From Rare Mutations to Common Treatments in Autism - M. Lalli PhD, Icahn School of Med. @Synchrony22

The latest exome-wide association study in neurodevelopmental disorders identified over 350 genes that harbor mutations strongly contributing to the risk for autism spectrum disorder (ASD) and developmental delay. To translate these findings into eventual therapeutics, we first need to investigate the functions of each of these genes and their mutations in the context of brain development. Studying each of these genes separately in animal or cell models is a daunting task.

By coupling CRISPR-Cas9 transcriptional repression (CRISPRi) to single-cell RNA sequencing (scRNA-seq), we have enabled the high-throughput perturbation of multiple ASD risk genes at once with a parallel functional readout of the transcriptional consequences. Using this technology, we have extracted functional signatures for 77 of the top ASD risk genes in human neural progenitor cells and neurons derived from induced pluripotent stem cells (iPSCs).

We have identified several ASD risk genes that altered cell fate specification when repressed. Several ASD risk genes pushed neural progenitor cells to adopt glial fates. Furthermore, we identified multiple ASD risk genes that altered neural differentiation, including some that accelerated or delayed this process. Finally, we found that ASD risk genes clustered by shared co-expression modules, indicating shared signatures.

🎥 This talk was part of Synchrony 2022 Online Symposium - 'From Bench to Biopharma', organised by the The BRAIN Foundation

🎥 For more Synchrony 2022 talks and highlights:

🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠

🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠 🧠

To accomplish this, it funds impactful research through #philanthropy and our network of partners in the venture, corporate, and grassroots community.