RNA-based drug discovery for spinal muscular atrophy: a story of small molecules and antisense oligonucleotides.

Introduction: Spinal Muscular Atrophy (SMA), the second most prevalent autosomal genetic disease affecting infants, is caused by the lack of , which encodes a neuron functioning vital protein, SMN. Improving exon 7 splicing in the paralogous gene , also coding for SMN protein, increases protein production efficiency from to overcome the genetic deficit in . Several molecular mechanisms have been investigated to improve SMN2 functional splicing.

Areas Covered: This manuscript will cover two of the three mechanistically distinct available treatment options for SMA, both targeting the SMN2 splicing mechanism. The first therapeutic, nusinersen (Spinraza®, 2017), is an antisense oligonucleotide (ASO) targeting the splicing inhibitory sequence in the intron downstream of exon 7 from SMN2, thus increasing exon 7 inclusion. The second drug is a small molecule, risdiplam (Evrysdi®, 2021), that enhances the binding of splice factors and also promotes exon 7 inclusion. Both therapies, albeit through different mechanisms, increase full-length SMN protein expression.

Expert Opinion: Nusinersen and risdiplam have directly helped SMA patients and families, but they also herald a sea change in drug development for genetic diseases. This piece aims to draw parallels between both development histories; this may help chart the course for future targeted agents.