Restoration of FMR1 and FMRP levels by targeting FMR1-217 with ASOs. In typically developing individuals, the FMR1 gene, which contains fewer than 55 CGG repeats and 17 exons, is transcribed and translated to produce the FMRP protein. In FXS, CGG triplets expand to 200 or more, leading to FMR1 gene silencing. In the many cases where the gene is not fully silenced, the repeat expansion results in FMR1 missplicing, producing FMR1-217 in various cells and tissues, including lymphoblastoid cell lines (LCLs), fibroblasts, leukocytes, and brain tissues. The FMR1-217 splicing isoform is composed of exon 1 and a pseudo-exon derived from intron 1. Treatment with ASOs targeting the FMR1-217 pseudo-exon region reduces the accumulation of the FMR1-217 isoform, rescues the production of full-length FMR1 RNA, and restores FMRP protein. Created with BioRender.com.
