A mixed modality approach towards Xi reactivation for Rett syndrome and other X-linked disorders

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Significance The X-chromosome harbors hundreds of disease genes, a subset of which gives rise to neurodevelopmental disorders such as Rett syndrome (RTT), fragile X syndrome, and CDKL5 syndrome. There is presently no disease-specific treatment. Here, we work toward a therapeutic program based on reactivation of the silent X chromosome to restore expression of the missing protein. We develop a mixed modality approach that combines a small-molecule inhibitor of DNA methylation and an antisense oligonucleotide against Xist RNA. This combination achieves up to 30,000-fold methyl-CpG binding protein 2 upregulation in cultured cells. In vivo modeling using a conditional Xist knockout and 5-aza-2′-deoxycytidine recapitulates inactive X reactivation. These findings provide proof of concept for the mixed modality approach to treat X-linked disorders, including RTT.

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