Rescue of spinal muscular atrophy mouse models with AAV9-Exon-specific U1 snRNA

Donadon, Irving and Bussani, Erica and Riccardi, Federico and Licastro, Danilo and Romano, Giulia and Pianigiani, Giulia and Pinotti, Mirko and Kostantinova, Pavlina and Evers, Melvin and Lin, Shuo and Rüegg, Markus A. and Pagani, Franco. (2019) Rescue of spinal muscular atrophy mouse models with AAV9-Exon-specific U1 snRNA. Nucleic acids research, 47 (14). pp. 7618-7632.

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Official URL: https://edoc.unibas.ch/70996/

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Oxford University Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 Jan 2022 04:12
Deposited On:17 Aug 2020 13:14

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