Therapeutic strategies for fragile X syndrome and implications for other gene-silencing disorders

Gene-silencing disorders, of which fragile X syndrome (FXS) is the most prevalent, are diseases caused by a blockade of gene transcription, usually due to DNA hypermethylation. FXS is a common form of inherited intellectual disability and autism. Unlike most hereditary diseases driven by mutations within the protein-coding region of a gene, FXS is caused by a trinucleotide expansion in the 5′-untranslated region of the FMR1 gene, leading to hypermethylation and transcriptional silencing. Modeling FXS with human pluripotent stem cells offers a clinically relevant platform to study disease mechanisms and explore potential therapies through reactivating FMR1 expression by genetic and epigenetic means or through drug screening. This Perspective reviews the various cellular models and therapeutic strategies proposed over the past decade, highlighting their potential to advance the treatment of FXS. We also discuss the benefits and challenges of gene activation therapies, drawing comparisons with other gene-silencing disorders, including imprinting diseases and X-linked disorders.