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@ARTICLE{Cebulla:299825,
author = {G. M. Cebulla$^*$ and L. Hai$^*$ and U. Warnken$^*$ and C.
Güngör and D. C. Hoffmann$^*$ and M. Korporal-Kuhnke and
B. Wildemann and W. Wick$^*$ and T. Kessler$^*$ and M.
Weiler},
title = {{L}ong-term {CSF} responses in adult patients with spinal
muscular atrophy type 2 or 3 on treatment with nusinersen.},
journal = {Journal of neurology},
volume = {272},
number = {4},
issn = {0367-004X},
address = {[Darmstadt]},
publisher = {Steinkopff},
reportid = {DKFZ-2025-00562},
pages = {270},
year = {2025},
note = {#EA:B320#LA:B320#},
abstract = {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.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.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.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.},
keywords = {Humans / Adult / Oligonucleotides: pharmacology /
Oligonucleotides: administration $\&$ dosage / Male / Female
/ Spinal Muscular Atrophies of Childhood: drug therapy /
Spinal Muscular Atrophies of Childhood: cerebrospinal fluid
/ Middle Aged / Young Adult / Biomarkers: cerebrospinal
fluid / Adolescent / Treatment Outcome / Antisense
oligonucleotide (ASO) (Other) / Cerebrospinal fluid (CSF)
(Other) / Mass spectrometry (MS) (Other) / Nusinersen
(Other) / Proteomics (Other) / Spinal muscular atrophy (SMA)
(Other) / nusinersen (NLM Chemicals) / Oligonucleotides (NLM
Chemicals) / Biomarkers (NLM Chemicals)},
cin = {B320 / HD01},
ddc = {610},
cid = {I:(DE-He78)B320-20160331 / I:(DE-He78)HD01-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40085221},
pmc = {pmc:PMC11909034},
doi = {10.1007/s00415-025-12984-7},
url = {https://inrepo02.dkfz.de/record/299825},
}