Novel therapy for Fragile X syndrome

PROJECT SUMMARY Fragile X syndromeFXSis the most common inheritable form of cognitive impairment and the leading known genetic cause of autismFXS is caused by the loss of expression of the fragile X mental retardation proteinFMRPA major challenge for FXS research is to develop treatment strategies that improve the intellectual capabilities of patientsDysregulated protein synthesis is widely accepted as a core molecular abnormality associated with FXSBecause neuronal protein synthesis is critical for learning and memoryaltered synaptic translation is considered a major contributor to the intellectual deficits seen in FXSCurrently available pharmacological intervention strategies for FXS primarily treat behavioral problems and have focused largely on targets upstream of translational control to normalize FXS related phenotypesWe have identified a specific target that is a common downstream effector of both mTORCand ERK signaling and plays a direct role in regulating translationGenetic deletion of the target in an animal model of FXS corrected exaggerated protein synthesis and other biochemicalneuroanatomical and behavioral abnormalities associated with FXSThese results suggest a strategy for developing a disease modifying therapeutic for FXSBy using a rational design approach that combines structural protein information and optimal ADME propertieswe have discovered a novel series of potent inhibitorsEpigen has developed specific and drug like small molecule inhibitors to this targetas exemplified by lead compound EPGNWe have teamed up with DrAlysson Muotri s laboratories at UCSD to propose a novel discovery paradigm for effective drug candidate compounds for FXS by using newly developed cerebral organoidsormini brainsto model the disease inD in the laboratoryThe goal of this phaseSBIR work is to conduct focused lead optimization of our newly discovered series of novel inhibitors as agents to treat FXSIn this worknew compounds will be identified utilizing our assay cascade combining in vitro receptor pharmacologyADME assays and mouse pharmacokinetics to selectadvanced lead moleculeswhich will be evaluated in a human FXSmini brainThe best advanced lead identified will be evaluated in a mouse model of FXS for biochemical and neuroanatomical outcomesThis work will set the stage for detailed in vivo pharmacology assessment and IND enabling studies in the phaseSBIROur study will open up a new avenue of target specific drug development for Autism Spectrum Disorders such as FXS