Challenge: Brain disorders such as autism, major depressive disorder and Alzheimer’s disease are among the greatest medical challenges of our era. Many drugs targeting the central nervous system (CNS) have been developed to modulate G-protein coupled receptors, ion channels or transporters, with mitigated success. There remains a shortage of disease-relevant targets that can be harnessed for drug discovery to treat the onset and progression of brain disorders/diseases.

Solution: This project focused on RNA-binding proteins (RBPs) as untapped therapeutic targets because of their important role in the brain. Members of the RBP family provide powerful post-transcriptional control over cellular phenotype. The team’s goal was to develop a first-in-kind sensitive, adaptable, and validated high–throughput–screening (HTS) platform called ShARP for Screenable Assays for RNA-binding Proteins, based on the use of specific untranslated regions (UTRs) that are targeted by RBPs to modulate recruitment of messenger RNA to ribosomes during protein synthesis. Screening cell-based assays were developed for one such RBP, FXR1, though not compatible with HTS yet. Novel 5’ and 3’-UTR reporter libraries and associated RBP sequence databases were generated and are available for RBP screening. The platform was tested in partnership with Simon Fraser University on FXR1, a demonstration that this RBP could be targeted and its activity inhibited or activated using small pharmacological molecules. 

Achievements: A first platform to screen new CNS-relevant drugs that target the RBP family was elaborated and tested, opening the path for RBPs to be considered and validated as promising therapeutic targets in neurological diseases.