Neuronal Pentraxin 2 as a Potential Biomarker for Nusinersen Therapy Response in Adults with Spinal Muscular Atrophy: A Pilot Study

Background: The treatment landscape for spinal muscular atrophy (SMA) has changed significantly with the approval of gene-based therapies such as nusinersen for adults with SMA (pwSMA). Despite their efficacy, high costs and treatment burden highlight the need for biomarkers to objectify or predict treatment response. This study aimed to identify such biomarkers. Methods: A proteomic analysis of cerebrospinal fluid (CSF) from pwSMA (n = 7), who either significantly improved (SMA Improvers) or did not improve in motor function (SMA Non-Improvers) under nusinersen therapy, was performed. Data are available via ProteomeXchange with identifier PXD065345. Candidate biomarkers—Neuronal Pentraxin 2 (NPTX2), Contactin 5 (CNTN5), and Anthrax Toxin Receptor 1 (ANTXR1)—were investigated by ELISA in serum and CSF from an independent pwSMA cohort (n = 14) at baseline, 2 and 14 months after therapy initiation. Biomarker concentrations were correlated with clinical outcomes. Additionally, NPTX2 was stained in spinal cord sections from a mild SMA mouse model (FVB.Cg-Smn1tm1Hung Tg(SMN2)2Hung/J). Results: CSF NPTX2 levels decreased in pwSMA after 14 months of nusinersen therapy, independent of clinical response. In serum, NPTX2 levels were lower in SMA Improvers compared to Non-Improvers at 14 months. CNTN5 and ANTXR1 showed no significant changes. In the SMA mouse model, NPTX2 immunoreactivity increased at motoneuron loss onset. Conclusion: NPTX2 emerges as a potential biomarker of treatment response to nusinersen in pwSMA suggesting its significant pathophysiological role in late-onset SMA, warranting further investigation.