Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterised by impairments in communication and social interaction, and by restricted or repetitive behaviours and interests. Although the genetic component is significant, the pathogenic role and biological mechanisms of many genes associated with ASD remain poorly defined. Furthermore, conventional animal models do not always adequately replicate the complexity of human brain development and behaviour, and some genes of interest do not have a mouse orthologue.

The MULTI-ASD project aims to develop a multidimensional and integrated platform for the study of human genes associated with autism, combining computational modelling and artificial intelligence, brain organoids derived from human cells, and non-human primate models. As a first case study, DDX53 will be analysed; this gene is located at locus Xp22.11 and has recently been associated with forms of ASD with Mendelian inheritance. DDX53 is of particular interest because it is expressed in the human brain, is poorly characterised and has no mouse orthologue.

The platform will integrate genomic and multi-omic data using computational models and digital twins; it will study the effects of DDX53 variants on neuronal differentiation, synaptogenesis and connectivity using iPSCs and brain organoids, and will validate the results in genetically modified non-human primate models. The integration of different levels of analysis will enable a link to be established between genetic variants, molecular mechanisms, the development of neuronal circuits and behavioural phenotypes. MULTI-ASD thus aims to develop an approach that can also be applied to other poorly characterised autism-associated genes, particularly those specific to primates, contributing to a better understanding of the pathophysiology of ASD and the identification of potential targeted therapeutic strategies