Long-term CSF responses in adult patients with spinal muscular atrophy type 2 or 3 on treatment with nusinersen.

IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Journal of Neurology Pub Date : 2025-03-14 DOI:10.1007/s00415-025-12984-7
Gina Cebulla, Ling Hai, Uwe Warnken, Cansu Güngör, Dirk C Hoffmann, Mirjam Korporal-Kuhnke, Brigitte Wildemann, Wolfgang Wick, Tobias Kessler, Markus Weiler
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引用次数: 0

Abstract

Background: 5q-associated spinal muscular atrophy (SMA) is a monogenic 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: A total of 130 cerebrospinal fluid (CSF) samples from 24 adult patients with SMA type 2 or 3 were collected over 3.5 years, and CSF proteome was analyzed using mass spectrometry (MS). By applying 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 response to 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. CSF macrophages increased in number and showed an altered morphology. Albumin quotient (qAlb), glucose, and lactate concentrations were inversely correlated with clinical improvement. MS analysis of CSF identified 1,674 (TMT) and 441 (LFQ) proteins. Protein profiles reflected reduced inhibition of "nervous system development" and "axogenesis" pathways under therapy. In addition, clinical improvement was associated with upregulation of the interacting proteins α-dystroglycan and beta-1,4-glucuronyltransferase 1, reduction of complement factors, negative correlation in immunoglobulin- and B cell-related pathways, and reduction of cellular mediators such as lymphocytes.

Conclusion: The present multi-proteomic analysis contributes to the understanding of the molecular mechanisms underlying nusinersen's therapeutic effects and offers potential biomarkers for monitoring treatment response in SMA.

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来源期刊
Journal of Neurology
Journal of Neurology 医学-临床神经学
CiteScore
10.00
自引率
5.00%
发文量
558
审稿时长
1 months
期刊介绍: The Journal of Neurology is an international peer-reviewed journal which provides a source for publishing original communications and reviews on clinical neurology covering the whole field. In addition, Letters to the Editors serve as a forum for clinical cases and the exchange of ideas which highlight important new findings. A section on Neurological progress serves to summarise the major findings in certain fields of neurology. Commentaries on new developments in clinical neuroscience, which may be commissioned or submitted, are published as editorials. Every neurologist interested in the current diagnosis and treatment of neurological disorders needs access to the information contained in this valuable journal.
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