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AAV9-mediated SMN gene therapy rescues cardiac desmin but not lamin A/C and elastin dysregulation in Smn2B/- spinal muscular atrophy mice Human Molecular Genetics

Brown, Sharon; Šoltić, Darija; Synowsky, Silvia A; Shirran, Sally L; Chilcott, Ellie; Shorrock, Hannah K; Gillingwater, Thomas H; Yáñez-Muñoz, Rafael J; Schneider, Bernard; Bowerman, Melissa; Fuller, Heidi


Darija Šoltić

Silvia A Synowsky

Sally L Shirran

Ellie Chilcott

Hannah K Shorrock

Thomas H Gillingwater

Rafael J Yáñez-Muñoz

Bernard Schneider


Structural, functional and molecular cardiac defects have been reported in spinal muscular atrophy (SMA) patients and mouse models. Previous quantitative proteomics analyses demonstrated widespread molecular defects in the severe Taiwanese SMA mouse model. Whether such changes are conserved across different mouse models, including less severe forms of the disease, has yet to be established. Here, using the same high-resolution proteomics approach in the less-severe Smn2B/− SMA mouse model, 277 proteins were found to be differentially abundant at a symptomatic timepoint (post-natal day (P) 18), 50 of which were similarly dysregulated in severe Taiwanese SMA mice. Bioinformatics analysis linked many of the differentially abundant proteins to cardiovascular development and function, with intermediate filaments highlighted as an enriched cellular compartment in both datasets. Lamin A/C was increased in cardiac tissue whilst another intermediate filament protein, desmin, was reduced. The extracellular matrix (ECM) protein, elastin, was also robustly decreased in the heart of Smn2B/− mice. AAV9-SMN1-mediated gene therapy rectified low levels of survival motor neuron (SMN) protein and restored desmin levels in heart tissues of Smn2B/− mice. In contrast AAV9-SMN1 therapy failed to correct lamin A/C or elastin levels. Intermediate filament proteins and the ECM have key roles in cardiac function and their dysregulation may explain cardiac impairment in SMA, especially since mutations in genes encoding these proteins cause other diseases with cardiac aberration. Cardiac pathology may need to be considered in the long-term care of SMA patients, as it is unclear whether currently available treatments can fully rescue peripheral pathology in SMA.

Journal Article Type Article
Acceptance Date Jul 25, 2023
Online Publication Date Jul 27, 2023
Publication Date Jul 27, 2023
Deposit Date Aug 1, 2023
Publicly Available Date Aug 1, 2023
Journal Human Molecular Genetics
Print ISSN 0964-6906
Electronic ISSN 1460-2083
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Article Number ddad121
Keywords spinal muscular atrophy; lamin A/C; desmin; elastin; AAV9


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