Modeling neurodevelopmental and psychiatric diseases with human iPSCs

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Neurodevelopmental and psychiatric disorders, including autism spectrum disorder (ASD), schizophrenia (SZ), and bipolar disorder (BD), are complex and heterogeneous disorders characterized by complex genetics, variable symptomatology, and anatomically distributed pathology (Geschwind, 2009; Sullivan et al., 2012). They affect a large portion of the world's population and are devastating to the patients and their families. The currently available drugs, most of which treat only symptoms, are only partially effective and have significant side effects on well‐functioning neural systems (Al‐Harbi, 2012). The hunt for better therapeutics for these disorders has been challenging, and few novel treatments have been developed in the last few decades. One major obstacle is the lack of suitable preclinical models that can be used for studying disease mechanisms, identifying therapeutic targets, and testing potential drugs.
A breakthrough in human disease research over the last decade has emerged from cellular reprogramming technologies, which turn differentiated cells, such as human skin fibroblasts or blood cells, into induced pluripotent stem cells (iPSCs) (Takahashi and Yamanaka, 2006; Takahashi et al., 2007; Kunisato et al., 2011). By differentiating human iPSCs (hiPSCs) into disease‐relevant cell types, we can now conduct biopsy‐like experiments on previously inaccessible living tissues from patients. In addition, we can also study, for the first time, the initial development and progression of pathology in live human cells. Since patient‐derived iPSCs capture identical risk alleles as the donor individual, we now have the ability to study cellular and molecular mechanisms in genetic contexts that are known to be permissive for a given disease, thereby creating a genetically faithful human model of disease (Bellin et al., 2012; Wen et al., 2016). Importantly, hiPSCs allow us to study the interaction of genetic susceptibility and environmental factors and their contributions to the pathogenesis of human diseases. hiPSCs thus provide a new platform for disease modeling and drug development. Here, I review the recent progress in the use of hiPSCs for modeling neurodevelopmental/psychiatric disorders and drug discovery, and discuss the major challenges in this rapidly moving field.
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