Novel therapy for Fragile X syndrome

PROJECT SUMMARY 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. Lead optimization efforts in the phase 1 STTR portion of the work identified EPGN2036 as a candidate for pharmacological evaluation. This compound dose-dependently corrected behavioral deficits in FMR1 KO2 mice after oral administration. Moreover, EPGN2036 demonstrated target engagement in hippocampal lysates of FMR1 KO mice treated with the compound. In collaboration with Dr. Alysson Muotri at UCSD, we have started development of brain organoids derived from FXS patients to model the disease in 3D in the laboratory. Preliminary safety studies in rats indicate that EPGN2036 has sufficient safety margin to warrant further investigation. The goal of this phase 2 SBIR work is to characterize the preclinical efficacy of EPGN2036 using a translatable biomarker of drug efficacy, evaluate drug-drug interaction potential of leads, conduct focused back-up / follow-up discovery and assess safety of select leads to determine development potential. Recent work demonstrated that EEG measures in FMR1 KO mice are in excellent agreement with EEG signals of FXS patients and that EEG could be used as a biomarker predictive of early disease modulation. As such, we will evaluate the effect of EPGN2036 on both mouse FMR1 KO mouse EEG and FXS brain organoids. At the end of the grant period, we expect to be in a position to select a development candidate for initiation of IND-enabling studies and progression to phase 1 clinical trials in humans for assessment of safety and tolerability of EPGN2036 in normal healthy volunteers.