Advances in Molecular Mechanisms and Therapies for Rett Syndrome: From MECP2 Dysfunction to Small-Molecule Interventions

Department of Human Biology, University of Toronto, Toronto, Canada

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Abstract

Rett syndrome (RTT) is a rare and severe neurodevelopmental disorder primarily affecting females, caused by pathogenic mutations in the MECP2 gene, which disrupts neuronal transcriptional regulation and synaptic function. Understanding the molecular basis of MECP2dysfunction has catalyzed the development of targeted therapies aiming to restore neuronal homeostasis. This paper integrates current knowledge of MECP2 structure, function and mutation-driven pathology, highlighting how disruptions in its methyl-CpG-binding, transcriptional repression, and C-terminal domains lead to widespread neuronal deficits. This study summarizes emerging therapeutic strategies, focusing on small-molecule approaches including protein stabilization, readthrough compounds, synaptic and neurotrophic pathway modulation and epigenetic regulation. Notably, trofinetide, the first FDA-approved therapy, underscores the potential of translational progress while revealing limitations in delivery and efficacy. This paper further discusses cutting-edge drug discovery pipelines leveraging iPSC-derived neurons and organoids, and explores future solutions such as nanocarriers, PROTACs and precision medicine approaches. By bridging molecular mechanisms to therapeutic innovation, this review underscores the promise of rationally designed treatments to move beyond symptomatic management toward disease modification in RTT.