RTTOPHAGY · "Investigating autophagy enhancement as a therapeutic approach for the treatment of Rett syndrome.""""

"Investigating autophagy enhancement as a therapeutic approach for the treatment of Rett syndrome."

Mutations in the X-linked MECP2 gene cause Rett syndrome (RTT), a devastating neurological disorder which represents a first cause of severe intellectual disability in 1 out 10.000 girls worldwide. Affected females have an apparently normal development until 6-18 months of life when a regression phase begins, the purposeful use of hands is substituted by involuntary stereotyped movement, and all acquired motor and cognitive skills are lost. To date, there is no cure for Rett syndrome and current treatments are usually directed to alleviate secondary symptoms such as epilepsy, irritability and insomnia. However, experimental evidence obtained in a mouse model of the disease, in which Mecp2 is missing, suggested that the disease is reversible. In particular, by gene therapy approach it was demonstrated that re-activation of Mecp2 gene reverted the majority of RTT symptoms. Unfortunately, this approach is not applicable to human being for many reasons but set it up the proof of principle that a cure is possible. From there, several researchers exploited novel therapeutic strategy for RTT especially based on pharmacological approach aimed at modulating MeCP2-downstream pathways. Autophagy is a catabolic process that is crucial for maintaining cellular homeostasis, energy balancing and ensuring quality control inside the cells, especially in neurons that are post-mitotic cell and metabolically very active. Interestingly, defective autophagy has been recently recognized in fibroblasts of RTT patients and in the cerebellum of Mecp2-null mice, however it was not further investigated in the central nervous system. Thus, this project aimed at the pinpointing the molecular deficits responsible for altered autophagy in RTT and determining a strategy could alleviate the developmental defects in cellular and animal models of the disease. - Specifically, the characterization of the autophagy signal in brain cortices of RTT mouse model led to the identification an impairment of autophagy flux and a downregulation of a key regulator of autophagy biogenesis (objective 1). - Given that autophagy flux is blocked and since that autophagy enhancement has been demonstrated to be effective for several neurological disorders, modulation of autophagy flux in cultured cortical neurons revealed an amelioration of RTT neuronal phenotypes (objective 2). - Finally, it was demonstrated in a pre-clinical study the pharmacological potential of promoting autophagy. Mice model of the disease were treated with an autophagy enhancer which improved spontaneous and non-spontaneous motor skills, positively acted on explorative behaviour and more importantly ameliorated the general conditions and the survival of mutant mice (objective 3). Overall all these data reinforced the hypothesis that autophagy dysfunction could contribute to RTT manifestations and that its modulation could be a good strategy to treat other neurodevelopmental disorders. The social value of this project is twofold: 1) From a clinical perspective it will lead the way for further validation of a novel therapeutic option for RTT syndrome, which can currently benefit from very few treatments that are only symptomatic. Importantly, several modulators of autophagy are already FDA-approved drugs for other diseases, thus making future repurposing easily feasible. 2) Defects in autophagic flux have been only scarcely investigated in neurodevelopmental disorders in general and RTT in particular. Thus, from the scientific perspective, this proposal led to a better comprehension of the basic pathological mechanisms underlying the disease.

Data: CORDIS, © European Union