基于多组学的丙戊酸钠个体化给药方案的生物标志物的发现与确证

Epilepsy has been included in the World Health Organization as one of the five major neuropsychiatric disorders in the world. Sodium valproate (VPA) is widely used as a first-line antiepileptic drug because of its curative effect. However, the big individual differences of VPA drug reaction, especially the adverse effects including hepatotoxicity and obesity lead to drug withdrawal or replacement clinically. Therefore, therapeutic drug monitoring (TDM) of VPA routinely is needed after taking medicine; but its clinical guidance has been controversial. Studies in recent years have shown that pharmacogenomics can well explain the individual differences of VPA. Since 2008, our team has been carrying out research for reasons of VPA individual differences using technology like pharmacogenomics and so on. Significantly, we found the genetic polymorphisms of its metabolic enzymes and related targets of efficacy and toxicity including UGT2B7, LEPR, FABP4 and so on, meanwhile the concentration of its metabolite 4-ene-VPA but not the concentration of VPA partly explained the individual differences and molecular mechanism of VPA’s pharmacokinetics, obesity and hepatotoxicity, but can only explain 25% of individual differences. Based on the previous studies on pharmacogenomics and combined with the epigenetics, metabolomics and gut microbiomics platform established by our laboratory, this study will further explore the mechanism of individual differences, discover and confirm biomarkers with clinical significance; meanwhile we aim to establish the TDM treatment window based on VPA metabolomics spectrum and finally develop individualized dosing regimens.

癫痫是常见的神经精神疾患之一。丙戊酸（VPA）疗效确切，是一线抗癫痫药物。但VPA药物反应个体差异大，尤其是其肝毒性及肥胖常导致临床停药换药。因此，使用VPA需要开展治疗药物浓度监测（TDM），然而其对临床指导作用一直存在争议。近年来的研究表明药物基因组学可较好地阐释VPA的个体差异。我们从2008年开始采用药物基因组学等手段探究VPA个体化差异，发现代谢酶以及疗效和毒性相关靶点UGT2B7、LEPR、FABP4等基因多态性、VPA代谢物4-ene-VPA浓度而非原药血药浓度与疗效及毒性显著相关，解释了部分VPA药动学、毒性的个体差异，但只能解释约25%的个体差异。本课题将在前期药物基因组学研究基础上，结合已建立的表观遗传学、代谢组学和肠道微生物组学技术，进一步探索VPA的个体差异和机制，发现并确证具有临床意义的生物标志物，并建立基于VPA代谢组学谱图的TDM治疗窗，制定个体化给药方案。

丙戊酸（VPA）作为经典的一线抗癫痫药物，其治疗窗窄、个体差异大困扰着临床应用。本项目旨在运用药动学、基因组学、表观遗传学、代谢组学及肠道微生物组学等多组学研究方法，系统研究VPA药物反应个体差异的影响因素，以期为其临床合理应用提供科学依据。.药动学研究中，考察了VPA原型药及其5种代谢物2-PGA、3-OH-VPA、3-keto-VPA、4-OH-VPA及4-ene-VPA的药物浓度与VPA药物反应的关系。发现VPA原型血药浓度与疗效及毒性不存在相关性，而其主要代谢物2-PGA和4-ene-VPA分别与疗效和肝毒性相关，并建立了相应治疗窗。.基因组学研究中，全面考察了412个参与VPA体内药动学过程的相关代谢酶、转运体及其上游调控因子、药效学靶点、药物不良反应相关基因及编码miRNA基因的单核苷酸多态性（SNPs）与VPA药物反应的关系，发现血脑屏障转运体ABCC2、MCT1及代谢酶CYP2C9的基因多态性与疗效相关；线粒体代谢关键酶PRORP、ACTA1及PCK2的基因多态性与肝毒性相关；食欲调控相关基因LEPR、ADRA2A及脂肪酸转运相关基因CD36的多态性与肥胖相关。.表观遗传学研究中，考察了2590种已知的miRNA丰度以及m6A修饰程度与VPA 药物反应的关系，发现VPA疗效与神经元的生长发育程度相关，而其所致肝毒性及肥胖与能量代谢调控和脂肪酸转运显著相关。.代谢组学研究中，考察了多种内源性物质的个体差异与VPA药物反应的关系，发现鞘磷脂和磷酰胆碱对VPA的疗效具有较好预测作用，丝氨酸及甘油三酯对其所致肝毒性有较好预测作用。.肠道微生物组学研究中，初步发现了一些与VPA药物反应相关的差异性菌群，但由于疫情原因，收样未能达到预期。.最终，基于多组学方法筛选出的多个候选生物标志物，我们建立了VPA药物反应预测模型，为指导VPA临床合理用药提供了研究依据。相关研究成果发表10余篇SCI与核心期刊论文，培养博士1名、硕士4名。