From Gene to Hope: Rett Syndrome and the Rise of Molecular Therapies.

Abstract

Rett syndrome is a rare X-linked neurodevelopmental disorder caused by mutations in MECP2, a gene critical for neuronal function, chromatin organization, and synaptic plasticity. After a period of apparently normal early development, individuals with Rett syndrome experience rapid regression followed by lifelong neurological impairment. Notably, preclinical studies have shown that restoration of MeCP2 expression can reverse established symptoms in adult mice, positioning Rett syndrome as a promising target for molecular therapies. However, MECP2 is extremely dosage sensitive and both insufficient and excessive expression are harmful, creating a narrow therapeutic window and a major challenge for treatment design. This review examines the evolving landscape of gene- and RNA-based therapies for Rett syndrome, with a focus on strategies that enable precise MeCP2 replacement, dosage control, and widespread central nervous system delivery. We discuss clinical-stage adeno-associated virus gene replacement programs, including TSHA-102 and NGN-401, highlighting their vector designs, regulatory elements, delivery approaches, and emerging clinical data. Advances in adeno-associated virus capsid engineering and vector optimization aimed at improving neuronal targeting while minimizing peripheral exposure and immune toxicity are also reviewed. Beyond gene supplementation, we explore approaches that restore endogenous MECP2 regulation, such as reactivation of the inactive X chromosome, as well as DNA and RNA editing strategies. Collectively, these advances reflect a shift toward precision-regulated therapies for Rett syndrome that may provide a model for treating other dosage-sensitive neurodevelopmental disorders.