Rac GTPase in Intellectual Disability: preclinical opportunities from interfering with a Rac1 protein::protein interaction

For long time inherited Intellectual Disability (ID) has been considered uncurable: however recently scientific advancements in neuroscience field supported the possibility that neurons are sufficiently plastic to recover their physiological architecture and connectivity.  The reduced function of the Rac1 enzyme is one of the possible causes of ID, linked to an altered development of the nervous system.  In this view, we have the possibility to use a peptide, designed by chemo-informatics and partially verified in our laboratories, to correct the ID caused by loss of ArhGEF6 or loss of Rac1. Here we propose an articulated project that will: complete the characterization of the initial peptide, design new peptides or small organic molecules, test them in cultured cells and in mice with ArhGEF6 mutation, develop a new cell model of ID using human pluripotent cells. We aim to show that X-linked ID due to hypoactive Rac pathway is reversible, at least in principle.