Pharmacological reactivation of inactive genes: the fragile X experience

The present review on the pharmacological reactivation of inactive genes focuses on our experience with the fragile X syndrome. The fragile X syndrome of mental retardation is the prototype of a series of inherited neurological disorders caused by abnormal expansion of repeated trinucleotide sequences embedded in various genes. In a number of these disorders, such as Huntington disease and several forms of spinocerebellar ataxias, the expanded CAG repeat is translated, resulting in a polyglutamine-containing protein that indirectly causes neurodegeneration. On the contrary, in the fragile X syndrome, the expanded CGG repeat is contained in the regulatory region of the FMR1 gene and causes transcriptional inactivation. The mutation spares the coding region of the FMR1 gene, which potentially would allow synthesis of a normal protein if transcription could be restored. This prompted us to try and reactivate the gene function with different pharmacological regimens. We discuss our successful results with DNA demethylating and histone hyperacetylating drugs and their implications for future treatments of the fragile X syndrome.