There is no cure for RTT currently, thus it represents a major unmet medical need to allow proper neural development and ensure higher quality of life for individuals with Rett Syndrome and their families. Building from a strong foundational body of knowledge in the visual system and our seminal work on critical period plasticity mechanisms in primary visual cortex, we were the first to establish a clear sensory phenotype that faithfully tracks the progression of Rett syndrome (RTT) across species. Specifically, Visual Evoked Potentials (VEP) and spontaneous pupillary fluctuations emerged as quantitative and non-invasive biomarkers to track both the regression and potential treatment efficacy in mice that could be effectively translated to human patients. Consequently, sensory event-related potentials, further expanded to other modalities like hearing, are now part of the NIH Natural History Study for Rett Syndrome and related disorders.

Growing evidence in mouse models of RTT point to an accelerated hyper-maturation of fast-spiking, large basket parvalbumin-positive (PV+) interneurons as one of the first alterations of cortical circuitry before the onset of RTT phenotypes and start of regression. Chronic pharmacological treatment with ketamine preferentially dampening NMDA receptor activation in PV+ cells also ameliorates RTT phenotype across multiple domains. Together, these results support the hypothesis that PV circuits may represent a target for therapeutic intervention in RTT. Developing an intervention that modulates PV+ circuit function in patients thus represents a significant advance toward an effective therapy.

In this context, we are testing the hypothesis that the choroid plexus, and specifically OTX2, could serve as a therapeutic target for RTT, paving the way for future clinical studies in RTT patients. From a practical perspective on therapeutic strategies, it is important to note that the choroid plexus is easily accessible via the circulatory system and has already been exploited as a target for gene therapy in pediatric neurological diseases. Since the normal flow of cerebrospinal fluid transports molecules secreted by the choroid plexus through the ventricular system to the brain parenchyma, our data suggest that a single administration of safe AAV vectors could make gene therapy via the choroid plexus a promising approach.