Gene therapies have greatly changed the outlook in spinal muscular atrophy (SMA), and this disorder provides a rare opportunity to study longitudinal biomarker changes correlated with reduced disease burden and improved clinical outcomes. Recent work suggests clinical response to correlate with declining cerebrospinal fluid (CSF) levels of the neurodegenerative marker neurofilament light chain (NfL) in children receiving serial anti-sense oligonucleotide therapy. However, change in CSF NfL levels is no longer a practical biomarker as more children undergo single-dose gene replacement therapy. Here we leverage serial CSF samples (median of 4 per child) collected in 13 children with SMA undergoing anti-sense oligonucleotide therapy to characterize the longitudinal profiles of NfL as well as inflammatory and neuronal proteins. In contrast to neurodegeneration in adults, we found NfL levels to first decrease following initiation of treatment but then increase upon further treatment and improved motor functions. We then examined additional CSF inflammatory and neuronal markers for linear association with motor function during SMA treatment. We identified longitudinal IL-8 levels to inversely correlate with motor functions determined by clinical examination (F(1, 47) = 12.903, p = 0.001) or electromyography in the abductor pollicis brevis muscle (p = 0.064). In keeping with this, lower baseline IL-8 levels were associated with better longitudinal outcomes, even though this difference diminished over 2 years in the younger group. We thus propose CSF IL-8 as a biomarker for baseline function and short-term treatment response in SMA, and a candidate biomarker for future treatment trials in other neurodegenerative disorders.

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