SMN2 as a therapeutic target in spinal muscular atrophy: advances in gene expression modulation

Abstract

Spinal muscular atrophy (SMA) is a progressive neuromuscular degenerative disorder caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to insufficient production of the survival motor neuron (SMN) protein. The nearly identical SMN2 gene modifies disease severity but generates only limited amounts of functional SMN protein due to a C-to-T transition in exon 7 that disrupts proper splicing. This review summarizes advances in understanding SMN2 splicing regulation and post-transcriptional modification in SMA pathogenesis. It discusses the roles of cis- and trans-acting elements in exon 7 inclusion, as well as the impact of epigenetic mechanisms such as histone acetylation and DNA methylation on SMN2 expression. This review also examines available therapeutic strategies, including antisense oligonucleotides (Nusinersen), small-molecule splicing modulators (Risdiplam and Branaplam), and gene therapy (Onasemnogene abeparvovec). Emerging approaches such as CRISPR/Cas9 genome editing and nanotechnology-based delivery systems are also highlighted. In addition, this review explores translational research using animal models, iPSC-derived neurons, and multi-omics approaches. Finally, it emphasizes the need for integrated therapeutic strategies that address both SMN-dependent and -independent pathways to improve treatment outcomes.