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AAV9-mediated delivery of miR-23a reduces disease severity in Smn2B/-SMA model mice.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2019 Oct 01; Vol. 28 (19), pp. 3199-3210. - Publication Year :
- 2019
-
Abstract
- Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in survival motor neuron 1 (SMN1). The molecular mechanisms underlying motor neuron degeneration in SMA remain elusive, as global cellular dysfunction obscures the identification and characterization of disease-relevant pathways and potential therapeutic targets. Recent reports have implicated microRNA (miRNA) dysregulation as a potential contributor to the pathological mechanism in SMA. To characterize miRNAs that are differentially regulated in SMA, we profiled miRNA levels in SMA induced pluripotent stem cell (iPSC)-derived motor neurons. From this array, miR-23a downregulation was identified selectively in SMA motor neurons, consistent with previous reports where miR-23a functioned in neuroprotective and muscle atrophy-antagonizing roles. Reintroduction of miR-23a expression in SMA patient iPSC-derived motor neurons protected against degeneration, suggesting a potential miR-23a-specific disease-modifying effect. To assess this activity in vivo, miR-23a was expressed using a self-complementary adeno-associated virus serotype 9 (scAAV9) viral vector in the Smn2B/- SMA mouse model. scAAV9-miR-23a significantly reduced the pathology in SMA mice, including increased motor neuron size, reduced neuromuscular junction pathology, increased muscle fiber area, and extended survival. These experiments demonstrate that miR-23a is a novel protective modifier of SMA, warranting further characterization of miRNA dysfunction in SMA.<br /> (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Dependovirus genetics
Disease Models, Animal
Down-Regulation
Humans
Induced Pluripotent Stem Cells metabolism
Mice
MicroRNAs metabolism
Motor Neurons metabolism
Muscular Atrophy, Spinal genetics
Severity of Illness Index
Survival of Motor Neuron 2 Protein genetics
Genetic Vectors administration & dosage
MicroRNAs genetics
Muscular Atrophy, Spinal therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 28
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 31211843
- Full Text :
- https://doi.org/10.1093/hmg/ddz142