Fragile X syndrome (FXS) is the most common form of intellectual disability and autism spectrum disorder and is caused by CGG repeat expansion in the promoter region of the FMR1 gene, which encodes fragile X mental retardation protein. This event leads to gene silencing and the loss of gene products through DNA methylation and chromatin remodeling. Due to the pathogenesis of FXS, targeted, symptomatic, and etiological approaches have been developed for its treatment. Despite their rapid development, symptomatic and targeted treatment approaches have numerous limitations; etiological approaches have the greatest potential because they affect the main causes of transcriptional silencing. In this review, we consider three potential etiological therapeutic methods that affect the reactivation of FMR1 gene expression: treatment with inhibitors of chromatin-modifying enzymes, the use of noncoding RNAs and the application of gene therapy. Inhibitors of chromatin-modifying enzymes are not clinically applicable because of their low reactivity and high cytotoxicity, and noncoding RNAs are currently only under study. Thus, we discuss gene therapy as the most promising approach for treating FXS in the near future.
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The reported study was funded by the Russian Foundation for Basic Research (RFBR) under research project 18-29-07033.
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Shitik, E.M., Velmiskina, A.A., Dolskiy, A.A. et al. Reactivation of FMR1 gene expression is a promising strategy for fragile X syndrome therapy. Gene Ther 27, 247–253 (2020). https://doi.org/10.1038/s41434-020-0141-0