RNA splicing modifier is an emerging concept extending drug discovery beyond conventional protein-based R&D
Eukaryotic genes consist of multiple exons (coding sequences) interspersed with introns that undergo RNA splicing to join exons and form mature mRNA. In addition, various mRNAs are generated from a single gene by arranging exons into different combinations in a process called alternative splicing. It has been known that alternative splicing not only contributes to diverse proteome, but also promotes pathological conditions, such as certain cancers and rare diseases.
RNA splicing is regulated by both trans-acting factors and cis-acting regulatory elements. The trans-acting factors, including large spliceosome complex, interact with cis-acting regulatory elements to maintain correct exon recognition and splicing outcome. Therefore, mutations in trans-acting regulatory proteins and cis-acting regulatory elements give rise to various pathological conditions. For example, mutations in MET gene cause exon-skipping and generate MET gene lacking exon 14 (METexon14△). Since a key residue in exon 14 is critical for ubiquitin-mediated MET degradation, METexon14△ promotes proliferation of lung adenocarcinomas. In addition, decades of studies have shed light on the pathological alternative splicing as the causative factor of spinal muscular atrophy (SMA). Remarkably, risdiplam, the first orally active small-molecule RNA splicing modifier, was approved by FDA in 2020 for the treatment of SMA. Similarly, Novartis is running Phase 2 clinical trials to treat Huntington's Disease with its small-molecule RNA splicing modifier, branaplam.
Overall, RNA splicing modifier is an emerging concept extending drug discovery beyond conventional protein-based R&D. At ScinnoHub, we set forth into this vast but unexplored RNA territories with techniques in medicinal chemistry, cell and molecular biology, RNA biology, etc. in order to discover treatment with novel mechanism of action (MOA). The path is challenging, but the future is promising.