Sphingolipid metabolic imbalance in murine and hiPSC RTT models: development of a drug repurposing-based therapy

Rett syndrome (RTT) is a neurodevelopmental disease characterized by severe motor and cognitive disabilities, mainly caused by abnormalities in MeCP2, a protein crucial for brain functioning. The mechanism by which MeCP2 defects lead to RTT symptoms has not yet been fully clarified and no effective cure is available so far, but only palliative treatments. Studies performed in RTT mouse models underlined the potential reversibility of the disease, paving the way for the design of therapeutic strategies. We found, in the brain of RTT mouse models and in mouse and human (patient-specific iPSC-derived neurons) neuronal cells, altered metabolism of sphingolipids, molecules important for neuronal functioning. Moreover, pharmacological treatments with two molecules similar to sphingosine, a basic component of sphingolipids, attenuated RTT phenotype in mice lacking MeCP2. The main goal of this proposal is to fully characterize perturbations of sphingolipid metabolism in both murine (in vivo) and human (in vitro) RTT models genetically more similar to RTT patients, and evaluate the efficacy of a treatment with the sphingosine analog Ozanimod - a next-generation drug used for the treatment of other neurological disorders - in correcting the sphingolipid metabolic defect and RTT-related phenotypes. The obtained results, potentially, will increase the knowledge of molecular mechanisms underlying RTT pathogenesis and will open new perspectives for the set-up of therapeutic protocols for RTT patients.