01732nas a2200193   4500000000100000008004100001260000900042100002300051700001800074700001500092700002500107700002200132700001800154245009100172856006700263490000700330520118700337022001401524       2021                            d  c20211 aFlorencia D. Haase1 aBronte Coorey1 aLisa Riley1 aLaurence C. Cantrill1 aPatrick P. L. Tam1 aWendy A. Gold00aPre-clinical Investigation of Rett Syndrome Using Human Stem Cell-Based Disease Models  uhttps://www.frontiersin.org/articles/10.3389/fnins.2021.6988120 v153 aRett syndrome (RTT) is an X-linked neurodevelopmental disorder, mostly caused by mutations in MECP2. The disorder mainly affects girls and it is associated with severe cognitive and physical disabilities. Modeling RTT in neural and glial cell cultures and brain organoids derived from patient- or mutation-specific human induced pluripotent stem cells (iPSCs) has advanced our understanding of the pathogenesis of RTT, such as disease-causing mechanisms, disease progression, and cellular and molecular pathology enabling the identification of actionable therapeutic targets. Brain organoid models that recapitulate much of the tissue architecture and the complexity of cell types in the developing brain, offer further unprecedented opportunity for elucidating human neural development, without resorting to conventional animal models and the limited resource of human neural tissues. This review focuses on the new knowledge of RTT that has been gleaned from the iPSC-based models as well as limitations of the models and strategies to refine organoid technology in the quest for clinically relevant disease models for RTT and the broader spectrum of neurodevelopmental disorders.  a1662-453X