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Multiomics profiling in Spinal Muscular Atrophy (SMA): Insights from longitudinal CSF analysis of patients under treatment with Nusinersen

ABSTRACT: Spinal Muscular Atrophy (SMA) is a rare neuromuscular disease caused by biallelic mutations in the SMN1 gene, leading to progressive muscle weakness due to degeneration of the anterior horn cells. Since 2017, SMA patients can be treated with the anti-sense oligonucleotide Nusinersen, which promotes alternative splicing of the SMN2 gene, by regular intrathecal injections. In this prospective study we applied metabol-, lipid-, and proteomic analysis to examine sequential CSF samples from 13 SMA patients and controls. This multiomic approach identified over 800 proteins and 400 small molecules including lipids. Multivariate analysis of multiomic data successfully discriminated between the CSF derived from SMA patients and control subjects. Lipidomic analysis revealed increased levels of cholesteryl esters and lyso-phospholipids, along with reduced levels of cholesterol and phospholipids in the CSF of SMA patients as compared to the healthy control group. This data, combined with results from functional assays, led us to conclude that SMA patients exhibit altered levels and function of HDL-like particles in the CSF. Notably, Nusinersen therapy was observed to reverse disease-specific profile changes towards a physiological state, potentially explicable by restoring HDL-function.

INSTRUMENT(S): maXis

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Childhood Spinal Muscular Atrophy

SUBMITTER: Barbara Darnhofer

LAB HEAD: Harald Koefeler

PROVIDER: PXD060060 | Pride | 2025-04-01

REPOSITORIES: Pride

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			Action	DRS
	S-01_GD6_01_21455.mzML	Mzml
	S-02_GC5_01_21435.mzML	Mzml
	S-04_BD4_01_21361.mzML	Mzml
	S-05_GA7_01_21403.mzML	Mzml
	S-06_GA2_01_21393.mzML	Mzml

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Preliminary insights into RNA in CSF of SMA patients after Nusinersen “loading dose”

Project description:Antisense oligonucleotide (ASO) nusinersen (Spinraza®) modulates the pre–mRNA splicing of the SMN2 gene, allowing rebalance of biologically active SMN. It is administered intrathecally via lumbar puncture after removing an equal amount of cerebrospinal fluid (CSF). Its effect was proven beneficial and approved since 2017 for SMA treatment. Since the direct effect of nusinersen on RNA metabolism, the aim of this project was to evaluate cell-free RNA (cfRNA) in CSF of SMA patients under ASOs treatment for biomarker discovery.

2023-07-03 | GSE221900 | GEO

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.

2020-01-07 | PXD016757 | Pride

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

Project description:Background: 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. Methods: In this prospective proof-of-concept and feasibility study, we evaluated non-targeted CSF proteomic profiles by mass spectrometry along with basic CSF parameters of ten adult patients with SMA types II or III before and after ten months of nusinersen therapy, in comparison with ten age- and gender-matched controls. These data were bioinformatically analyzed and correlated with clinical outcomes assessed by the Hammersmith Functional Rating Scale Expanded (HFMSE). Results: CSF proteomic profiles of patients with SMA 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 neuroregeneration or neurodegeneration. Intraindividual CSF differences in response to nusinersen treatment varied between patients who clinically improved and those who did not. Conclusions: Comparative CSF proteomic analysis in adult SMA patients before and after treatment identified subgroups and treatment-related changes and may therefore be suitable for diagnostic and predictive analysis. These results require verification in larger multicenter cohorts.

2019-12-18 | PXD015117 | Pride

Cell-mediated cytotoxicity surrounding the brain in spinal muscular atrophy

Project description:We here longitudinally investigated how SMA and nusinersen shaped local immune responses in the cerebrospinal fluid (CSF) using single cell RNA-sequencing and single cell TCR-sequencing.

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Longitudinal Proteomic Fingerprinting in CSF of Nusinersen-Treated Patients with 5q-Associated Spinal Muscular Atrophy

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.

2025-05-07 | PXD054900 | Pride

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

Project description:The availability of disease-modifying therapies and newborn screening programs for spinal muscular atrophy (SMA) has generated an urgent need to identify reliable biomarkers to monitor disease progression, therapeutic response and classify patients according to disease severity. Objectives of this study were to identify potential biomarkers for disease severity, and to describe changes in the proteomic profile after 302 days of nusinersen administration (T302). In this multicenter retrospective longitudinal study, we employed an untargeted non-targeted mass spectrometry-based proteomic approach (LC-MS) on cerebrospinal fluid (CSF) samples collected from 61 SMA patients treated with nusinersen (SMA1 n=19, SMA2 n=19, SMA3 n=23) at baseline and T302. A machine learning classifier approach (Random Forest, RF) was applied to exploit proteins able to stratify disease severity at baseline. Bioinformatics analysis was performed to investigate Gene Ontology (GO) functional annotation of differentially expressed proteins (DEPs) at T302. The RF algorithm identified CNTN1 and NRXN3 as new potential biomarkers of disease severity based on their expression at baseline. Analysis of changes in proteomic profiles identified 147 DEPs after nusinersen treatment in SMA1, 135 in SMA2, and 289 in SMA3. Overall, Nusinersen-induced changes on proteomic profile were consistent with i) common effects observed in all SMA types (i.e. regulation of axonogenesis), and ii) disease severity-specific changes, namely regulation of glucose metabolism in SMA1, of coagulation processes in SMA2, and of complement cascade in SMA3. By analyzing a large cohort of CSF samples from SMA patients, and applying cutting-edge bioinformatic analysis and artifical intelligence alghorithms, this study has identified new potential biomarkers of disease severity, and provided new insights on biological processes modulation after 302 days of nusinersen treatment.

2024-10-02 | PXD047529 | Pride

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Preliminary insights into RNA in CSF of SMA patients after Nusinersen “loading dose”

Project description:Preliminary insights into RNA in CSF of SMA patients after Nusinersen “loading dose”

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Type I PRMT inhibitor MS023 promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue the phenotype of SMA mice

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