Spinal muscular atrophy (SMA) is a rare monogenic disease of mostly paediatric onset, affecting approximately 1:8,000 - 10,000 live births. If untreated, it leads to progressive muscle weakness and paralysis, due to degeneration of lower α-motor neurons in the spinal cord and brainstem. Three therapies are currently approved for SMA and while effective, they are extremely costly and not without limitations. It is becoming apparent that with SMA individuals living longer, new therapies, alone and/or in combination with the ones already on the market, are needed to improve quality of life and ensure sustained benefit for patients. Epigenetic mechanisms have been implicated in several neuroprotection and neurodegeneration processes as well as SMA itself. The aim of this project is to identify novel epigenetic mechanisms involved in the regulation of SMN with the ultimate goal to identify new therapeutic targets. To this end, I have screened a library of epigenetic probes from the Structural Genomic Consortium, for their ability to modulate SMN2 in SMA patient-derived fibroblasts. Lead molecules have been further validated in the SMA mouse model. Among these molecules, I have identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), and IOX2, an inhibitor of prolyl hydroxylase domain 2 (PHD2), and characterized MS023 in depth. MS023 is able to increase the levels of SMN protein in vitro and in vivo, via a splice switching mechanism and improve survival and weights in a severe mouse model of SMA. Furthermore, the combinatorial treatment of oral MS023 and the market-approved antisense oligonucleotide nusinersen, is able to prolong the lifespan of severe SMA mice to a greater extent than the oligonucleotide treatment alone. MS023 alters the methylation pattern of hnRNPA1, the main negative regulator of exon 7 inclusion, weakening its binding to SMN2 pre-mRNA. Transcriptomic analysis in spinal cords of SMA mice identified correction of immune-related pathways by the combinatorial treatment but not nusinersen alone. These results provide a new insight into epigenetic regulation of SMN and PRMT function in splicing and justify moving forward with MS023 preclinical development as an add-on therapy for SMA.