- Awarded: 2021
- Award Type: Targeted: Genomics of ASD: Pathways to Genetic Therapies
- Award #: 890477
While genetic studies have identified numerous risk variants and genes for autism spectrum disorder (ASD), therapeutic development requires both better understanding of the genes’ neurobiological roles and scalable assays to identify potential chemical or genetic interventions. This challenge is especially daunting given the large number of ASD risk genes found to date — at present there are 207 high-confidence SPARK genes including 50 prioritized by SFARI for their translational potential, with even more likely to come. Tackling this list piecemeal with traditional techniques will be prohibitively time consuming, and new, highly parallel discovery approaches are required.
Meanwhile, emerging lines of evidence show that fingerprinting of cells — defined here as measurements which parameterize cell state among hundreds to thousands of separate features — not only can offer insight about the phenotypic consequences of a genetic perturbation but also can cluster genetic or chemical perturbations by likely common mechanisms of action. Fingerprinting assays typically scale well, in principle simplifying the transition from neurobiological discovery to assay development.
Samouil Farhi and Ralda Nehme’s laboratories have developed a rich assay palette for transcriptomic, morphological and electrophysiological fingerprinting pooled cultures of human neurons derived from induced pluripotent stem cells. In this project, their teams will leverage these assays to perform pooled knockdown screens of high-confidence ASD risk genes, identifying modulated features and gaining insight into the neurobiological roles of the genes. They will then use the same assays in large case-control pools harboring ASD risk variants in the same genes to identify features linked to gene rather than genetic background and confirm this by correcting the relevant mutation. The overall approach will both provide information about the roles of genes, enable clustering of genes by potential common roles and guide the development of highly scalable therapeutic discovery assays.
- Building phenotypic maps based on neuronal activity and transcriptional profiles in human cell models of syndromic forms of ASD
- Human gene editing and in situ sequencing of neuronal microcircuit arrays
- Leveraging a high-throughput CRISPR screen to assess convergent neurogenesis phenotypes across autism risk genes
- In vitro modeling of genetic subtypes of autism