Modeling autism using genome engineering in human 2-D and 3-D neural systems

  • Awarded: 2019
  • Award Type: Bridge to Independence
  • Award #: 479754

Autism spectrum disorders (ASDs) are complex neurodevelopmental disorders with a strong genetic component. Recent efforts to identify genes associated with ASD have yielded a growing list of potential targets. Elucidating the roles of these candidate ASD genes during the development, maturation and function of the human brain will provide much-needed insights into the etiology of ASDs. Animal models have been extraordinarily powerful at revealing evolutionarily conserved biological mechanisms. However, they are less effective at investigating evolutionarily divergent — in particular, human-specific — processes, including many aspects that are relevant to neurodevelopment disorders.

To address these issues, Yun Li and colleagues have used human embryonic stem cells and induced pluripotent stem cells, together with gene-editing technologies, to study neurodevelopmental disorders in human neural cells and brain organoids. They generated and characterized isogenic human stem cell-derived neuronal models of Rett syndrome1, revealing novel disease phenotypes that are now being used for therapeutic discoveries. They used CRISPR and 3-D brain organoid technologies to study important features of cortical development that diverge between humans and mice2. Looking beyond neurons, they have developed novel methods to derive microglia, the resident immune cells of the brain, from human stem cells3.

In the current project, Li and colleagues propose to systematically investigate the function of candidate ASD genes in human stem cell-derived 2-D neural cultures and 3-D brain organoids. They will study intrinsic neural and glial properties during development, as well as the dynamic cell-cell communications that occur within the neural lineage and between the neural and immune compartments. Their long-term goal is to apply these human cellular and organoid models to understand ASD mechanisms, and to develop therapeutic strategies that prevent, delay and reverse disease progression.


1.Li Y. et al. Cell Stem Cell 13, 446-458 (2013) PubMed
2.Li Y. et al. Cell Stem Cell 20, 385-396 (2017) PubMed
3.Muffat J. et al. Nat. Med. 22, 1358-1367 (2016) PubMed
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