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

被引：4

作者：

Kordala, Anna J. ^{[1
,2
,3
]}

Stoodley, Jessica ^{[2
,3
]}

Ahlskog, Nina ^{[2
,3
]}

Hanifi, Muhammad ^{[2
]}

Garcia Guerra, Antonio ^{[2
,3
]}

Bhomra, Amarjit ^{[2
,3
]}

Lim, Wooi Fang ^{[2
,3
]}

Murray, Lyndsay M. ^{[4
,5
]}

Talbot, Kevin ^{[6
,7
]}

Hammond, Suzan M. ^{[2
]}

Wood, Matthew J. A. ^{[2
,3
,8
]}

Rinaldi, Carlo ^{[2
,3
,8
]}

机构：

[1] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England

[2] Univ Oxford, Dept Psychiat, Oxford, England

[3] Inst Dev & Regenerat Med IDRM, Oxford, England

[4] Univ Edinburgh, Coll Med & Vet Med, Ctr Discovery Brain Sci, Edinburgh, Scotland

[5] Univ Edinburgh, Euan McDonald Ctr Motor Neuron Dis Res, Edinburgh, Scotland

[6] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford, England

[7] Univ Oxford, Kavli Inst Nanosci Discovery, Oxford, England

[8] MDUK Oxford Neuromuscular Ctr, Oxford, England

来源：

EMBO MOLECULAR MEDICINE | 2023年 / 15卷 / 11期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

nusinersen; PRMT inhibitor; small molecule; spinal muscular atrophy; SPINAL MUSCULAR-ATROPHY; SURVIVAL MOTOR-NEURON; MESSENGER-RNA; MOUSE-MODEL; PROTEIN INTERACTS; GENE-PRODUCT; ARGININE METHYLATION; SINGLE NUCLEOTIDE; DISEASE SEVERITY; VALPROIC ACID;

D O I：

10.15252/emmm.202317683

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：16