FMR1 knockout mouse models 103,104 and post-mortem brain tissue 105101,102. Halevy et al. have also assessed and partially reversed the abnormal transcriptional signatures that may underlie the abnormalities 106. Interestingly these findings imply early neurodedevelopmental alterations, prior to synaptogenesis, although more studies are needed to understand in depth the pathophysiology of these defects. Four groups have used FXS 107–109110 patient-derived hiPSCs to create proof of concept high-throughput drug discovery systems, though unfortunately the sensitivity and robustness of these screens is still poor and will require significant work. Promisingly though, Park et al. 111 used a genomic engineering technique known as CRISPR/Cas (Box 3) to ablate CGG repeats in FXS patient-derived hiPSCs and thus restore expression of FMR1 mRNA and consequently FMRP protein. Unfortunately, they did not assess for any phenotypic reversal in this study.
