Rational development of small molecule splicing modifiers – EpiCor

The specific correction of RNA splicing using small molecule is an emerging field of drug discovery. The specific correction of gene expression by modulating RNA splicing has begun to provide therapeutic solutions against inherited conditions. In this context, we have deciphered the mode of action of the first small molecule that corrects the splicing of the SMN2 gene and provided the first orally available treatment for Spinal Muscular Atrophy, a devastating neuromuscular syndrome. The small molecules, SMN-C5 and Risdiplam®, act as molecular glues between the first particle of the spliceosome (U1 snRNP) and the A-1 bulged 5’-splice site of SMN2 exon 7. By modifying the 5’-splice site selectivity of U1 snRNP, the small molecule allosterically activates the assembly of the spliceosome on SMN2 exon 7 and induces the production of functional SMN protein. We term this mechanism "5'-splice site bulge repair". Since many human diseases, including inherited diseases and cancers, originate from 5’-splice site mutations, we are convinced that the mechanism of 5’-splice site bulge repair could be used to develop innovative therapeutic approaches. Along these lines, small molecule splicing modifiers were recently described in the context of Huntington’s diseases and these small molecules are currently under clinical evaluations. Our research aims to understand the gene selectivity of the current splicing modifiers and design new ones with varied gene specificities. We'll examine the chemical diversity of splicing modifiers acting on A-1 bulged 5’-splice sites, investigate the molecular mechanisms of the exon purine-rich element dependency of the SMN2 splicing modifiers, and rationally discover novel splicing modifiers acting on U-1 or C-1 bulged 5’-splice sites. Altogether, we will establish the fundamental basis of this emerging class of RNA therapeutics and ultimately herald significant biomedical advancements to push forward the development of personalized medicine.