Real-world evidence on nusinersen treatment of persons with SMA: a focused review

Nusinersen is a designer drug for spinal muscular atrophy (SMA) and was the first approved treatment for this once deadly disease. It is an antisense oligonucleotide that pairs with a specific locus of the Survival Motor Neuron 2 (SMN2) gene, to modify splicing and generate an increase in full-length SMN2 transcript. This in turn increases expression of survival motor neuron protein, deficiency of which results in motor neuron dysfunction and reduced cellular survival, the principal cause of SMA. Pre-clinical studies of nusinersen in animal models of SMA demonstrated substantial clinical responses and proof-of-concept, leading to successful clinical trials in symptomatic children and then in infants. Nusinersen's favorable safety profile after repeated lumbar intrathecal delivery as well as improvement in motor function and survival resulted in US regulatory approval for SMA in 2016. Other countries have followed with variable coverage policies depending upon age, weight, genotype and/or clinical severity. In the current treatment era, two populations of individuals with SMA exist: symptomatic patients identified in the clinic and pre-symptomatic patients (having no or few early clinical features of disease) largely identified by newborn screening. Real-world experience with nusinersen, the topic of this focused review, presents post-approval data in a broad range of patients beyond those studied in clinical trials. The favorable clinical response and safety profile are discussed, as well as the emerging new phenotypes of disease. Nusinersen, one of three FDA-approved drugs for SMA (as of 2025) remains an important therapeutic consideration for infants, children and adults with SMA.