PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice
Abstract 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 effo...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2023-11-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202317683 |
| _version_ | 1797281102224687104 |
|---|---|
| author | Anna J Kordala Jessica Stoodley Nina Ahlskog Muhammad Hanifi Antonio Garcia Guerra Amarjit Bhomra Wooi Fang Lim Lyndsay M Murray Kevin Talbot Suzan M Hammond Matthew JA Wood Carlo Rinaldi |
| author_facet | Anna J Kordala Jessica Stoodley Nina Ahlskog Muhammad Hanifi Antonio Garcia Guerra Amarjit Bhomra Wooi Fang Lim Lyndsay M Murray Kevin Talbot Suzan M Hammond Matthew JA Wood Carlo Rinaldi |
| author_sort | Anna J Kordala |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-07T16:51:41Z |
| format | Article |
| id | doaj.art-0a6be327d14849d1ae2a1fc49bf73886 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:51:41Z |
| publishDate | 2023-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-0a6be327d14849d1ae2a1fc49bf738862024-03-03T04:58:42ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-11-011511n/an/a10.15252/emmm.202317683PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA miceAnna J Kordala0Jessica Stoodley1Nina Ahlskog2Muhammad Hanifi3Antonio Garcia Guerra4Amarjit Bhomra5Wooi Fang Lim6Lyndsay M Murray7Kevin Talbot8Suzan M Hammond9Matthew JA Wood10Carlo Rinaldi11Department of Physiology Anatomy and Genetics University of Oxford Oxford UKDepartment of Paediatrics University of Oxford Oxford UKDepartment of Paediatrics University of Oxford Oxford UKDepartment of Paediatrics University of Oxford Oxford UKDepartment of Paediatrics University of Oxford Oxford UKDepartment of Paediatrics University of Oxford Oxford UKDepartment of Paediatrics University of Oxford Oxford UKCentre for Discovery Brain Sciences, College of Medicine and Veterinary Medicine University of Edinburgh Edinburgh UKNuffield Department of Clinical Neurosciences, John Radcliffe Hospital University of Oxford Oxford UKDepartment of Paediatrics University of Oxford Oxford UKDepartment of Paediatrics University of Oxford Oxford UKDepartment of Paediatrics University of Oxford Oxford UKAbstract 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.https://doi.org/10.15252/emmm.202317683nusinersenPRMT inhibitorsmall moleculespinal muscular atrophy |
| spellingShingle | Anna J Kordala Jessica Stoodley Nina Ahlskog Muhammad Hanifi Antonio Garcia Guerra Amarjit Bhomra Wooi Fang Lim Lyndsay M Murray Kevin Talbot Suzan M Hammond Matthew JA Wood Carlo Rinaldi PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice EMBO Molecular Medicine nusinersen PRMT inhibitor small molecule spinal muscular atrophy |
| 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 | nusinersen PRMT inhibitor small molecule spinal muscular atrophy |
| url | https://doi.org/10.15252/emmm.202317683 |
| work_keys_str_mv | AT annajkordala prmtinhibitorpromotessmn2exon7inclusionandsynergizeswithnusinersentorescuesmamice AT jessicastoodley prmtinhibitorpromotessmn2exon7inclusionandsynergizeswithnusinersentorescuesmamice AT ninaahlskog prmtinhibitorpromotessmn2exon7inclusionandsynergizeswithnusinersentorescuesmamice AT muhammadhanifi prmtinhibitorpromotessmn2exon7inclusionandsynergizeswithnusinersentorescuesmamice AT antoniogarciaguerra prmtinhibitorpromotessmn2exon7inclusionandsynergizeswithnusinersentorescuesmamice AT amarjitbhomra prmtinhibitorpromotessmn2exon7inclusionandsynergizeswithnusinersentorescuesmamice AT wooifanglim prmtinhibitorpromotessmn2exon7inclusionandsynergizeswithnusinersentorescuesmamice AT lyndsaymmurray prmtinhibitorpromotessmn2exon7inclusionandsynergizeswithnusinersentorescuesmamice AT kevintalbot prmtinhibitorpromotessmn2exon7inclusionandsynergizeswithnusinersentorescuesmamice AT suzanmhammond prmtinhibitorpromotessmn2exon7inclusionandsynergizeswithnusinersentorescuesmamice AT matthewjawood prmtinhibitorpromotessmn2exon7inclusionandsynergizeswithnusinersentorescuesmamice AT carlorinaldi prmtinhibitorpromotessmn2exon7inclusionandsynergizeswithnusinersentorescuesmamice |