PLX110487

GSE97077: Xi-reactivation: A mixed modality approach to MECP2 restoration for Rett Syndrome and other X-linked disorders

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

The X-chromosome harbors hundreds of disease genes whose associated diseases predominantly affect males. However, a subset including neurodevelopmental disorders, Rett, Fragile X, and CDKL5 Syndromes also affects females. These disorders lack disease-specific treatment. Because female cells carry two X-chromosomes, an emerging treatment strategy has been to reawaken the healthy allele on the inactive X (Xi). Here we focus on MECP2 restoration for Rett Syndrome and combinatorially target factors in the interactome of Xist, the noncoding RNA responsible for X-inactivation. We identify a mixed modality approach combining an Xist antisense oligonucleotide and a small molecule inhibitor of DNA methylation, which together achieve 30,000-fold MECP2 upregulation from the Xi in cultured cells. Combining a brain-specific genetic Xist ablation with short-term Aza treatment models the synergy in vivo without evident toxicity. The Xi is selectively reactivated. These experiments provide proof of concept for a mixed modality approach for treating X-linked disorders in females. SOURCE: Chen-Yu Wang (cywang@molbio.mgh.harvard.edu) - Jeannie T. Lee Massachusetts General Hospital