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Neurodevelopmental diseases such as intellectual disability and autism spectrum disorders remain difficult to treat because the underlying mechanisms are largely unknown. What’s more, it is almost impossible to experimentally study these diseases in humans at the cellular level, given the relative inaccessibility of live human neuronal material. In this project, Pierre Vanderhaeghen and his team will focus on several important orphan neurodevelopment diseases of genetic origin using an innovative model of human neuronal development in a living organism: following xenotransplantation in the mouse brain. This is a highly interdisciplinary project, with potentially high impact for our basic knowledge of human brain function and translation to understand and treat orphan diseases. It will rely on the synergistic combination of human clinical genetics, pluripotent stem cell technologies, brain xenotransplantation, combined with neuronal cell biology, electrophysiology and in vivo multiphoton microscopy. Specifically, the team will test the hypothesis that the rate of maturation that characterizes human neuron development in the cortex is abnormal in these diseases, thereby revealing a novel mechanism that may make the human brain uniquely sensitive to developmental defects. Moreover and importantly, this innovative model will be used as a tool to validate new potential therapeutic compounds identified by other partners. Collectively, these experiments will allow for the first time to study in the impact of key genes linked to human disease on human neuronal development and function in a living organism, hopefully leading to novel insights on orphan diseases, and leading in the long run to efficient therapeutic development.