Spinal Muscular Atrophy (SMA)—the leading genetic cause of childhood mortality—is a disease in which the gene SMN1 is deleted or mutated. The highly similar gene SMN2 can undergo alternative splicing to generate functional protein transcripts of the SMN1 gene product, although native levels of the protein are too low to overcome the pathology. Here we highlight Roche and PTC Therapeutics scientists’ discovery of the first approved small molecule splicing modulator, risdiplam.
Risdiplam works in SMA by inducing splicing to include exon 7 of SMN2 to elevate levels of functional survival motor neuron 1 (SMN1) in SMA patients. Pivotal scientific achievements in the story, among many, include:
- A target agnostic screen of >200k compounds identifies small molecule splicing modulators that include exon 7 of SMN2
- A med. chem. campaign to improve EC1.5x from >32 µM to 29 nM and selectivity to 10:1 selectivity for SMN2 over FOXM1
- Identification of the target as a complex of the exon 7 pre-mRNA and the U1-C zinc finger protein
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