Rais Rana, Jiang Weiwei, Zhai Huihong, Wozniak Krystyna M, Stathis Marigo, Hollinger Kristen R, Thomas Ajit G, Rojas Camilo, Vornov James J, Marohn Michael, Li Xuhang, Slusher Barbara S
Department of Neurology, Baltimore, Maryland, USA; Johns Hopkins Drug Discovery, Baltimore, Maryland, USA.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
JCI Insight. 2016 Aug 4;1(12). doi: 10.1172/jci.insight.88634.
Recent gene-profiling analyses showed significant upregulation of the folate hydrolase () gene in the affected intestinal mucosa of patients with inflammatory bowel disease (IBD). The gene encodes a type II transmembrane glycoprotein termed glutamate carboxypeptidase II (GCPII). To establish that the previously reported increased gene expression was functional, we quantified the glutamate carboxypeptidase enzymatic activity in 31 surgical specimens and report a robust 2.8- to 41-fold increase in enzymatic activity in the affected intestinal mucosa of IBD patients compared with an uninvolved area in the same patients or intestinal mucosa from healthy controls. Using a human-to-mouse approach, we next showed a similar enzymatic increase in two well-validated IBD murine models and evaluated the therapeutic effect of the potent / GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) (IC = 300 pM). In the dextran sodium sulfate (DSS) colitis model, 2-PMPA inhibited the GCPII activity in the colonic mucosa by over 90% and substantially reduced the disease activity. The significance of the target was confirmed in mice who exhibited resistance to DSS treatment. In the murine IL-10 model of spontaneous colitis, daily 2-PMPA treatment also significantly reduced both macroscopic and microscopic disease severity. These results provide the first evidence of /GCPII enzymatic inhibition as a therapeutic option for IBD.
近期的基因谱分析显示，炎症性肠病（IBD）患者受累肠黏膜中叶酸水解酶（）基因显著上调。该基因编码一种名为谷氨酸羧肽酶II（GCPII）的II型跨膜糖蛋白。为证实先前报道的基因表达增加具有功能性，我们对31份手术标本中的谷氨酸羧肽酶活性进行了定量分析，结果显示，与同一患者的未受累区域或健康对照者的肠黏膜相比，IBD患者受累肠黏膜中的酶活性强劲增加了2.8至41倍。接下来，我们采用人源化小鼠模型，在两种经过充分验证的IBD小鼠模型中证实了类似的酶活性增加，并评估了强效/ GCPII抑制剂2-膦酰甲基戊二酸（2-PMPA）（IC = 300 pM）的治疗效果。在葡聚糖硫酸钠（DSS）结肠炎模型中，2-PMPA使结肠黏膜中的GCPII活性抑制超过90%，并显著降低了疾病活动度。在对DSS治疗具有抗性的小鼠中证实了该靶点的重要性。在自发性结肠炎的小鼠IL-10模型中，每日给予2-PMPA治疗也显著降低了宏观和微观疾病严重程度。这些结果首次证明了/GCPII酶抑制作为IBD治疗选择的有效性。
