Cerebrospinal Fluid Proteomic Changes after Nusinersen in Patients with Spinal Muscular Atrophy

Abstract

Disease-modifying treatments have transformed the natural history of spinal muscular atrophy (SMA), but the cellular pathways altered by SMN restoration remain undefined and biomarkers cannot yet precisely predict treatment response. We performed an exploratory cerebrospinal fluid (CSF) proteomic study in a diverse sample of SMA patients treated with nusinersen to elucidate therapeutic pathways and identify predictors of motor improvement. Proteomic analyses were performed on CSF samples collected before treatment (T0) and at 6 months (T6) using an Olink panel to quantify 1113 peptides. A supervised machine learning approach was used to identify proteins that discriminated patients who improved functionally from those who did not after 2 years of treatment. A total of 49 SMA patients were included (10 type 1, 18 type 2, and 21 type 3), ranging in age from 3 months to 65 years. Most proteins showed a decrease in CSF concentration at T6. The machine learning algorithm identified ARSB, ENTPD2, NEFL, and IFI30 as the proteins most predictive of improvement. The machine learning model was able to predict motor improvement at 2 years with 79.6% accuracy. The results highlight the potential application of CSF biomarkers to predict motor improvement following SMA treatment. Validation in larger datasets is needed.

Alteration of LARGE1 abundance in patients and a mouse model of 5q-associated spinal muscular atrophy

“…In the plasma of younger patients with SMA type 1 and 2, pNF-H was found to be increased, and a faster decrease was detected during nusinersen treatment in these patients compared to untreated patients [ 31 ]. A recent study applying proteomic profiling of CSF confirmed the suitability of pNF-L and Cathepsin D and moreover introduced Arylsulfatase B (ARSB), Ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2), and Gamma-interferon-inducible lysosomal thiol reductase (IFI30) as the CSF-proteins most predictive of clinical improvement upon therapeutic intervention with nusinersen [ 1 ]. However, it is important to note that significant changes are mostly identified in patients younger than 1 year of age, limiting the use in clinical routine.…”

Study of nusinersen metabolites in the cerebrospinal fluid of children with spinal muscular atrophy using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry

“…Current research on CSF samples predominantly revolves around the quantitative analysis of the active substance and broader proteomic and metabolomic investigations. 4,5,18–21 Therefore, further studies on nusinersen metabolites in CSF are essential to understand the drug's pharmacokinetics and metabolic pathways comprehensively.…”