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PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice
Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The advent of approved treatments for this devastating condition has significantly changed SMA patients' life expectancy and quality of life. Nevertheless, these are not without limitations, and research efforts are u...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10630883/ https://www.ncbi.nlm.nih.gov/pubmed/37724723 http://dx.doi.org/10.15252/emmm.202317683 |
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author | Kordala, Anna J Stoodley, Jessica Ahlskog, Nina Hanifi, Muhammad Garcia Guerra, Antonio Bhomra, Amarjit Lim, Wooi Fang Murray, Lyndsay M Talbot, Kevin Hammond, Suzan M Wood, Matthew JA Rinaldi, Carlo |
author_facet | Kordala, Anna J Stoodley, Jessica Ahlskog, Nina Hanifi, Muhammad Garcia Guerra, Antonio Bhomra, Amarjit Lim, Wooi Fang Murray, Lyndsay M Talbot, Kevin Hammond, Suzan M Wood, Matthew JA Rinaldi, Carlo |
author_sort | Kordala, Anna J |
collection | PubMed |
description | Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The advent of approved treatments for this devastating condition has significantly changed SMA patients' life expectancy and quality of life. Nevertheless, these are not without limitations, and research efforts are underway to develop new approaches for improved and long‐lasting benefits for patients. Protein arginine methyltransferases (PRMTs) are emerging as druggable epigenetic targets, with several small‐molecule PRMT inhibitors already in clinical trials. From a screen of epigenetic molecules, we have identified MS023, a potent and selective type I PRMT inhibitor able to promote SMN2 exon 7 inclusion in preclinical SMA models. Treatment of SMA mice with MS023 results in amelioration of the disease phenotype, with strong synergistic amplification of the positive effect when delivered in combination with the antisense oligonucleotide nusinersen. Moreover, transcriptomic analysis revealed that MS023 treatment has minimal off‐target effects, and the added benefit is mainly due to targeting neuroinflammation. Our study warrants further clinical investigation of PRMT inhibition both as a stand‐alone and add‐on therapy for SMA. |
format | Online Article Text |
id | pubmed-10630883 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-106308832023-11-15 PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice Kordala, Anna J Stoodley, Jessica Ahlskog, Nina Hanifi, Muhammad Garcia Guerra, Antonio Bhomra, Amarjit Lim, Wooi Fang Murray, Lyndsay M Talbot, Kevin Hammond, Suzan M Wood, Matthew JA Rinaldi, Carlo EMBO Mol Med Articles Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The advent of approved treatments for this devastating condition has significantly changed SMA patients' life expectancy and quality of life. Nevertheless, these are not without limitations, and research efforts are underway to develop new approaches for improved and long‐lasting benefits for patients. Protein arginine methyltransferases (PRMTs) are emerging as druggable epigenetic targets, with several small‐molecule PRMT inhibitors already in clinical trials. From a screen of epigenetic molecules, we have identified MS023, a potent and selective type I PRMT inhibitor able to promote SMN2 exon 7 inclusion in preclinical SMA models. Treatment of SMA mice with MS023 results in amelioration of the disease phenotype, with strong synergistic amplification of the positive effect when delivered in combination with the antisense oligonucleotide nusinersen. Moreover, transcriptomic analysis revealed that MS023 treatment has minimal off‐target effects, and the added benefit is mainly due to targeting neuroinflammation. Our study warrants further clinical investigation of PRMT inhibition both as a stand‐alone and add‐on therapy for SMA. John Wiley and Sons Inc. 2023-09-19 /pmc/articles/PMC10630883/ /pubmed/37724723 http://dx.doi.org/10.15252/emmm.202317683 Text en © 2023 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Kordala, Anna J Stoodley, Jessica Ahlskog, Nina Hanifi, Muhammad Garcia Guerra, Antonio Bhomra, Amarjit Lim, Wooi Fang Murray, Lyndsay M Talbot, Kevin Hammond, Suzan M Wood, Matthew JA Rinaldi, Carlo PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice |
title |
PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice |
title_full |
PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice |
title_fullStr |
PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice |
title_full_unstemmed |
PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice |
title_short |
PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice |
title_sort | prmt inhibitor promotes smn2 exon 7 inclusion and synergizes with nusinersen to rescue sma mice |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10630883/ https://www.ncbi.nlm.nih.gov/pubmed/37724723 http://dx.doi.org/10.15252/emmm.202317683 |
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