Uncovering phenotypic convergence across high-risk autism genes using forebrain assembloids
- Awarded: 2022
- Award Type: Targeted: Genomics of ASD: Pathways to Genetic Therapies
- Award #: 1013010
Rare and high-penetrance mutations are key contributors to the risk of autism spectrum disorder (ASD). The genes that accrue such mutations, “ASD risk genes,” provide some of the most direct links between gene function and disease. To date, over 200 ASD risk genes with a broad range of functions, such as chromatin modifiers, transcription factors, synaptic protein, RNA-binding proteins and ion channels, have been identified. Understanding how perturbations in genes with seemingly diverse functions converge to impart ASD risk remains a major challenge.
The mid-to-late gestational period of cortical development, during which the majority of ASD risk genes are thought to confer susceptibility for the condition, is when the first cortical networks are formed and early principles of circuit function are established. The ability to investigate these processes in individuals with ASD has been limited by a lack of access to functional human tissue, hindering therapeutic progress. In response to this, Fikri Birey and colleagues developed the “forebrain assembloid” system, which is a stem cell-derived brain organoid model of the developing human cortex. Forebrain assembloids enable in vitro modeling and functional interrogation of higher order phenomena that are fundamental for the assembly of the human cerebral cortex such as cortical interneuron migration and synaptic integration into cortical networks, in health and disease1,2.
Leveraging a multi-disciplinary approach which combines the assembloid platform with various cellular and molecular readouts, including single cell omics, live cell imaging and multielectrode arrays, Birey and colleagues will seek to identify previously inaccessible points of phenotypic convergence shared across eight high-risk ASD gene variants at the cellular, molecular and network levels. Moving away from one gene/one drug approaches, Birey’s long-term goal is to identify next-generation therapeutic interventions that target high-risk convergent pathways in ASD.
References
- Assessing the functions of autism risk genes in deep layer cortical neurons during primate midfetal development
- Developmental and cell type-specific origin of autism pathology at single-cell resolution
- Modeling autism using genome engineering in human 2-D and 3-D neural systems
- Spatiotemporal dissection of UBE3A expression with engineered human cerebral organoids