Muscle microRNAs in the cerebrospinal fluid predict clinical response to nusinersen therapy in type II and type III spinal muscular atrophy patients.
Biomarkers
Cerebrospinal Fluid
Muscle microRNAs
Nusinersen
Response predictors
Spinal muscular atrophy
miR-133
miR-206
Journal
European journal of neurology
ISSN: 1468-1331
Titre abrégé: Eur J Neurol
Pays: England
ID NLM: 9506311
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
revised:
13
04
2022
received:
11
02
2022
accepted:
28
04
2022
pubmed:
6
5
2022
medline:
19
7
2022
entrez:
5
5
2022
Statut:
ppublish
Résumé
The antisense oligonucleotide nusinersen (Spinraza) regulates splicing of the survival motor neuron 2 (SMN2) messenger RNA to increase SMN protein expression. Nusinersen has improved ventilator-free survival and motor function outcomes in infantile onset forms of spinal muscular atrophy (SMA), treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients. Thirty-four SMA patients were included. We applied next generation sequencing to identify microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers predicting response to nusinersen. Hammersmith Functional Motor Scale Expanded (HFMSE) was conducted at baseline and 6 months after initiation of nusinersen therapy to assess motor function. Patients changing by ≥3 or ≤0 points in the HFMSE total score were considered to be responders or nonresponders, respectively. Lower baseline levels of two muscle microRNAs (miR-206 and miR-133a-3p), alone or in combination, predicted the clinical response to nusinersen after 6 months of therapy. Moreover, miR-206 levels were inversely correlated with the HFMSE score. Lower miR-206 and miR-133a-3p in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinersen in later onset SMA patients and call for testing the ability of miRNAs to predict more sustained long-term benefit.
Sections du résumé
BACKGROUND AND PURPOSE
The antisense oligonucleotide nusinersen (Spinraza) regulates splicing of the survival motor neuron 2 (SMN2) messenger RNA to increase SMN protein expression. Nusinersen has improved ventilator-free survival and motor function outcomes in infantile onset forms of spinal muscular atrophy (SMA), treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients.
METHODS
Thirty-four SMA patients were included. We applied next generation sequencing to identify microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers predicting response to nusinersen. Hammersmith Functional Motor Scale Expanded (HFMSE) was conducted at baseline and 6 months after initiation of nusinersen therapy to assess motor function. Patients changing by ≥3 or ≤0 points in the HFMSE total score were considered to be responders or nonresponders, respectively.
RESULTS
Lower baseline levels of two muscle microRNAs (miR-206 and miR-133a-3p), alone or in combination, predicted the clinical response to nusinersen after 6 months of therapy. Moreover, miR-206 levels were inversely correlated with the HFMSE score.
CONCLUSIONS
Lower miR-206 and miR-133a-3p in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinersen in later onset SMA patients and call for testing the ability of miRNAs to predict more sustained long-term benefit.
Identifiants
pubmed: 35510740
doi: 10.1111/ene.15382
pmc: PMC9544362
doi:
Substances chimiques
Biomarkers, Pharmacological
0
MIRN206 microRNA, human
0
MicroRNAs
0
Oligonucleotides
0
nusinersen
5Z9SP3X666
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2420-2430Informations de copyright
© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
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