Matthew Disney, PhD — Scripps Research Institute, FL

Design of small molecules to target r(CGG) expansions as a therapeutic option for Fragile X Syndrome

Matthew Disney, PhD, at Scripps Research Institute, FLwith Wang-Yong Yang, PhD
Co-Principal Investigator

FRAXA Awards:
$45,000 in 2013
$45,000 in 2012

Dr. Disney’s lab is working to correct the underlying problem in Fragile X: the silencing of the Fragile X gene (FMR1) and the resultant lack of FMRP (Fragile X Mental Retardation Protein). Their approach is to use novel small molecules to target the abnormal CGG repeats before 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 aims to design small molecules that target the expanded CGG repeat area in Fragile X and thereby increase production of FMRP. If successful, these studies will identify first-in-class lead compounds to treat the root cause of Fragile X.

Dr. Disney’s work is in early stages of drug development for a targeted treatment for Fragile X. For more information about the small molecule approach as potential drug therapy for Fragile X, see the SMaRT Therapeutics drug pipeline.

2013 program project grant:
Project Overview
Design of small molecules to target r(CGG) expansions as a therapeutic option for Fragile X Syndrome

Wang pic 2013

by Wang-Yong Yang, PhD, 5/31/2013

We are identifying small molecules targeting CGG expanded RNA repeats (r(CGG)exp). Because it is 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.

We 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, we 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.

These optimized compounds are being tested if they can improve defects in FXS patient-derived cell lines.