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 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. image Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. To address the urgent need to develop new approaches for improved and long‐lasting benefits for SMA patients, an orally available, epigenetic‐targeting small molecule was identified and tested in SMA models alone and in combination with a recently approved treatment. From a cell‐based screening of potent and selective epigenetic probes, type I protein methyltransferases inhibitor MS023 was able to promote exon 7 inclusion in SMN2 pre‐mRNA. MS023 mechanism of action entails altering the methylation pattern and binding affinity of the heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), a negative SMN2 splicing regulator. Oral administration of MS023 improves the phenotype of SMA mice alone and enhances the effects of nusinersen when used in combination. Transcriptomic analyses revealed that targeting neuroinflammation in SMA is key to achieve the superior beneficial effects of the combinatorial treatment compared to nusinersen or MS023 alone.