Reactivation of FMR1 gene expression is a promising strategy for fragile X syndrome therapy

• Published in: Gene therapy Vol. 27; no. 6; pp. 247 - 253
• Main Authors: Shitik, Ekaterina M., Velmiskina, Anastasia A., Dolskiy, Alexander A., Yudkin, Dmitry V.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2020; Nature Publishing Group
• Subjects: 631/1647/2017; 631/1647/2300; 631/208/200; 692/699/375; Aripiprazole; Autism; Biomedical and Life Sciences; Biomedicine; Cell Biology; Chromatin; Chromatin remodeling; Cytotoxicity; DNA methylation; Enzymes; Etiology; FMR1 gene; FMR1 protein; Fragile X syndrome; Gene Expression; Gene silencing; Gene Therapy; Genes; Genetic engineering; Genetic research; Health aspects; Human Genetics; Intellectual disabilities; Mental illness; Methylation; Nanotechnology; Review Article; Romidepsin; Vorinostat
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/s41434-020-0141-0

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.