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.

中文翻译：

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PRMT抑制剂促进SMN2外显子7包含并与nusinersen协同拯救SMA小鼠

脊髓性肌萎缩症（SMA）是婴儿死亡的主要原因。针对这种破坏性疾病的批准治疗方法的出现显着改变了 SMA 患者的预期寿命和生活质量。然而，这些方法并非没有局限性，研究工作正在进行中，以开发新方法，以改善患者的长期利益。蛋白质精氨酸甲基转移酶 (PRMT) 正在成为可药物化的表观遗传靶点，几种小分子 PRMT 抑制剂已进入临床试验。通过表观遗传分子的筛选，我们发现了 MS023，一种有效的选择性 I 型 PRMT 抑制剂，能够促进临床前 SMA 模型中SMN2外显子 7 的包含。用 MS023 治疗 SMA 小鼠可改善疾病表型，与反义寡核苷酸 nusinersen 联合使用时，可强烈协同放大积极效果。此外，转录组分析显示，MS023治疗的脱靶效应最小，而额外的益处主要是由于针对神经炎症。我们的研究需要对 PRMT 抑制作为 SMA 的独立疗法和附加疗法进行进一步的临床研究。