Updates of spinal muscular atrophy in advanced therapies.

Abstract

Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder caused by biallelic pathogenic variants in SMN1 gene, with disease severity mainly modified by SMN2 gene copies. There are remarkable advances in SMA treatment in the last decade with the approval of three disease-modifying therapies: nusinersen, an antisense oligonucleotide; onasemnogene abeparvovec, a gene replacement therapy; and risdiplam, an oral splicing modifier. These therapies have transformed SMA from a fatal condition into a treatable disease. Clinical trials and real-world experiences have confirmed their efficacy across presymptomatic, infantile-onset, and later-onset patients, though age at treatment initiation, pre-treatment disease duration, baseline function, and SMN2 copies influence outcomes. Ongoing research is exploring optimized dosing, combination therapies, and SMN-independent strategies, such as myostatin inhibition and neuromuscular junction enhancement. Meanwhile, the advent of newborn screening enables presymptomatic intervention, though challenges remain in identifying optimal timing for specific genotypes and managing patients with 4 SMN2 copies. Biomarkers including compound muscle action potential and circulating neurofilaments are under evaluation to refine personalized treatment strategies. As survival improves, new phenotypes and multisystem manifestations are emerging, underscoring the need for integrated multidisciplinary care and updated guidelines. Lessons learned from SMA therapy development may serve as a paradigm for other neurological diseases.