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Mind the translational gap: using iPS cell models to bridge from genetic discoveries to perturbed pathways and therapeutic targets
Molecular Autism ( IF 6.2 ) Pub Date : 2021-02-08 , DOI: 10.1186/s13229-021-00417-x
Greta Pintacuda 1, 2 , Jacqueline M Martín 1, 2 , Kevin C Eggan 1, 2
Affiliation  

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by impaired social interactions as well as the presentation of restrictive and repetitive behaviors. ASD is highly heritable but genetically heterogenous with both common and rare genetic variants collaborating to predispose individuals to the disorder. In this review, we synthesize recent efforts to develop human induced pluripotent stem cell (iPSC)-derived models of ASD-related phenotypes. We firstly address concerns regarding the relevance and validity of available neuronal iPSC-derived models. We then critically evaluate the robustness of various differentiation and cell culture protocols used for producing cell types of relevance to ASD. By exploring iPSC models of ASD reported thus far, we examine to what extent cellular and neuronal phenotypes with potential relevance to ASD can be linked to genetic variants found to underlie it. Lastly, we outline promising strategies by which iPSC technology can both enhance the power of genetic studies to identify ASD risk factors and nominate pathways that are disrupted across groups of ASD patients that might serve as common points for therapeutic intervention.

中文翻译:

注意翻译差距:使用 iPS 细胞模型将遗传发现与扰动的途径和治疗靶点联系起来

自闭症谱系障碍 (ASD) 包括一组神经发育障碍,其特征是社交互动受损以及出现限制性和重复性行为。自闭症谱系障碍具有高度遗传性,但在遗传上具有异质性,常见和罕见的遗传变异共同导致个体易患这种疾病。在这篇综述中,我们综合了最近开发人类诱导多能干细胞 (iPSC) 衍生的 ASD 相关表型模型的努力。我们首先解决有关可用神经元 iPSC 衍生模型的相关性和有效性的问题。然后,我们严格评估用于产生与 ASD 相关的细胞类型的各种分化和细胞培养方案的稳健性。通过探索迄今为止报道的 ASD iPSC 模型,我们研究了与 ASD 潜在相关的细胞和神经元表型在多大程度上与 ASD 背后的遗传变异相关。最后,我们概述了一些有希望的策略,通过这些策略,iPSC 技术既可以增强基因研究的能力,以识别 ASD 危险因素,又可以指定 ASD 患者群体中被破坏的途径,这些途径可能作为治疗干预的共同点。
更新日期:2021-02-08
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