Cerebrospinal fluid (CSF) levels of the lysosomal protease, cathepsin D, significantly decreased following nusinersen treatment for spinal muscular atrophy (SMA), according to new findings published in the European Journal of Neurology.

The decline of cathepsin D occurred only in patients exhibiting a positive motor response to treatment, identifying the protein as a potential prognostic biomarker for SMA. Researchers conducted a 2-step prospective study to identify potential biomarkers in pediatric patients diagnosed with SMA at the university hospitals of Essen and Freiburg in Germany.

In the discovery phase, they obtained CSF samples on days 1, 14, and 180 from a small cohort of 3 patients with SMA type 1. Day 1 indicated nusinersen treatment initiation. Using untargeted Western blot and enzyme-linked immunosorbent assay profiling techniques, the researchers identified 5 potential biomarkers that demonstrated significant dysregulation during treatment—cathepsin D, cyclophilin A, insulin-like growth factor-binding protein-like 1 (IGFBPL1), and peripheral neurofilament H (pNF-H) and peripheral neurofilament L (pNF-L).

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In the validation analysis, they examined CSF samples collected on days 1, 60, and 300 from a larger cohort of 31 patients including all SMA types (type 1=12, type 2=9, type 3=6). The researchers correlated candidate biomarker levels with a positive response to nusinersen treatment as reflected by improved motor function.

Cyclophilin A, IGFBPL1, and pNF-H were unsuitable as prognostic biomarkers in SMA. In contrast, cathepsin D CSF levels decreased significantly following 300 days of nusinersen treatment regardless of SMA disease type; however, declines occurred only in patients who started nusinersen treatment after 2 months of age.

Positive motor responses occurred in patients whose cathepsin D levels declined compared with patients deemed “nonresponders” (126.0±25.4 ng/ml vs 150.3±38.3 ng/ml; P =.082). When only applying the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores to analyze treatment response, the difference in cathepsin D levels between groups reached statistical significance (124.4±26.7 ng/ml vs 167.1±27.1 ng/ml; P =.015).

Most “nonresponder” patients began treatment at older ages, suggesting an already significant loss of motor units prior to treatment initiation. Muscle biopsies confirmed the downregulation of cathepsin D, also suggesting its potential use as a tissue marker in SMA. Additionally, the researchers noted a correlation between decreasing cathepsin D and pNF-L levels in patients older than 12 months at treatment initiation.

“Combined analysis of pNFL-L and Cathepsin D therefore might be suitable as a biomarker of motor response in patients [with SMA] from 12 months of age to adolescence,” the authors said.


Schorling DC, Kölbel H, Hentschel A, et al. Cathepsin D as biomarker in CSF of nusinersen-treated patients with spinal muscular atrophy. Eur J Neurol. Published online March 23, 2022. doi:10.1111/ene.15331