As the world of small-molecule therapeutics continues to expand, researchers are broadening their horizons to discover not only straightforward inhibitors of enzymatic activity but also compounds that modulate protein abundance and activity by targeting the upstream steps of RNA transcription, splicing, and translation. An archetypal success story of this approach is risdiplam, currently marketed by Genentech as Evrysdi, an FDA-approved treatment for spinal muscular atrophy (SMA) in adults and children two months and older. SMA patients, due to homozygous deletions or mutations in the SMN1 gene, produce insufficient levels of the essential survival motor neuron (SMN) protein. This deficiency leads to progressive motor neuron degeneration and, in turn, muscle weakness and atrophy, with significant risk of respiratory complications. SMA affects 1 in 10,000 to 20,000 live births and, while disease severity varies, the most serious forms of SMA have an untreated life expectancy of less than two years.

Clinical efforts have sought to increase levels of SMN protein in SMA patients through orthogonal strategies. For example, the gene therapy onasemnogene abeparvovec (marketed as Zolgensma) delivers a transgenic copy of SMN1, which can be transcribed in vivo to produce functional protein. Another compelling approach to SMA treatment leverages the SMN1 paralog SMN2. SMN2 is typically spliced to remove exon 7, producing a non-functional protein that is rapidly degraded. Occasionally, however, exon 7 is retained, such that functional SMN protein is produced from 10-15% of SMN2 transcripts. While these low levels of SMN are insufficient to restore function in SMA patients, this alternative route to SMN production was identified as a promising point for therapeutic intervention. The antisense oligonucleotide drug nusinersen (marketed as Spinraza) increases SMN levels using this approach; however, the numerous downsides associated with oligonucleotide-based therapeutics encouraged researchers to continue to seek a small molecule drug with similar functionality.

In 2014, these efforts came to fruition when a screen for small molecules promoting exon 7 retention identified a precursor to risdiplam capable of effectively increasing SMN levels in mice. Subsequent optimization efforts led to the discovery of risdiplam, a potent, selective modulator of SMN2 splicing that promotes inclusion of exon 7 to effectively increase levels of functional SMN. In clinical trials, risdiplam was shown to improve motor function in patients with Type 2 and 3 SMA; 32% of risdiplam-treated patients showed significant improvement after 24 months, while a further 58% were stabilized. Additional trials have affirmed the therapeutic benefits of risdiplam in infants with Type 1 SMA, presymptomatic newborns with genetically diagnosed SMA, and previously treated SMA patients. In August 2020, the U.S. FDA approved risdiplam (Evrysdi) for the treatment of individuals two months and older with infantile-onset or later-onset SMA.

Given that RNA mis-splicing has been implicated in up to 15% of inherited diseases, the success of risdiplam has sparked broad interest in the clinical applications of splice-modifying drugs. In particular, small molecules offer improved deliverability, reduced toxicity, and superior pharmacokinetic profiles compared to oligonucleotide-based approaches, Small-molecule splice-modulating therapies have clear potential for the treatment of diseases associated with the defective or alternative splicing of critical genes, such as Duchenne muscular dystrophy (DMD), familial dysautonomia (IKBKAP), and early-onset Parkinson disease (PINK1). In these contexts, the ideal small-molecule drug is exquisitely selective, affecting splicing only of a specific, disease-relevant transcript (as with risdiplam/SMA2). In other contexts, therapeutic benefit could be achieved by modulating splicing more generally, such as to exploit a synthetic vulnerability in spliceosome-mutant cancers or to combat viral infection. These potent strategies highlight the transformative power of RNA-targeted drugs to treat challenging diseases and exemplify the ongoing scientific innovations that continue to expand the clinical small-molecule toolkit.

To learn more about how Momentum’s comprehensive suite of drug discovery and development services can help you explore the therapeutic application of small-molecule splicing modulators, contact our scientific team.

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