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

Autor:	Brown SJ; School of Pharmacy and Bioengineering, Keele University, Keele ST5 5BG, UK.; Wolfson Centre for Inherited Neuromuscular Disease, TORCH Building, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK., Šoltić D; School of Pharmacy and Bioengineering, Keele University, Keele ST5 5BG, UK.; Wolfson Centre for Inherited Neuromuscular Disease, TORCH Building, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK., Synowsky SA; BSRC Mass Spectrometry and Proteomics Facility, University of St Andrews, St Andrews KY16 9ST, UK., Shirran SL; BSRC Mass Spectrometry and Proteomics Facility, University of St Andrews, St Andrews KY16 9ST, UK., Chilcott E; AGCTlab.org, Centre of Gene and Cell Therapy, Centre for Biomedical Sciences, Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham Hill, Egham, Surrey TW20 0EX, UK., Shorrock HK; Edinburgh Medical School: Biomedical Sciences, Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh EH8 9XD, UK., Gillingwater TH; Edinburgh Medical School: Biomedical Sciences, Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh EH8 9XD, UK., Yáñez-Muñoz RJ; AGCTlab.org, Centre of Gene and Cell Therapy, Centre for Biomedical Sciences, Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham Hill, Egham, Surrey TW20 0EX, UK., Schneider B; Bertarelli Platform for Gene Therapy, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1202 Geneva, Switzerland.; Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland., Bowerman M; Wolfson Centre for Inherited Neuromuscular Disease, TORCH Building, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK.; School of Medicine, Keele University, Keele ST5 5BG, UK., Fuller HR; School of Pharmacy and Bioengineering, Keele University, Keele ST5 5BG, UK.; Wolfson Centre for Inherited Neuromuscular Disease, TORCH Building, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2023 Oct 04; Vol. 32 (20), pp. 2950-2965.
DOI:	10.1093/hmg/ddad121
Abstrakt:	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 the cardiac tissue, whereas 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 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. (© The Author(s) 2023. Published by Oxford University Press.)
Databáze:	MEDLINE
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