Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy.
alternative splicing
antisense oligonucleotide therapy
chromatin
histone acetylation
spinal muscular atrophy
transcriptional elongation
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
09 06 2022
09 06 2022
Historique:
received:
27
09
2021
revised:
17
03
2022
accepted:
26
04
2022
entrez:
10
6
2022
pubmed:
11
6
2022
medline:
15
6
2022
Statut:
ppublish
Résumé
Spinal muscular atrophy (SMA) is a motor-neuron disease caused by mutations of the SMN1 gene. The human paralog SMN2, whose exon 7 (E7) is predominantly skipped, cannot compensate for the lack of SMN1. Nusinersen is an antisense oligonucleotide (ASO) that upregulates E7 inclusion and SMN protein levels by displacing the splicing repressors hnRNPA1/A2 from their target site in intron 7. We show that by promoting transcriptional elongation, the histone deacetylase inhibitor VPA cooperates with a nusinersen-like ASO to promote E7 inclusion. Surprisingly, the ASO promotes the deployment of the silencing histone mark H3K9me2 on the SMN2 gene, creating a roadblock to RNA polymerase II elongation that inhibits E7 inclusion. By removing the roadblock, VPA counteracts the chromatin effects of the ASO, resulting in higher E7 inclusion without large pleiotropic effects. Combined administration of the nusinersen-like ASO and VPA in SMA mice strongly synergizes SMN expression, growth, survival, and neuromuscular function.
Identifiants
pubmed: 35688133
pii: S0092-8674(22)00529-3
doi: 10.1016/j.cell.2022.04.031
pmc: PMC9555286
mid: NIHMS1831280
pii:
doi:
Substances chimiques
Chromatin
0
Oligonucleotides, Antisense
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2057-2070.e15Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R37 GM042699
Pays : United States
Organisme : Wellcome Trust
ID : 107928/Z/15/Z
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA045508
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM042699
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests A.R. Krainer is an inventor in nusinersen patents licensed by Cold Spring Harbor Laboratory to Ionis Pharmaceuticals, and sublicensed to Biogen, and is also a consultant to Biogen, which commercializes Spinraza. Patent: the content of this work was included in PCT/US21/41466 “Compositions for treatment of SMA.”
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