Nusinersen Induces Disease-Severity-Specific Neurometabolic Effects in Spinal Muscular Atrophy.
cerebrospinal fluid (CSF)
nuclear magnetic resonance (NMR)
nusinersen
spinal muscular atrophy (SMA)
survival motor neuron (SMN)
Journal
Biomolecules
ISSN: 2218-273X
Titre abrégé: Biomolecules
Pays: Switzerland
ID NLM: 101596414
Informations de publication
Date de publication:
06 10 2022
06 10 2022
Historique:
received:
30
08
2022
revised:
29
09
2022
accepted:
01
10
2022
entrez:
27
10
2022
pubmed:
28
10
2022
medline:
29
10
2022
Statut:
epublish
Résumé
Intrathecal delivery of Nusinersen-an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction-is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of SMA patients across disease severity. Modulation of amino acid metabolism is a common denominator of biochemical changes induced by Nusinersen, with distinct downstream metabolic effects according to disease severity. In severe SMA1 patients, Nusinersen stimulates energy-related glucose metabolism. In intermediate SMA2 patients, Nusinersen effects are also related to energy homeostasis but involve ketone body and fatty acid biosynthesis. In milder SMA3 patients, Nusinersen mainly modulates amino acid metabolism. Moreover, Nusinersen modifies the CSF metabolome of a more severe clinical group towards the profile of untreated SMA patients with milder disease. These findings reveal disease severity-specific neurometabolic signatures of Nusinersen treatment, suggesting a selective modulation of peripheral organ metabolism by this CNS-directed therapy in severe SMA patients.
Identifiants
pubmed: 36291640
pii: biom12101431
doi: 10.3390/biom12101431
pmc: PMC9599672
pii:
doi:
Substances chimiques
nusinersen
5Z9SP3X666
Oligonucleotides, Antisense
0
Glucose
IY9XDZ35W2
Amino Acids
0
Fatty Acids
0
Ketones
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NINDS NIH HHS
ID : R01 NS102451
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS114218
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS116400
Pays : United States
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