The human X-chromosome harbors only 4% of our genome but carries over 20% of genes associated with intellectual disability. Given that they inherit only one X-chromosome, males are more frequently affected by X-linked neurodevelopmental genetic disorders than females. However, despite inheriting two X-chromosomes, females can also be affected because X-chromosome inactivation enables only one of two X-chromosomes to be expressed per cell. For Rett syndrome and similar X-linked disorders affecting females, disease-specific treatments have remained elusive. However, a cure may be found within their own cells because every sick cell carries a healthy copy of the affected gene on the inactive X (Xi). Therefore, selective Xi reactivation may be a viable approach that would address the root cause of various X-linked disorders. Here, we discuss Rett syndrome and compare current approaches in the pharmaceutical pipeline to restore MECP2 function. We then focus on Xi reactivation and review available methods, lessons learned, and future directions.
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