggest that HFMSE is a responsive clinical outcome measure in nusinersen-treated patients with SMA and that CSF proteomic profiling may provide complementary insights into biological treatment effects. However, given the heterogeneity in study design, patient characteristics, and proteomic platforms, the current evidence should be interpreted cautiously. Further large-scale, standardized, and longitudinal studies are required to validate candidate biomarkers and to clarify their integration with motor function assessments in monitoring treatment response in SMA.