With the food and drug administration (FDA) approval of nusinersen (trade name Spinraza) for treatment of spinal muscular atrophy patients on December 23, 2016 [1] brought us not one, but two approved splice modulating oligonucleotides to treat neuromuscular disorders. Eteplirsen, an oligonucleotide to treat a subset of Duchenne muscular dystrophy (DMD) patients, was approved earlier this year. However, where the approval of eteplirsen was highly controversial [2], this one seemed to be crystal clear: the drug was approved only 91 days after Biogen filed the new drug application (NDA) with FDA, and the application was not referred to an FDA advisory committee because ‘‘outside expertise was not necessary and there were no controversial issues that would have benefited from advisory committee discussion’’[3]. Spinal muscular atrophy (SMA) is an autosomal recessively inherited disease, which is characterized by progressive loss of motor neurons, leading to muscle atrophy and paralyzation. Most patients (60%) suffer from the most severe form of the disease, type I SMA. Symptoms start in infants before 6 months of age, patients never achieve independent sitting, need intensive supportive care, including ventilation, and seldom live beyond 2 years of age. Type II and type III SMA are milder forms of the disease. For type II, onset is after 6–18 months, patients are able to sit independently, but never able to walk and can live 20–40 years with good supportive care. Type III SMA patients are able to walk, but generally loose this ability when disease progresses. Survival is normal. It should be noted that all types of SMA are severe and debilitating and that the term ‘‘milder’’is only relative to the very severe type I SMA. There is a type IV SMA, with onset in adulthood (after 30 years of age) and a slowly progressive course, but this is a very rare form [4]. Type I–IV SMA are all caused by loss of function mutations involving the SMN1 gene, precluding the production of the protein survival of motor neurons (SMN). As the name suggests, this protein is crucial for the survival of motor neurons. SMN is ubiquitously expressed and is a component of the SMN complex, which has a role in assembling the small nuclear RNA proteins involved in the splicing process [5]. It is not yet fully elucidated why lack of SMN protein primarily appears to have an impact on motor neurons.

Complete lack of SMN protein is embryonic lethal. However, humans have an almost identical copy of theSMN1gene, SMN2. Transcripts of this gene are unfortunately mostly improperly spliced because exon 7 of SMN2 is poorly recognized by the spliceosome due to single nucleotide changes. As such, exon 7 is spliced out in 90% of SMN2 transcripts, leading to only* 10% of full-length SMN2 transcripts and low levels of SMN protein, which are sufficient to prevent lethality before birth, but not enough to prevent the loss of motor neurons in infancy (type I) or childhood (type II and III)[4, 5]. The reason that some patients suffer from a more severe disease than others is that there is copy number variation of the SMN2 gene. Type I patients generally have two SMN2 copies, while type II and type III patients generally have three and three to four copies, respectively [4]. While for each SMN2 transcript only 10% contains exon 7, the absolute amount of full-length transcripts—and thus SMN protein—of course increases when patients have more gene copies, leading to a less severe disease. Since all SMA patients have at least two copies of the SMN2 gene, and since more SMN protein is associated with a less severe disease, it stands to reason that increasing the amount of full-length SMN2 transcripts …