Trinucleotide Repeat Expansion and RNA Dysregulation in Fragile X Syndrome: Emerging Therapeutic Approaches

Fragile X syndrome (FXS) is characterized by intellectual impairment caused by CGG repeat expansion in the gene. When repeats exceed 200, they induce DNA methylation of the promoter and the repeat region, resulting in transcriptional silencing of the gene and the subsequent loss of FMRP protein. In the past decade or so, research has focused on the role of FMRP as an RNA-binding protein involved in translation inhibition in the brain in FXS model mice, particularly by slowing or stalling ribosome translocation on mRNA. More recent advances have shown that FMRP has a profound role in RNA splicing, at least in some cases by modulating the translation of splicing factor mRNAs. In a surprise, the human gene is transcribed in most cases even with a full CGG expansion. However, much of the that is produced is misspliced, which can be corrected by splice-switching antisense oligonucleotide (ASO) administration. Other recent findings suggest that inhibition of multiple kinases can demethylate the gene and induce the formation of an R-loop in the CGG repeat region, leading to contraction of the repeat and FMRP restoration. These insights are paving the way for possible future therapeutic approaches for this disorder. We highlight the importance of FMRP restoration by ASO-mediated splice switching or CGG repeat modulation as key advances that may lead to successful treatments for FXS.