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Neuronal Pentraxin 2 as a Potential Biomarker for Nusinersen Therapy Response in Adults with Spinal Muscular Atrophy: A Pilot Study

ABSTRACT: This project investigates cerebrospinal fluid (CSF) proteome changes in adults with spinal muscular atrophy (pwSMA) treated with the antisense oligonucleotide nusinersen. A label-free quantitative proteomic analysis was conducted on CSF samples from a subset of pwSMA (n=7) classified as clinical responders or non-responders based on motor function changes under therapy. The aim was to identify proteins differentially abundant between these groups. Candidate biomarkers emerging from this discovery phase—Neuronal Pentraxin 2 (NPTX2), Contactin 5 (CNTN5), and Anthrax Toxin Receptor 1 (ANTXR1)—were selected for follow-up analysis using orthogonal validation methods in an independent cohort. This dataset contains the primary CSF proteomic data used for the identification of potential treatment-associated protein changes in adult SMA.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Adult Spinal Muscular Atrophy

SUBMITTER: Svenja Neuhoff

LAB HEAD: Prof. Dr. med. Tim Hagenacker

PROVIDER: PXD065345 | Pride | 2025-08-25

REPOSITORIES: Pride

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			Action	DRS
	2452_UK-Essen_R03.kit	Other
	2452_UK-Essen_R11.sne	Other
	2452_UK-Essen_code.xlsx	Xlsx
	C_D190719_S2452-UK-Essen-01_MHRM_R01_T0.raw	Raw
	C_D190719_S2452-UK-Essen-02_MHRM_R01_T0.raw	Raw

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Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy

Project description:Promising results from recent clinical trials on the approved antisense oligonucleotide nusinersen in pediatric patients with 5q-linked spinal muscular atrophy (SMA) still have to be confirmed in adult patients but are hindered by a lack of sensitive biomarkers that indicate an early therapeutic response. Changes of the overall neurochemical composition of cerebrospinal fluid (CSF) under therapy may yield additive diagnostic and predictive information. With this prospective proof-of-concept and feasibility study, we evaluated non-targeted CSF proteomic profiles by mass spectrometry along with basic CSF parameters of 10 adult patients with SMA types 2 or 3 before and after 10 months of nusinersen therapy, in comparison with 10 age- and sex-matched controls. These data were analyzed by bioinformatics and correlated with clinical outcomes assessed by the Hammersmith Functional Rating Scale Expanded (HFMSE). CSF proteomic profiles of SMA patients differed from controls. Two groups of SMA patients were identified based on unsupervised clustering. These groups differed in age and expression of proteins related to neurodegeneration and neuroregeneration. Intraindividual CSF differences in response to nusinersen treatment varied between patients who clinically improved and those who did not. Data are available via ProteomeXchange with identifier PDX015117. Comparative CSF proteomic analysis in adult SMA patients before and after treatment with nusinersen identified subgroups and treatment-related changes and may therefore be suitable for diagnostic and predictive analyses.

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Cell-mediated cytotoxicity surrounding the brain in spinal muscular atrophy

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Project description:Abstract Introduction: 5q-associated spinal muscular atrophy (SMA) is a motor neuron disease causing progressive alpha motor neuron degeneration, muscle atrophy, and weakness. Intrathecal therapy with the antisense oligonucleotide Nusinersen modifies the disease course. However, biomarkers for understanding underlying molecular pathomechanisms and monitoring therapy are not yet known. Methods: 130 cerebrospinal fluid (CSF) samples from 24 SMA type 2 and 3 adult patients were collected over 3.5 years and CSF proteome was using mass spectrometry (MS). By employing two complementary MS protein quantification methods, label-free quantification (LFQ) and tandem mass tag (TMT) isotopic labeling, specific protein patterns reflecting changes in the CSF in the context of nusinersen therapy were identified. These results were combined with cellular and metabolic profiles. Results: Nusinersen therapy led to a median motor function improvement of 2.2 Hammersmith Functional Motor Scale Expanded points after 10 months and 2.6 points after 34 months. Albumin concentration and albumin quotient (CSF/serum) increased, as did the number of macrophages in the CSF under nusinersen therapy. Albumin, glucose, and lactate concentrations were inversely correlated with clinical improvement. MS analysis of CSF identified 1,674 (TMT) and 441 (LFQ) proteins. Protein profiles associated with clinical improvement reflected the reconstitution of neuronal circuits. Additionally, clinical improvement was associated with reduced humoral mediators of the immune response such as complement factors and immunoglobulins and cellular mediators such as lymphocytes. Discussion: Our multi-proteomic analysis provides new insights into the pathobiology of SMA and defines potential biomarker profiles in CSF for the disease course under nusinersen therapy.

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Mass-Spectrometry-based proteomics on cerebrospinal fluid combined with artificial intelligence approach identified novel potential biomarkers for Spinal Muscular Atrophy

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