Genetic models of autism in human neural progenitor cells: a platform for therapeutic discovery
University of California, Los Angeles
Meixner Translational Postdoctoral Fellowship
The major challenge facing drug development for ASDs has been creating therapeutics in the face of very limited understanding of the cause of the disease. Research in the past decade has identified some of the genetic changes that create large risk for autism: the first understandings of its causal basis. These changes include single base pair differences or large, many-thousand base pair deletions or duplications of the genome. Advances in genetics and genomics provide us with an unprecedented mechanistic lever for biological pathway and drug target discovery by allowing us to model mutations in human cells. Human neural progenitors are cells that are derived from fetal tissue. They grow and multiply, maturing to create the many cell types of the brain, including neurons. By inserting genetic changes associated with autism into human neural progenitors, we can monitor how brain development is different in autistic patients. Genetic changes can cause cellular differences in neuronal development and eventually manifest themselves as the core social and behavioral symptoms observed in autistic patients. These cellular models, or “autism in a dish,” can be used to screen a broad spectrum of drugs. Drugs that reverse the cellular changes caused by induced genetic mutations can be selected for preclinical testing. Just as cancer research has moved from the level of histological characterization to molecular profiling and targeted therapy, so must neuroscience. Here, the investigators will utilize an innovative, potentially high-payoff strategy to make multiple cellular models based on specific single genetic risk variants for autism spectrum disorders. This project will determine whether there are convergent phenotypes in distinct genetic models, a critical question facing the field. The investigators also will use gene expression patterns to identify candidate FDA-approved drugs that reverse ASD-associated phenotypes (gene expression, either morphological or physiological) in human neurons. The research training will combine experimental biology and bioinformatics skills that will support the fellow’s pursuit of an academic research career focused on therapeutic development for neuropsychiatric illness.