RNA targeting for the treatment of Fragile-X syndrome: target validation toward future drug discovery – TREAT-X

Proteins serve as primary targets for most pharmaceutical interventions, yet the therapeutic focus on disease-related proteins, which represent a mere fraction of the human genome, limits the scope of medicinal chemistry. Expanding the target landscape to include coding and non-coding RNAs offers a promising avenue to address incurable diseases. This project aims to validate new RNA targets to alleviate symptoms associated with neurodevelopmental disorders, such as fragile X syndrome (FXS), through the use of small molecules targeting deregulated mRNA transcripts. FXS, the leading monogenetic cause of Autism Spectrum Disorders (ASD), lacks effective treatments, necessitating urgent therapeutic advancements. FXS results from the absence of Fragile X Messenger Ribonucleoprotein 1 (FMRP), an RNA-binding protein crucial for synaptic protein translation modulation. Through comprehensive molecular analysis, numerous mRNA targets of FMRP, characterized by G-rich sequences prone to forming G-quadruplexes (G4s), have been identified. The absence of FMRP in FXS leads to dysregulation of these G4-containing mRNAs, contributing to disease pathology. Leveraging a cell model with reduced FMRP expression, a phenotypic screening identified potential therapeutic compounds capable of rescuing aberrant neuronal differentiation. This project aims to validate RNAs as therapeutic targets for FXS and develop RNA ligands to stabilize these structures, mimicking FMRP's physiological role and restoring translation inhibition. Key objectives include validating mRNA targets, optimizing compounds for enhanced potency and safety, evaluating effects on translation regulation, and assessing biological activity in FXS cellular models. This innovative strategy holds promise for developing novel treatments and chemical tools to deepen understanding of FXS pathophysiology.