Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Boulevard Louis Pasteur s/n, 29071 Malaga, Spain.
Departamento de Biología Molecular e Ingeniería Bioquímica, Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide (UPO), UPO/CSIC/JA, Ctra Utrera Km1, 41013 Sevilla, Spain.
Int J Mol Sci. 2023 Jul 28;24(15):12079. doi: 10.3390/ijms241512079.
Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 10 single-nucleotide polymorphisms performed on Alzheimer's disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a humanized model over-expressing the Aβ peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin's effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.
全基因组关联研究（GWAS）是一种强大的工具，可以识别与疾病相关的不同生化途径。这些知识可用于优先考虑针对这些途径的药物，为临床应用铺平道路。在这里，我们描述了 DAGGER（通过 GWAS 和基因表达在 R 中的分析进行药物重定位），这是一种简单的流水线，可以找到具有重新定位潜力的当前批准药物。作为概念验证，我们分析了对阿尔茨海默病（AD）进行的 1.6×10 个单核苷酸多态性的元 GWAS。我们的流水线使用基因型组织表达（GTEx）和药物基因相互作用（DGI）数据库对 22 个可药物治疗的靶标进行合理的优先级排序。接下来，我们进行了两阶段的体内功能测定。我们使用过表达 Aβ肽的人源化模型。我们测定了五种得分最高的候选药物，发现多靶点蛋白激酶抑制剂米哚妥林是一种保护药物。接下来，我们使用 3xTg AD 转基因小鼠对米哚妥林的作用进行了最终评估。三周腹腔内 20mg/kg 治疗后的行为测试显示，行为有了显著改善，包括运动、焦虑样行为和新位置识别。总的来说，我们认为我们的流水线可能是复杂疾病药物重新定位的有用工具。
