Ranjan Jai, Bhattacharya Aniket
Department of Microbiology, All India Institute of Medical Sciences, Bathinda 151001, India.
Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
Cells. 2025 Jun 16;14(12):908. doi: 10.3390/cells14120908.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1-3% of the population globally. Owing to its multifactorial origin, complex genetics, and heterogeneity in clinical phenotypes, it is difficult to faithfully model ASD. In essence, ASD is an umbrella term for a group of individually rare disorders, each risk gene accounting for <1% of cases, threaded by a set of overlapping behavioral or molecular phenotypes. Validated behavioral tests are considered a gold standard for ASD diagnosis, and several animal models (rodents, pigs, and non-human primates) have traditionally been used to study its molecular basis. These models recapitulate the human phenotype to a varying degree and have been indispensable to preclinical research, but they cannot be used to study human-specific features such as protracted neuronal maturation and cell-intrinsic attributes, posing serious limitations to translatability. Human stem cell-based models, both as monolayer 2D cultures and 3D organoids and assembloids, can circumvent these limitations. Generated from a patient's own reprogrammed cells, these can be used for testing therapeutic interventions that are more condition and patient relevant, targeting developmental windows where the intervention would be most effective. We discuss some of these advancements by comparing traditional and recent models of ASD.
自闭症谱系障碍（ASD）是一种神经发育障碍，全球1%-3%的人口受其影响。由于其多因素起源、复杂的遗传学以及临床表型的异质性，很难如实地模拟ASD。从本质上讲，ASD是一组各自罕见的疾病的统称，每个风险基因导致的病例占比不到1%，由一组重叠的行为或分子表型串联起来。经过验证的行为测试被认为是ASD诊断的金标准，传统上使用了几种动物模型（啮齿动物、猪和非人类灵长类动物）来研究其分子基础。这些模型在不同程度上再现了人类表型，对临床前研究不可或缺，但它们不能用于研究人类特有的特征，如长期的神经元成熟和细胞内在属性，这对可转化性造成了严重限制。基于人类干细胞的模型，无论是作为单层二维培养物还是三维类器官和组装体，都可以规避这些限制。这些模型由患者自身重编程的细胞生成，可用于测试更符合病情和患者情况的治疗干预措施，针对干预最有效的发育窗口期。我们通过比较传统和最新的ASD模型来讨论其中的一些进展。
