The Salk Institute, Laboratory of Genetics, La Jolla, CA, 92037, USA.
Department of Anthropology, University of California, San Diego, La Jolla, CA, 92037, USA.
Mol Autism. 2020 Jun 26;11(1):55. doi: 10.1186/s13229-020-00359-w.
Research evidence accumulated in the past years in both rodent and human models for autism spectrum disorders (ASD) have established insulin-like growth factor 1 (IGF-1) as one of the most promising ASD therapeutic interventions to date. ASD is phenotypically and etiologically heterogeneous, making it challenging to uncover the underlying genetic and cellular pathophysiology of the condition; and to efficiently design drugs with widespread clinical benefits. While IGF-1 effects have been comprehensively studied in the literature, how IGF-1 activity may lead to therapeutic recovery in the ASD context is still largely unknown.
In this study, we used a previously characterized neuronal population derived from induced pluripotent stem cells (iPSC) from neurotypical controls and idiopathic ASD individuals to study the transcriptional signature of acutely and chronically IGF-1-treated cells.
We present a comprehensive list of differentially regulated genes and molecular interactions resulting from IGF-1 exposure in developing neurons from controls and ASD individuals. Our results indicate that IGF-1 treatment has a different impact on neurons from ASD patients compared to controls. Response to IGF-1 treatment in neurons derived from ASD patients was heterogeneous and correlated with IGF-1 receptor expression, indicating that IGF-1 response may have responder and non-responder distinctions across cohorts of ASD patients. Our results suggest that caution should be used when predicting the effect of IGF-1 treatment on ASD patients using neurotypical controls. Instead, IGF-1 response should be studied in the context of ASD patients' neural cells.
The limitation of our study is that our cohort of eight sporadic ASD individuals is comorbid with macrocephaly in childhood. Future studies will address weather downstream transcriptional response of IGF-1 is comparable in non-macrocephalic ASD cohorts.
The results presented in this study provide an important resource for researchers in the ASD field and underscore the necessity of using ASD patient lines to explore ASD neuronal-specific responses to drugs such as IGF-1. This study further helps to identify candidate pathways and targets for effective clinical intervention and may help to inform clinical trials in the future.
过去几年，在自闭症谱系障碍（ASD）的啮齿动物和人类模型中积累的研究证据表明，胰岛素样生长因子 1（IGF-1）是迄今为止最有前途的 ASD 治疗干预措施之一。ASD 在表型和病因上具有异质性，因此很难揭示该疾病的潜在遗传和细胞病理生理学；并且难以有效地设计具有广泛临床益处的药物。虽然 IGF-1 的作用在文献中得到了全面研究，但 IGF-1 活性如何导致 ASD 情况下的治疗恢复仍知之甚少。
在这项研究中，我们使用了先前从神经正常对照和特发性 ASD 个体的诱导多能干细胞（iPSC）中获得的神经元群体，来研究急性和慢性 IGF-1 处理细胞的转录特征。
我们提供了一个全面的差异调节基因列表和分子相互作用，这些基因和分子相互作用是由 IGF-1 暴露在对照和 ASD 个体的发育神经元中产生的。我们的结果表明，IGF-1 处理对来自 ASD 患者的神经元的影响与对照不同。来自 ASD 患者的神经元对 IGF-1 治疗的反应具有异质性，并且与 IGF-1 受体表达相关，这表明 IGF-1 反应可能在 ASD 患者的队列中存在有反应者和无反应者的区别。我们的研究结果表明，在用神经正常对照来预测 IGF-1 治疗对 ASD 患者的效果时应谨慎。相反，应该在 ASD 患者的神经细胞背景下研究 IGF-1 反应。
我们的研究队列中，有八名散发性 ASD 个体在儿童时期患有大头畸形。未来的研究将解决 IGF-1 的下游转录反应是否在非大头畸形 ASD 队列中具有可比性的问题。
本研究的结果为 ASD 领域的研究人员提供了一个重要的资源，并强调了使用 ASD 患者系来探索 IGF-1 等药物对 ASD 神经元的特异性反应的必要性。这项研究进一步有助于确定有效的临床干预的候选途径和靶点，并可能有助于为未来的临床试验提供信息。
