Therapeutic strategies for spinal muscular atrophy: the history and future perspective

Abstract

Spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disorder characterized by progressive degeneration of lower motor neurons, leading to muscle weakness and atrophy predominantly manifesting in childhood. The disease is caused by homozygous deletion or loss-of-function mutations in the survival motor neuron 1 (SMN1) gene, with the nearly identical SMN2 gene acting as a critical modifier of disease severity. Since the initial clinical descriptions in 1891 and the identification of the causative gene in 1995, the field has witnessed transformative therapeutic progress. The FDA approval of nusinersen, an antisense oligonucleotide targeting SMN2 splicing, in 2016 marked the first disease-modifying therapy, followed by the gene replacement therapy onasemnogene abeparvovec in 2019 and the orally administered small-molecule splicing modifier risdiplam in 2020. These SMN-targeted therapies have substantially improved survival and motor outcomes, particularly when administered presymptomatically as enabled by increasingly widespread newborn screening programs. However, a significant proportion of patients, especially those with later-onset disease and adults, show limited responses, and existing therapies cannot reverse established neurodegeneration or muscle pathology. In this review, we trace the history of SMA research and therapy development, critically compare the three approved treatments, and discuss key unresolved challenges including treatment-switching criteria, management of late-diagnosed patients, and the emerging role of biomarkers such as neurofilament light chain and compound muscle action potential. We further explore non-SMN therapeutic strategies targeting PTEN, plastin 3, neurocalcin delta, myostatin, and neuroinflammation, and examine the rationale for combination approaches that integrate SMN restoration with muscle- and neuro-protective agents. Finally, we address future directions encompassing precision medicine, next-generation gene editing, and biomarker-driven trial design. While SMA has been transformed from a fatal childhood disorder to a treatable condition, a definitive cure for all patients remains the goal of ongoing and future research.