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

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 res...

Full description

Saved in:
Bibliographic Details
Published in:Journal of neurochemistry 2020-06, Vol.153 (5), p.650-661
Main Authors: Kessler, Tobias, Latzer, Pauline, Schmid, Dominic, Warnken, Uwe, Saffari, Afshin, Ziegler, Andreas, Kollmer, Jennifer, Möhlenbruch, Markus, Ulfert, Christian, Herweh, Christian, Wildemann, Brigitte, Wick, Wolfgang, Weiler, Markus
Format: Article
Language:English
Subjects:
antisense oligonucleotide
Antisense oligonucleotides
Atrophy
Bioinformatics
Biomarkers
Cerebrospinal fluid
Chemical compounds
Clinical trials
Clustering
Correlation analysis
Diagnostic systems
Feasibility studies
Mass spectrometry
Mass spectroscopy
Neurodegeneration
Neuromuscular diseases
nusinersen
Patients
Pharmaceuticals
proteomics
Spinal muscular atrophy
Subgroups
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 in 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 gender‐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 PXD016757. 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. The approved antisense oligonucleotide nusinersen demonstrated convincing clinical results in patients with 5q‐linked spinal muscular atrophy (SMA) but predictive biomarkers are lacking to date. We evaluated cerebrospinal fluid (CSF) proteomic profiles by mass spectrometry from 10 adult patients with SMA types 2 or 3 before and after nusinersen treatment compared with matched healthy controls. We identified two clusters of different proteomic profiles related to neurodegeneration and neuroregeneration, and intraindividual treatment‐related changes varying between patients who clinically improved and those who did not. We think that CSF proteomic profiling according to our protocol is suitable for diagnostic and predictive analyses. Read the Editorial Highlight for this article on page 545.
ISSN:0022-3042
1471-4159
DOI:10.1111/jnc.14953