Pharmacological reactivation of inactive genes: The fragile X experience

The present review on the pharmacological reactivation of inactive genes fo cuses on our experience with the fragile X syndrome. The fragile X syndrome of mental retardation is the prototype of a series of inherited neurologic al disorders caused by abnormal expansion of repeated trinucleotide sequenc es embedded in various genes. In a number of these disorders, such as Hunti ngton disease and several forms of spinocerebellar ataxias, the expanded CA G repeat is translated, resulting in a polyglutamine-containing protein tha t indirectly causes neurodegeneration. On the contrary, in the fragile X sy ndrome, the expanded CGG repeat is contained in the regulatory region of th e FMR1 gene and causes transcriptional inactivation. The mutation spares th e coding region of the FMR1 gene, which potentially would allow synthesis o f a normal protein if transcription could be restored. This prompted us to try and reactivate the gene function with different pharmacological regimen s. We discuss our successful results with DNA demethylating and histone hyp eracetylating drugs and their implications for future treatments of the fra gile X syndrome. (C) 2001 Elsevier Science Inc.