Rett syndrome: advances in Understanding MeCP2 function, potential gene therapies, and public health implications

Rett syndrome (RTT) is a devastating X-linked neurodevelopmental disorder, primarily affecting females, caused by mutations in the MECP2 gene. After a brief period of normal development, affected children experience rapid regression, losing motor and communication skills. Core features include microcephaly, seizures, stereotypic hand movements, and breathing abnormalities. While rooted in neurological dysfunction, growing evidence reveals RTT's widespread impact extends beyond the brain, implicating MECP2 in multisystem disruption. This review provides a comprehensive overview of RTT's genetic and neuropathological basis and highlights the significant advances in gene therapy to restore MECP2 function. Notably, adeno-associated virus (AAV)-based approaches have shown promise in preclinical models by improving survival and motor function in RTT mouse models. Recent advancements in AAV vector design have optimized targeted delivery to neurons and enhanced the regulation of MECP2 expression to prevent overexpression-related toxicity. Additionally, nanoparticle-based delivery systems are being explored as non-viral alternatives, offering the potential for improved targeting and safety. These advancements in gene therapy hold promise for RTT, bringing the possibility of effective targeted treatments closer to clinical application. As research continues to unravel RTT's complex pathophysiology, emerging therapies may offer new hope for improving patient outcomes and quality of life.