基于药物基因组学之他克莫司对重症肌无力精准治疗的研究

The safety of low dose FK-506 in the treatment of myasthenia gravis have already been confirmed, but the pharmacokinetics and pharmacodynamics of FK-506 have been reported significantly affected by the genetic difference among patients, and this difference leads to different drug effects. Due to the high cost of FK-506, it is necessary to establish a method to predict the drug effects in different MG patients and provide guidance for clinical perscription. This research would firstly use high throughput sequencing technology to detect SNPs which are located on the genes encoding key signals in the pharmacokinetics and pharmacodynamics pathways of FK-506, then from the SNPs detected above, we will select tagSNPs and the SNPs closely relative to the tagSNPs, we define these SNPs as target SNPs. Besides, we would further construct the biological models to imitate the target SNPs’ biological effects to FK-506 with CRISPRCas9 technology and confirm the biological effects of these target SNPs. Finaly, we would make use of the medical records and selected target SNPs to establish a mathematical model to predict whether the patient is suitable for taking FK-506 or not and the recommended dose of FK-506. The achievements of this research would provide theoretical basis and technical support for the individual medication of MG patients, improve the efficiency of the treatment, and provide a new way for the accurate treatment of autoimmune diseases in the future.

低剂量他克莫司治疗MG安全可靠，但患者个体间遗传差异明显影响其药物代谢及药效，从而影响疗效。由于FK-506价格昂贵，有必要建立一个可以预测MG患者对FK-506的治疗反应，从而指导治疗方案的方法。本研究将首先应用高通量测序法检测影响MG患者对FK-506治疗反应的药物代谢和药效通路中关键信号编码基因上的SNP，筛选出tagSNP及与其相关的SNP，作为目标SNP；进一步用CRISPRCas9技术建立更加贴切模仿目标SNP对于FK-506影响的生物模型，验证这些SNP的生物学功能；最后将筛选出的目标SNP结合我们MG患者临床信息库的资料，建立指导MG患者是否适合服用FK-506，以及服用剂量的数学模型，为指导MG患者个体化用药提供理论依据和技术支持，提高了疾病治疗的效益，为今后自身免疫性疾病的精准治疗提供新的思路。

他克莫司是一种治疗重症肌无力(MG)的新型有效免疫抑制剂。然而，狭窄的治疗窗口以及患者间和患者内的生物利用度差异很大程度上限制了其临床应用。本项目研究了影响他克莫司治疗MG临床结局的相关基因甲基化水平以及snp分型，并探讨FK506 联合WZC 治疗MG 患者的疗效与安全性，以及可能影响FK506 血药浓度、临床疗效和不良反应的临床因素；检测FK506 药代学和药效学通路中关键性蛋白编码基因的SNP 位点，探索其与FK506 血药浓度、临床疗效和不良反应的关联；分别从临床因素、遗传因素以及临床因素结合遗传因素这三个角度构建FK506 治疗MG 患者的血药浓度、临床疗效及不良反应的风险预测模型，指导FK506 治疗MG 患者的个体化用药方案。