Recent advances in epigenetic therapeutics for Rett syndrome: from mechanisms to clinical trials

Rett syndrome (RTT) stands at the forefront of the genetic therapy revolution. This severe X-linked neurodevelopmental disorder, primarily caused by mutations in the MECP2 gene, was historically considered a static condition but is now recognized as a potentially reversible neurodevelopmental disorder. This review synthesizes recent breakthroughs in our understanding of MeCP2's role in chromatin architecture, including its involvement in liquid-liquid phase separation (LLPS). We critically examine the transition from conventional symptom management to precision epigenetic therapeutics. Key advances discussed include next-generation gene replacement strategies with autoregulatory control to prevent toxicity, programmable epigenetic editing (e.g., CRISPR-off/on) to correct MECP2 expression endogenously, and novel approaches for X-chromosome reactivation (XCI). Furthermore, we propose a stratified therapeutic framework (genotype-guided therapies) based on specific mutation types. Finally, we analyze data from ongoing clinical trials and highlight the remaining hurdles-such as delivery efficiency, immunogenicity, and the urgent need for objective biomarkers-that must be overcome to translate these epigenetic innovations into a cure.