Histone Deacetylase and DNA Methylase Inhibitors in the Treatment of Fragile X Syndrome?

Fragile X syndrome (FXS), the most common inheritable form of mental retardation, is caused by expansion of a CGG‐repeat located in the 5′ untranslated region of the FMR1 (Fragile X Mental Retardation 1) gene. When the number of CGG repeats exceeds 200, the CpG‐rich promoter upstream of the repeats becomes methylated and associated with deacetylated histones. This is correlated with silencing of the FMR1 gene. While many patients show a complete silencing of the FMR1 gene, some patients do express low levels of mRNA. To reactivate or increase FMR1 gene expression we treated patient and normal cell lines with different histone deacetylase and DNA methylase inhibitors including 5‐aza‐2′‐deoxycytidine (5adC), valproic acid (VPA), zebularine, caffeine and hydralazine. Only 5adC was able to reactivate all of the totally silenced cell lines and increase the residual expression from partially silenced cells. VPA was able to reactivate one fibroblast cell line and increased the residual expression level in partially silenced cells. Zebularine, caffeine and hydralazine failed to show any effect on FMR1 gene expression. Decitabine is toxic, however VPA is already approved for long term use in children for treatment of epilepsy and bipolar disease. It may be useful to treat that subset of FXS patients with some residual FMR1 expression, particularly those with a seizure predisposition and depression.