Functional dissection of the molecular underpinnings of 7q11.23 syndromes: bridging pathogenic insight to drug discovery at single cell resolution

Williams-Beuren (WBS) and 7q11.23 microduplication (7DUP) syndromes represent a unique combination of developmental disorders that arise from genetic lesions affecting the same group of genes in opposite fashion. Remarkably, these opposite genetic lesions manifest either as shared or opposite traits, among which intellectual disability and sociability defects constitute a conspicuously heavy burden to the affected individuals and their families. Despite many promising results obtained in animal models along years of biomedical research, these insights have failed to translate into effective therapeutic interventions. This project builds on the groundbreaking technology of cell reprogramming through which cells from patients are converted in vitro into tailored models that faithfully recapitulate the tissues affected by the two conditions. In this project we focus particularly on the development of the brain and spearhead recently developed models for neurons and brain organoids, which mimic with high accuracy the main features seen during typical human brain development. By using these models, our preliminary results studying different molecular aspects of the diseases allowed us to identify a group molecular targets that are central to the development of the disease and that bear significant promise for the exploration of new therapeutic options. To this end we will use advanced computational and experimental approaches to identify compounds, already available for the treatment of other diseases, that can be repurposed for these two conditions