Nusinersen: A Novel Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) encompasses a group of autosomal recessively inherited degenerative neuromuscular disorders. They range in severity from neonatal onset with rapidly progressive weakness and early mortality (SMA-1), to onset in infancy (SMA-2), to adolescent/adult onset with indolent clinical course (SMA-3/-4). SMA patients share mutations in the survival motor neuron (SMN) gene; variations in clinical phenotypes are attributable to copy numbers of the closely related SMN2 gene. In December 2016, the US Food and Drug Administration (FDA) approved nusinersen (Spinraza, Biogen, Cambridge, MA) to treat SMA. Nusinersen, an antisense oligonucleotide, is administered directly into cerebrospinal fluid. It alters SMN2 pre-RNA splicing so exon 7 is included, increasing expression of functional SMN protein. Although nusinersen was FDA approved for treatment of all forms of SMA, the initial clinical trials were limited to patients up to age 14 years, diagnosed with SMA-1,-2, -3, not on mechanical ventilation support. Two subsequent phase 3 trials were completed for SMA-1 and SMA-2/-3 and demonstrated improved motor milestones and event-free survival, better than expected based on natural history studies. Efficacy assessments for patients receiving nusinersen are based on serial assessments of performance on age-appropriate standardized motor scales. Treatment requires complex financial and logistics because of the very high drug cost, intrathecal administration, and medical fragility of the patients. Treatment implementation also engenders ethical considerations related to cost, insurance coverage, limited clinical data on groups of patients not in clinical trials, and questions of duration of treatment. Nusinersen has been integrated into the treatment of many SMA patients.