DFMO Therapy for Polycystic Kidney Disease

摘要：DFMO治疗常染色体显性遗传性多囊肾病(ADPKD) ADPKD是一种重要的人类疾病，影响着60万所有种族和民族的美国人 研究背景约占终末期肾病(ESRD)的10%。我们发现免疫- 脑部疾病中精氨酸代谢的基础代谢重编程是基于M2免疫 部分定义为精氨酸到多胺途径中精氨酸酶过度表达的信号(Colton et 艾尔2006年，Kan等人。2015年)。由于在ADPKD和症状中报告了类似的M2免疫特征 在去除M2免疫签名后得到了改进(Swenson-Fields等人)。2013年，Karihaloo等人。2011年， Yang等人。2018年)，这些数据支持精氨酸到多胺的途径在 ADPKD.为了验证这一想法，我们测量了二氟甲基鸟氨酸的能力，它是一种 多胺合成，改变ADPKD同源Pkd1RC/RC小鼠模型的病程。 正如Fields等人所报道的那样。(2019)，我们显著减少了囊性生长和肾脏生长，并改善了其他 DFMO治疗ADPKD的特点。我们的DFMO结果与类似的结果相比非常有利 在同一模型中用托伐普坦治疗获得的结果(Hopp等人)。2015年)。使用不同的 精氨酸-多胺途径的抑制剂和不同的ADPKD小鼠模型， Yang等人。(2018)在囊肿量和肾脏体积方面显示出与Fields相似的减少 等人的研究。(2019)，并发现肾功能有所改善。有了这些积极的东西 数据在手，我们现在建议确认或拒绝精氨酸的重要性- 通往ADPKD的多胺途径(图1)。自9个月龄的Pkd1RC/RC小鼠出现 肾功能下降，我们建议用DFMO治疗9个月以抑制 ODC，用去甲伐他林(NVA)抑制精氨酸酶，用氨基胍(AG)抑制精氨酸酶 抑制诱导型一氧化氮合酶(INOS)并测量结果，包括 测量肾功能、代谢物和酶水平。等待结果 从这些实验中，精氨酸的重要性或非重要性- ADPKD的多胺途径是否得到确认是一个关键的决定 这是推进我们在ADPKD中进行DFMO临床计划的要点。

Abstract: DFMO Therapy for Autosomal Dominant Polycystic Kidney Disease (ADPKD) ADPKD is an important human disease affecting 600,000 Americans of all racial and ethnic backgrounds and accounts for about 10% of all end-stage renal disease (ESRD). We discovered that immune- based metabolic reprogramming of arginine metabolism in brain disease is based upon an M2-immune signature that is defined, in part, on arginase over-expression in the arginine to polyamine pathway (Colton et al. 2006, Kan et al. 2015). Since a similar M2-immune signature was reported in ADPKD and symptoms improved when the M2-immune signature was removed (Swenson-Fields et al. 2013, Karihaloo et al. 2011, Yang et al. 2018), these data support that the arginine to polyamine pathway plays an important role in ADPKD. To test this idea, we measured the ability of difluoromethylornithine, which is an inhibitor of polyamine synthesis, to change the course of disease in the orthologous Pkd1RC/RC mouse model of ADPKD. As reported in Fields et al. (2019), we significantly reduced cyst growth and kidney growth and improved other characteristics of ADPKD with DFMO treatment. Our results with DFMO compare very favorably to similar results obtained with Tolvaptan treatment in this same model (Hopp et al. 2015). Using a different inhibitor of the arginine-polyamine pathway and a different mouse model of ADPKD, Yang et al. (2018) showed similar reductions in cyst and kidney volumes to Fields et al. (2019) and found improvements in kidney function. With these positive data in hand, we now propose to confirm or reject the importance of the arginine- polyamine pathway to ADPKD (Figure 1). Since Pkd1RC/RC mice at 9-months show decreased kidney function, we propose treating for 9-months with DFMO to inhibit ODC, with Norvaline (Nva) to inhibit arginase, and with Aminoguanidine (AG) to inhibit inducible nitric oxide synthase (iNOS) and measure outcomes including measures of kidney function, metabolites and enzyme levels. Pending the results from these experiments, the importance or non-importance of the arginine- polyamine pathway to ADPKD will be confirmed or not, which is a critical decision point for moving forward with our clinical program for DFMO in ADPKD.