Table2_Drug repurposing candidates to treat core symptoms in autism spectrum disorder.xlsx

Autism spectrum disorder (ASD) is characterized by high heritability and clinical heterogeneity. The main core symptoms are social communication deficits. There are no medications approved for the treatment of these symptoms, and medications used to treat non-specific symptoms have serious side effects. To identify potential drugs for repurposing to effectively treat ASD core symptoms, we studied ASD risk genes within networks of protein-protein interactions of gene products. We first defined an ASD network from network-based analyses, and identified approved drugs known to interact with proteins within this network. Thereafter, we evaluated if these drugs can change ASD-associated gene expression perturbations in genes in the ASD network. This was done by analyses of drug-induced versus ASD-associated gene expression, where opposite gene expression perturbations in drug versus ASD indicate that the drug could counteract ASD-associated perturbations. Four drugs showing significant (p < 0.05) opposite gene expression perturbations in drug versus ASD were identified: Loperamide, bromocriptine, drospirenone, and progesterone. These drugs act on ASD-related biological systems, indicating that these drugs could effectively treat ASD core symptoms. Based on our bioinformatics analyses of ASD genetics, we shortlist potential drug repurposing candidates that warrant clinical translation to treat core symptoms in ASD.

自闭症谱系障碍（Autism Spectrum Disorder, ASD）以高遗传力与临床异质性为典型特征，核心症状为社交沟通缺陷。目前尚无获批药物可用于治疗此类核心症状，且用于治疗非特异性症状的现有药物存在严重不良反应。为筛选可通过药物重定位有效治疗ASD核心症状的潜在候选药物，本研究聚焦于基因产物所构成的蛋白质-蛋白质相互作用（protein-protein interactions）网络中的ASD风险基因。研究首先通过基于网络的分析构建ASD相关网络，并筛选出已知可与该网络内蛋白质发生相互作用的获批药物。随后，评估这些药物能否改变ASD相关网络中基因的表达扰动：通过对比药物诱导与ASD相关的基因表达谱，若药物与ASD呈现相反的基因表达扰动，则提示该药物可拮抗ASD相关的表达异常。最终筛选出4种在药物与ASD间呈现显著（p < 0.05）相反基因表达扰动的药物：洛哌丁胺、溴隐亭、屈螺酮与孕酮。上述药物可作用于ASD相关生物学系统，提示其或可有效治疗ASD核心症状。基于本研究针对ASD遗传学的生物信息学分析，我们遴选出具备临床转化潜力的药物重定位候选化合物，用于治疗ASD核心症状。