Evidence-based approach to treat hyperexcitability in Rett syndrome through splicing modulation

In the panorama of monogenic neurodevelopmental disorders, Rett's Syndrome stands at a level of extreme severity. More than 90% of clinical cases show mutations in a single gene, Mecp2. Each endophenotype of this rare disease, which affects one in 7000 girls aged 7 to 18 months, associates criticality and suffering, starting with the peculiar regression in young patients’ just acquired skills: from language to posture, from sociability to thought. The clinical features are further worsened by prominent anxiety crises and severe epileptic seizures often refractory to anticonvulsant medications. These aspects depict a neurological picture of decompensation between glutamate excitability and nervous inhibition, an aspect that can also be observed in animal models of the disease. Through this project, we propose to explore a new strategy to counteract the excessive glutamatergic excitability of the animal model of Rett syndrome. In this regard, we will test a newly developed drug aimed at decreasing the activity of a protein specifically expressed in the mammalian brain, which we have characterized over the years as a positive modulator of glutamate excitability. This factor, called neuroLSD1, is aberrantly overexpressed in murine models generated by deletion of the Mecp2 gene. The drug, which due to its molecular characteristics can also be used in humans, adopts a strategy that has already been proven effective in the treatment of other monogenic neurodevelopmental diseases.