Spinraza^Ⓡ: The First Approved Therapy for Spinal Muscular Atrophy

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Nusinersen (Spinraza^®), the first approved medicine for spinal muscular atrophy (SMA), exemplifies a successful path from basic studies of cellular mechanisms to an effective treatment for a devastating disease. This successful clinical application comes >120 years after the first description of the disease, and 40 years after the discovery of RNA splicing and the first reported use of antisense technology.

SMA is a motor-neuron disease, caused by mutations in SMN1. Patients retain one or more copies of the nearly identical SMN2 gene, which mainly expresses mRNA lacking exon 7, coding for an unstable protein isoform. The small amount of full-length mRNA and protein expressed from SMN2 only partially compensates for the loss of SMN1. Together with Ionis Pharmaceuticals, we developed nusinersen, a splice-switching antisense oligonucleotide (ASO) that efficiently promotes SMN2 exon 7 inclusion and restores SMN protein levels. Nusinersen hybridizes to intron 7 of the SMN2 pre-mRNA, preventing binding of the splicing repressors hnRNPA1/A2 to a bipartite intronic splicing silencer; this in turn facilitates binding of U1 snRNP to the intron 7 5' splice site, resulting in enhanced exon 7 inclusion. Clinical trials of nusinersen in SMA patients, sponsored by Ionis and Biogen, began at the end of 2011. Based on the results of two phase-3 trials in infants with the most severe form of SMA, and in children with an intermediate form of SMA, respectively, Spinraza was approved by the FDA in December 2016, for all SMA types. It was subsequently approved in Europe and Japan in 2017.

We are continuing to explore aspects of SMA pathogenesis and treatment, using ASO therapy in SMA mouse models. We are also exploring prenatal ASO treatment, as it is likely that early intervention will maximize the clinical benefit.