Fragile X syndrome (FXS) is the most common inheritable form of cognitive impairment and the leading known genetic cause of autism. FXS is caused by the loss of expression of the fragile X mental retardation protein (FMRP). A major challenge for FXS research is to develop treatment strategies that improve the intellectual capabilities of patients. Dysregulated protein synthesis is widely accepted as a core molecular abnormality associated with FXS. Because neuronal protein synthesis is critical for learning and memory, altered synaptic translation is considered a major contributor to the intellectual deficits seen in FXS. Currently available pharmacological intervention strategies for FXS primarily treat behavioral problems and have focused largely on targets upstream of translational control to normalize FXS-related phenotypes. We have identified a specific target that is a common downstream effector of both mTORC1 and ERK signaling and plays a direct role in regulating translation. Genetic deletion of the target in an animal model of FXS corrected exaggerated protein synthesis and other biochemical, neuroanatomical and behavioral abnormalities associated with FXS. These results suggest a strategy for developing a disease modifying therapeutic for FXS. By using a rational design approach that combines structural protein information and optimal ADME properties, we have discovered a novel series of potent inhibitors. Epigen has developed specific and drug-like small molecule inhibitors to this target, as exemplified by lead compound EPGN1370. We have teamed up with Dr. Alysson Muotri's laboratories at UCSD to propose a novel discovery paradigm for effective drug candidate compounds for FXS by using newly developed cerebral organoids, or ?mini-brains? to model the disease in 3D in the laboratory. The goal of this phase 1 SBIR work is to conduct focused lead optimization of our newly discovered series of novel inhibitors as agents to treat FXS. In this work, new compounds will be identified utilizing our assay cascade combining in vitro receptor pharmacology, ADME assays and mouse pharmacokinetics to select 1-3 advanced lead molecules, which will be evaluated in a human FXS ?mini-brain?. The best advanced lead identified will be evaluated in a mouse model of FXS for biochemical and neuroanatomical outcomes. This work will set the stage for detailed in vivo pharmacology assessment and IND-enabling studies in the phase 2 SBIR. Our study will open up a new avenue of target-specific drug development for Autism Spectrum Disorders such as FXS.
