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Stem Cell Based Organoid Models of Neurodevelopmental Disorders

      Abstract

      The last decade has seen an explosion in the identification of genetic causes of neurodevelopmental disorders (NDDs), including Mendelian, de novo, and somatic, factors. These discoveries provide opportunities to understand cellular and molecular mechanisms as well as potential gene-gene and gene-environment interactions, to support novel therapies. Stem cell-based models, particularly human brain organoids, can capture disease-associated alleles in the context of the human genome, engineered to mirror disease-relevant aspects of cellular complexity and developmental timing. These models have brought key insights into NDDs as diverse as microcephaly, autism, and focal epilepsy. But intrinsic organoid-to-organoid variability, low levels of certain brain-resident cell types, and long culture times required to reach maturity can impede progress. Several recent advances incorporate specific morphogen gradients, mixtures of diverse brain cell types, and organoid engraftment into animal models. Together with non-human primate organoid comparisons, mechanisms of human NDDs are emerging.

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