Abstract
BackgroundResearch 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.MethodsIn 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.ResultsWe 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.LimitationsThe 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.ConclusionsThe 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.
Highlights
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
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 Insulin-like growth factor 1 (IGF-1)
Our results indicate that in neurons derived from neurotypical individuals, IGF-1 treatment altered the gene expression profile in pathways previously identified as downstream of IGF-1 receptor (IGF1R) signaling such as the Mitogen-activated protein kinase (MAPK) pathway
Summary
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. Evidence from genetic screening suggests that susceptibility to ASD may arise from mutations in hundreds of different genes [2, 3] While this heterogeneity has posed a challenge for the development of effective drugs for ASD, recent studies on genetic and transcriptional profiling from both syndromic (monogenic) and non-syndromic (idiopathic) forms of ASD seem to converge on common pathways that are involved in neurogenesis, synaptic development, and chromatin remodeling [2,3,4,5,6,7]. The collective evidence for the potential efficacy of IGF-1 in the treatment of ASD core symptoms has encouraged the scientific and clinical community to launch a number of clinical trials for both syndromic and non-syndromic forms of the disorder [18, 19] (ClinicalTrials.gov Identifiers: NCT01525901, for PhelanMcDermid Syndrome; NCT01253317, NCT01777542, for Rett Syndrome; NCT01970345, for Autism Spectrum Disorder)
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