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

Area of Science:

• Neurology
• Biochemistry
• Genetics

Background:

• Disease-modifying treatments like nusinersen have improved spinal muscular atrophy (SMA) outcomes.
• However, the precise cellular pathways affected by SMN restoration are not fully understood.
• Current biomarkers do not accurately predict individual treatment responses in SMA patients.

Purpose of the Study:

• To explore cerebrospinal fluid (CSF) proteomic changes in SMA patients treated with nusinersen.
• To identify potential biomarkers that predict motor function improvement after treatment.
• To elucidate the cellular pathways influenced by SMN restoration in SMA.

Main Methods:

• An exploratory proteomic study involving 49 SMA patients (types 1-3) treated with nusinersen.
• Cerebrospinal fluid (CSF) samples were collected before treatment (T0) and at 6 months (T6).
• Olink proteomic panel quantified 1113 peptides; machine learning identified predictive proteins for motor improvement at 2 years.

Main Results:

• Most quantified CSF proteins decreased in concentration from T0 to T6.
• The machine learning model identified ARSB, ENTPD2, NEFL, and IFI30 as key predictors of motor improvement.
• The model achieved 79.6% accuracy in predicting 2-year motor improvement.

Conclusions:

• CSF proteomic analysis can identify biomarkers predictive of motor improvement in SMA patients treated with nusinersen.
• Identified proteins like ARSB, ENTPD2, NEFL, and IFI30 may indicate therapeutic pathways.
• Further validation in larger cohorts is necessary to confirm these predictive biomarkers for SMA treatment.