Rett syndrome (RTT), which is caused by loss-of-function mutations in the gene MECP2, is the leading cause of complex autism spectrum disorders (ASD). Children with RTT experience partial or even complete loss of previously acquired motor and communication skills and need help for most daily activities, which severely impacts not only the children but also their families. There is no cure for RTT, and current therapies have no effect on the neuropathological processes underlying the condition.

Gene therapy has emerged as a promising approach for addressing the underlying pathogenic mutations responsible for RTT. For example, it was recently demonstrated that delivering a healthy copy of the MECP2 gene by an adeno-associated virus (AAV) vector could not only restore MECP2 expression in vivo but also improve symptoms in mouse models of RTT¹. However, this approach faces critical challenges for implementation, such as the need to precisely modulate the expression of the MECP2 transgene to prevent complications derived from its overproduction, thus highlighting the need for therapies that can permanently correct the underlying genetic defects causing RTT.

To address these problems, Pablo Perez-Pinera and Thomas Gaj have created a targeted gene therapy that utilizes DNA base editing technology to directly correct mutations in vivo. In preliminary studies, they have demonstrated that this promising technology could efficiently correct several mutations in MECP2 that are responsible for RTT. Based on these results, they hypothesize that base editing can be used to effectively correct mutations in MECP2 in vivo and revert RTT phenotypes in a mouse model of the condition. This project will thus provide key preclinical data on the use of base editing technology for treating RTT and will be a critical step in advancing a therapy for this condition and other genetic neurodevelopmental conditions.