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Novel therapy for Fragile X syndrome

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44MH115529-03
Agency Tracking Number: R44MH115529
Amount: $2,206,174.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: 101
Solicitation Number: PA19-272
Solicitation Year: 2019
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-04-15
Award End Date (Contract End Date): 2023-03-31
Small Business Information
San Diego, CA 92121-2734
United States
DUNS: 963248807
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (619) 917-0639
Business Contact
Phone: (858) 337-1801
Research Institution

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.

* Information listed above is at the time of submission. *

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