PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice

EMBO Mol Med. 2023 Nov 8;15(11):e17683. doi: 10.15252/emmm.202317683. Epub 2023 Sep 19.


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.

Keywords: PRMT inhibitor; nusinersen; small molecule; spinal muscular atrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Exons
  • Humans
  • Infant
  • Mice
  • Muscular Atrophy, Spinal* / drug therapy
  • Muscular Atrophy, Spinal* / genetics
  • Oligonucleotides / pharmacology
  • Oligonucleotides / therapeutic use
  • Quality of Life*
  • Survival of Motor Neuron 2 Protein / genetics
  • Survival of Motor Neuron 2 Protein / therapeutic use


  • nusinersen
  • Oligonucleotides
  • SMN2 protein, human
  • Survival of Motor Neuron 2 Protein
  • SMN2 protein, mouse

Associated data

  • GEO/GSE206400