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Genetic normalization of <jats:italic>Dyrk1a<\/jats:italic> is sufficient to normalize early cortical developmental phenotypes in DS mouse models. Gyrencephalic human neocortical development is more complex than that in lissencephalic mice; hence, cerebral organoids (COs) can be used to model early neurodevelopmental defects of DS. Single copy <jats:italic>DYRK1A<\/jats:italic> knockout COs (sc<jats:italic>DYRK1A<\/jats:italic>KO\u2010COs) can be generated from manipulated DS derived (DS\u2010) induced pluripotent stem cells (iPSCs) and genetic normalization of <jats:italic>DYRK1A<\/jats:italic> is expected to result in corrected neurodevelopmental phenotypes that can be reminiscent of normal COs. <jats:italic>DYRK1A<\/jats:italic> knock\u2010in (<jats:italic>DYRK1A<\/jats:italic>KI) COs can be derived after genetic manipulations of normal iPSCs and would be valuable to evaluate impaired neocortical development as can be seen in DS\u2010COs. <jats:italic>DYRK1A<\/jats:italic> mutations cause severe human primary microcephaly; hence, dose optimization studies of DYRK1A inhibitors will be critical for prenatal therapeutic applications in DS. Several doses of DYRK1A inhibitors can be tested in the neurodevelopment process of DS\u2010COs and DS\u2010sc<jats:italic>DYRK1A<\/jats:italic>KO\u2010COs would be used as optimum models for evaluating phenotypic ameliorations. Overdose drug exposure in DS\u2010COs can be explained by similar defects present in DS\u2010ba<jats:italic>DYRK1A<\/jats:italic>KO\u2010COs and <jats:italic>DYRK1A<\/jats:italic>KO\u2010COs. There are several limitations in the current CO technology, which can be reduced by the generation of vascularized brain\u2010like organoids giving opportunities to mimic late\u2010stage corticogenesis and complete hippocampal development. In the future, improved DS\u2010<jats:italic>DYRK1A<\/jats:italic>KO\u2010COs can be efficient in studies that aim to generate efficiently transplantable and implantable neurons for tissue regeneration alternatives in DS individuals.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cbin.10694","type":"journal-article","created":{"date-parts":[[2016,10,15]],"date-time":"2016-10-15T11:43:00Z","timestamp":1476531780000},"page":"1256-1270","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Generation of improved human cerebral organoids from single copy <i>DYRK1A<\/i> knockout induced pluripotent stem cells in trisomy 21: hypothetical solutions for neurodevelopmental models and therapeutic alternatives in down syndrome"],"prefix":"10.1002","volume":"40","author":[{"given":"E. 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