Human pluripotent stem cell (hPSC)-derived models for autism spectrum disorder drug discovery.

Introduction: Autism spectrum disorder (ASD) is a prevalent and complex neurodevelopmental disorder (NDD) with genetic and environmental origins. Currently, there are no effective pharmacological treatments targeting core ASD features. This leads to unmet medical needs of individuals with ASD and requires relevant human disease models recapitulating genetic and clinical heterogeneity to better understand underlying mechanisms and identify potential pharmacological therapies. Recent advancements in stem cell technology have enabled the generation of human pluripotent stem cell (hPSC)-derived two-dimensional (2D) and three-dimensional (3D) neural models, which serve as powerful tools for ASD modeling and drug discovery.

Areas covered: This article reviews the applications of hPSC-derived 2D and 3D neural models in studying various forms of ASD using pharmacological perturbation and drug screenings, highlighting the potential use of these models to develop novel pharmacological treatment strategies for ASD.

Expert opinion: hPSC-derived models recapitulate early human brain development spatiotemporally and have allowed patient-specific mechanistic investigation and therapeutic development using advanced molecular technologies, which will contribute to precision medicine for ASD therapy. Improvements are still required in hPSC-based models to further enhance their physiological relevance, clinical translation, and scalability for ASD drug discovery.