Rescue of spinal muscular atrophy mouse models with AAV9-Exon-specific U1 snRNA.
Animals
Dependovirus
/ genetics
Disease Models, Animal
Exons
/ genetics
Genetic Therapy
/ methods
HEK293 Cells
Humans
Mice, Knockout
Muscular Atrophy, Spinal
/ genetics
Muscular Dystrophy, Animal
/ genetics
Mutation
RNA Splicing
Ribonucleoprotein, U1 Small Nuclear
/ genetics
Survival of Motor Neuron 1 Protein
/ genetics
Survival of Motor Neuron 2 Protein
/ genetics
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
22 08 2019
22 08 2019
Historique:
accepted:
16
05
2019
revised:
10
05
2019
received:
04
02
2019
pubmed:
28
5
2019
medline:
18
12
2019
entrez:
26
5
2019
Statut:
ppublish
Résumé
Spinal Muscular Atrophy results from loss-of-function mutations in SMN1 but correcting aberrant splicing of SMN2 offers hope of a cure. However, current splice therapy requires repeated infusions and is expensive. We previously rescued SMA mice by promoting the inclusion of a defective exon in SMN2 with germline expression of Exon-Specific U1 snRNAs (ExspeU1). Here we tested viral delivery of SMN2 ExspeU1s encoded by adeno-associated virus AAV9. Strikingly the virus increased SMN2 exon 7 inclusion and SMN protein levels and rescued the phenotype of mild and severe SMA mice. In the severe mouse, the treatment improved the neuromuscular function and increased the life span from 10 to 219 days. ExspeU1 expression persisted for 1 month and was effective at around one five-hundredth of the concentration of the endogenous U1snRNA. RNA-seq analysis revealed our potential drug rescues aberrant SMA expression and splicing profiles, which are mostly related to DNA damage, cell-cycle control and acute phase response. Vastly overexpressing ExspeU1 more than 100-fold above the therapeutic level in human cells did not significantly alter global gene expression or splicing. These results indicate that AAV-mediated delivery of a modified U1snRNP particle may be a novel therapeutic option against SMA.
Identifiants
pubmed: 31127278
pii: 5498632
doi: 10.1093/nar/gkz469
pmc: PMC6698663
doi:
Substances chimiques
Ribonucleoprotein, U1 Small Nuclear
0
SMN2 protein, mouse
0
Smn1 protein, mouse
0
Survival of Motor Neuron 1 Protein
0
Survival of Motor Neuron 2 Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7618-7632Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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