Advances in Understanding Disease Mechanisms and Translation to Therapeutics

Genetic syndromes with increased prevalence of autism spectrum disorder (ASD) and intellectual disability (ID) offer an opportunity to understand the brain pathophysiology that manifests as ASD; this knowledge can suggest potential targeted therapies. It is now clear that the genetics underlying ASD are complex; with at least several hundred genes conferring small amounts of risk. Studies utilizing genomic sequencing and found several rare variants in individuals with ASD. These studies suggest a high degree of convergence on particular cellular processes and biochemical pathways, suggesting there may be convergence of underlying mechanisms and potential therapeutic strategies. The study of monogenic or syndromic forms of ASD, has been a leading strategy to gain insight into the complex mechanisms of ASD. Fragile X Syndrome (FXS) is one of the most common inherited forms of ID and the leading single gene cause of ASD. Since the Fragile X gene (FMR1) was cloned in 1991, the field has used cellular assays and model organisms to elucidate the functions of the FMR1 protein (FMRP), the consequences of its loss and identify therapeutic targets for FXS and ASD. Other syndromic forms of ASD, such as tuberous sclerosis complex, Rett Syndrome, Angelman Syndrome and others, are being investigated using similar approaches. Recent technological advances in human stem-cell derived neurons, organoids, single cell sequencing, gene therapy and novel model organisms are setting the stage for transformative advances in therapeutic development for these neurodevelopmental disorders. This conference will bring together leading scientists and clinicians studying FXS, ASD and related neurodevelopmental disorders with the ultimate goal of identifying the mechanisms that underlie the heterogeneous symptomatology associated with these disorders and the best potential pathways for translating this knowledge into clinical trials.