The main research lines concern the identification of therapies able to improve the severe cognitive disability that characterizes two neurodevelopmental disorders: CDKL5 disorder and Down Syndrome (DS). CDKL5 disorder is a rare, severe neurodevelopmental disorder that mostly affects girls. CDKL5 patients show a range of phenotypes including seizures, visual impairment, mental retardation and autism. Currently, there is no cure or effective treatment for CDKL5 disorder, and the mainstay of care for this disorder is support for the families. Therefore, identification of therapies for CDKL5 disorder will represent an important social challenge. The goal of this project is to identify therapies for CDKL5 disorder. Precisely, we aim to develop and evaluate the efficacy of therapeutic approaches targeting molecules affected by CDKL5 mutations in a Cdkl5 knockout mouse model. Treatment options will range from pharmacological drug therapies, to gene therapy, to an innovative “protein substitution therapy" that compensates for CDKL5 deficiency through administration of a recombinant protein produced in the laboratory. Ours preliminary results, suggest that a CDKL5 protein therapy could be indeed an effective therapeutic approach. Altogether, we deem that the approaches used in this project shall ensure achievement of substantial advances in the development of new interventions for this disorder. A second topic concerns the study of mechanisms underlying mental retardation in DS (trisomy 21), the most common genetic cause of mental retardation and autosomal aneuplodia compatible with postnatal survival. The study is aimed to clarify the possible causes underlying changes in neurogenesis during critical phases of brain development. Research is carried out in the Ts65dn mouse model of DS and in human fetuses. In an attempt to find effective treatments, possibly useful in humans, we are focusing on therapies that could enhance neuron production.