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. 2023 Oct 23;12(20):6696.
doi: 10.3390/jcm12206696.

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

Marie Beaudin  1   2 , Tahereh Kamali  1 , Whitney Tang  1 , Katharine A Hagerman  1 , Sally Dunaway Young  1   2 , Lisa Ghiglieri  1 , Dana M Parker  1 , Benoit Lehallier  1 , Carolina Tesi-Rocha  1   2 , Jacinda B Sampson  1   2 , Tina Duong  1   2 , John W Day  1   2
Affiliations

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

Marie Beaudin et al. J Clin Med. .

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.

Keywords: biomarkers; neurofilament; nusinersen; proteomics; spinal muscular atrophy; treatment.

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Conflict of interest statement

M.B., T.K., W.T., K.H. and D.P.: no conflict of interest to declare. S.D.Y.: advisory boards for Biogen, Roche/Genentech, and Scholar Rock; consultant to Biogen, Cure SMA, and Scholar Rock; and research funding from Cure SMA. C.T.R.: advisory board, contracted research, and honoraria for educational lectures organized by Biogen. T.D.: advisory board, CuresSMA, DuchenneUK, Actigraph, Biogen, Scholar Rock, Roche, Novartis, Dyne, consultancy/speaker: Sarepta, Pfizer, Roche, Genentech, Trinds, NMDPharma, and Novartis. J.W.D.: advisory board, Muscular Dystrophy Association, Myotonic Dystrophy Foundation, Foundation Building Strength for Nemaline Myopathy, Cure Congenital Muscular Dystrophy, and Pepgen; consulting: Avidity, Biogen, and Novartis Gene Therapies, Roche/Genentech, Sarepta Therapeutics, Scholar Rock, and Vertex; contracted research: AMO Pharmaceuticals, Astellas, Avidity, Biogen, Ionis Pharmaceuticals, Novartis Gene Therapies, Roche Pharmaceuticals, Sanofi-Genzyme, Sarepta Therapeutics, and Scholar Rock.

Figures

Figure 1
Figure 1
Volcano plot of exploratory proteomic analysis showing CSF concentration changes between T0 and T6 for the whole cohort. Log2 of the fold change is represented on the x-axis and -log10 of the p value on the y-axis. The horizontal red line indicates p = 0.05 and the vertical red lines indicate a fold change greater than 1 or inferior to −1. Most samples with statistically significant p-values are clustered between −1 and −5 on the x-axis, which indicates a significant decrease (at least 0.5-fold change) in the concentration of these proteins. Top predictive proteins and CTSD are identified on the graph for reference, and all 43 significantly altered peptides are listed in the supplementary table.
Figure 2
Figure 2
Boxplots of the CSF concentrations of the top proteins and CTSD at baseline and after 6 months of nusinersen treatment in patients showing motor improvement vs. no motor improvement. First quartile, median, and third quartile are marked with horizontal lines, mean is marked with an X, and data spread is shown with the whiskers (1.5*IQR, adjusted for skewness). Concentrations of (a) ARSB, (b) ENTPD2, (c) NEFL, (d) IFI30, and (e) CSTD are represented. All these proteins decreased after nusinersen treatment. Statistically significant differences (p < 0.05) are marked with a *.
Figure 3
Figure 3
ROC curve of the machine learning predictive model of motor improvement at 2 years, depicting true positive rate (sensitivity) on the y axis and false positive rate (1-specificity) on the x-axis. The Random Forest model ROC AUC was 0.83, showing a strong discriminative ability. The blue dotted line represents a non-discriminatory (random) model.
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