CSF Proteomic Profiling in SMA Feasible for Finding Prognostic Information


Subgroups and treatment-related changes can be identified with comparative cerebrospinal fluid proteomic analysis in adult patients with spinal muscular atrophy who are treated with nusinersen.

Dr Tobias Kessler

Tobias Kessler, MD, department of neurology, Heidelberg University Hospital

Tobias Kessler, MD

Data from a proof-of-concept and feasibility assessment suggest that subgroups and treatment-related changes can be identified with comparative cerebrospinal fluid (CSF) proteomic analysis in adult patients with spinal muscular atrophy (SMA) who are treated with nusinersen (Spinraza; Biogen).1

The authors, including Tobias Kessler, MD, department of neurology, Heidelberg University Hospital, evaluated non‐targeted CSF proteomic profiles with mass spectrometry, as well as basic CSF parameters, in 10 adult patients with SMA types 2 (n = 1) or 3 (n = 9) at time points before treatment and after 10 months of nusinersen therapy and compared them to 10 matched controls.

“Concordant with recent findings from another group, we observed a higher number of reactive mononuclear cells in CSF of nusinersen-treated patients compared to baseline and control,” Kessler and colleagues detailed. “We also found a consistent increase of CSF total protein and a trend of rising [CSF/serum quotients of albumin] values during nusinersen therapy indicating a slight dysfunction in CSF flow. Whether this can be solely attributed to a specific pharmacologic effect of the antisense oligonucleotide nusinersen or, alternatively, might be a consequence of the repetitive lumbar punctures or the disease itself remains unclear and requires further investigation.”

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Kessler and co. recommended routinely assessing basic CSF parameters, including cytology, the total protein concentration, and the CSF/serum albumin ratio in those undergoing intrathecal treatments for safety readout. The group acknowledged that conducting proteomic analyses from CSF is technically demanding but noted that biomarkers in genetic disorders is an unmet need due to the rising number of available therapies. As such, changes of the overall neurochemical composition of CSF under therapy may yield additive diagnostic and predictive information.

“Hence, we provide here first proof-of-concept data showing that CSF proteomic analyses are feasible in this slowly progressive neurodegenerative disease,” they wrote. “Herewith they permit clustering of patient groups according to distinct molecular signaling networks in correlation with clinical outcome parameters, and thus might give rise to the identification of relevant, potentially predictive biomarkers.”

Mean white cell count (P = .33), lactate (P = .75), total protein (P = .50), and CSF quotients of albumin values (P = .58). Compared to their pretreatment conditions (0.441 g/L), the total protein concentrations were increased (0.372 g/L; P <.01) in the SMA group after 10 months of nusinersen.

Compared with pretreatment, CSF total protein concentrations were increased in every patient with SMA (P <.01). Kessler and colleagues defined a difference z-score matrix composed of the intraindividual abundance differences of each identified protein before and after nusinersen treatment, referred to as differential protein cluster 1 (DPC1; n = 7) and differential protein cluster 2 (DPC2; n = 3) clusters.

The patients of cluster DPC2 had relative upregulation of the following proteins: neuronal pentraxin-1 (NPTX1), semaphorin 7A (SEMA7A), carboxypeptidase E (CPE), and collagen type VI alpha 1 (COL6A1). The DPC2 group had downregulation of cadherin 18 (CDH18) and failed to improve in Hammersmith Functional Rating Scale Expanded (HFMSE) scores (score, 0.0). Those in DPC1 did improve however (score, 4.7; P = .04)

The data, Kessler and colleagues wrote, are available via ProteomeXchange with identifier PXD016757.


1. Kessler T, Latzer P, Schmid D, et al. Cerebrospinal fluid proteomic profiling in nusinersen&#8208;treated patients with spinal muscular atrophy. J Neurochem. Published online January 6, 2020. doi: 10.1111/jnc.14953.

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