With a 2-year, $90,000 grant from FRAXA Research Foundation, Drs. Matthew Disney and Wang-Yong Yang at Scripps Research Institute worked to correct the underlying problem in Fragile X: the silencing of the Fragile X gene (FMR1) and the resulting lack of FMRP (Fragile X Mental Retardation Protein). Their approach was to use novel small molecules to target the abnormal CGG repeats which silence the FMR1 gene.
Fragile X is a “loss-of-function” disorder: expression of FMRP is silenced by methylation of the expanded CGG area immediately in front of the FMR1 gene. The FMR1 gene itself could work normally, however, if the CGG repeat effects were corrected. Dr. Disney aimed to design small molecules that target the expanded CGG repeat area in Fragile X and thereby increase production of FMRP. If successful, these studies would identify first-in-class lead compounds to treat the root cause of Fragile X.
Drs. Disney and Yang identified small molecules targeting CGG expanded RNA repeats (r(CGG)exp). Because it was hypothesized that the formation of r(CGG)exp and protein (e.g. dicer) complex is an initiation step of RNAi-mediated DNA methylation causing silence of FMRP in FXS pathogenic mechanism, the inhibition of the complex by small molecules could prevent the DNA methylation as well as provide a chemical probe to further study this as a mechanism of disease.
They developed a library of modularly assembled small molecules to target r(CGG)exp with high affinity and selectivity. To evaluate inhibitory activity of small molecules, they used a well-established FXTAS model forming similar r(CGG)exp -Protein complex in its mechanism. Optimized compounds potently inhibit the formation of r(CGG)exp-protein complex and the compounds modulate toxicity in a FXTAS model cell line. The optimized compounds were tested to see if they can improve defects in FXS patient-derived cell lines.