Department of Informatics, Bioinformatics and Human Electrophysiology Laboratory, Ionian University, Corfu, Greece.
Adv Exp Med Biol. 2023;1424:201-211. doi: 10.1007/978-3-031-31982-2_22.
Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. There are currently limited approved drugs for the disorder, and for this reason the strategy of repositioning already approved therapeutics could exhibit a successful outcome. Herein, we used CMAP and L1000CDS databases which include gene expression profiles datasets (genomic signatures) to identify potent compounds and classes of compounds which reverse disease's signature which could in turn reverse its phenotype. ALS signature was obtained by comparing gene expression of muscle biopsy specimens between diseased and healthy individuals. Statistical analysis was conducted to explore differentially transcripts in patients' samples. Then, the list of upregulated and downregulated genes was used to query both databases in order to determine molecules which downregulate the genes which are upregulated by ALS and vice versa. These compounds, based on their chemical structure along with known treatments, were clustered to reveal drugs with novel and potentially more effective mode of action with most of them predicted to affect pathways heavily involved in ALS. This evidence suggests that these compounds are strong candidates for moving to the next phase of the drug repurposing pipeline which is in vitro and in vivo experimental evaluation.
肌萎缩侧索硬化症（ALS）是一种迟发性致命的神经退行性疾病，其特征是上运动神经元和下运动神经元的进行性丧失。目前针对这种疾病的批准药物有限，因此，重新定位已批准的治疗药物的策略可能会取得成功的结果。在此，我们使用了 CMAP 和 L1000CDS 数据库，其中包括基因表达谱数据集（基因组特征），以识别能够逆转疾病特征、进而逆转表型的有效化合物和化合物类别。通过比较患病和健康个体的肌肉活检标本中的基因表达，获得了 ALS 特征。对患者样本中的差异转录物进行了统计分析。然后，使用上调和下调基因的列表查询这两个数据库，以确定能够下调 ALS 上调基因和反之亦然的分子。基于这些化合物的化学结构以及已知的治疗方法，对它们进行了聚类，以揭示具有新颖且潜在更有效作用模式的药物，其中大多数被预测会严重影响与 ALS 密切相关的途径。这些证据表明，这些化合物是进入药物再利用管道的下一阶段的有力候选药物，下一阶段是体外和体内实验评估。
