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.
Public Health Relevance Statement: Narrative The objective of this work is to validate p70S6 kinase pre-clinically as a target for the treatment of Fragile X syndrome, a significant cause of intellectual disability.
Project Terms: Alpha Cell; Animal Model; autism spectrum disorder; Autistic Disorder; base; Behavioral; Biochemical; Biological Assay; Brain; Cells; Cerebrum; Characteristics; Chemistry; Clinical Trials; Computer Simulation; CYP2D6 gene; CYP3A4 gene; Dendritic Spines; design; Development; Disease; Disease model; Dose; drug candidate; drug development; Drug Interactions; Drug Kinetics; efficacy evaluation; efficacy testing; Enzymes; epigen; Exhibits; FMR1; Fragile X Syndrome; Genetic; Goals; High Pressure Liquid Chromatography; Homeostasis; Human; Impaired cognition; Impairment; improved; In Vitro; in vivo; induced pluripotent stem cell; Inherited; inhibitor/antagonist; innovation; Intellectual functioning disability; Intervention; Kinetics; Laboratories; Lead; Learning; Ligands; Liver Microsomes; Long-Term Depression; meetings; Memory; Modeling; Molecular Abnormality; Morphology; mouse model; multi-electrode arrays; Mus; Neurons; novel; novel therapeutics; object recognition; Oral; Oral Administration; Organoids; Outcome; Pathway Analysis; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; pharmacophore; Phase; Phenotype; Phosphorylation; Phosphotransferases; Play; pre-clinical; Preclinical Drug Evaluation; prevent; Problem behavior; programs; Property; Protein Biosynthesis; Proteins; Protocols documentation; Pyrimidine; receptor; Research; Ribosomal Protein S6 Kinase; Ribosomes; Risk; Role; scaffold; Series; Signal Transduction; Small Business Innovation Research Grant; small molecule; small molecule inhibitor; Social Interaction; Solubility; Structural Protein; Synapses; synaptogenesis; Technology; Testing; Therapeutic; Translations; treatment strategy; Vertebral column; Weight Gain; Work
