DFMO Therapy for Polycystic Kidney Disease

DFMO 治疗多囊肾病

基本信息

批准号：
10080836
负责人：
MICHAEL PETER VITEK
金额：
$ 29.99万
依托单位：
RESILIO THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080836
关键词：
ARG2 gene Address Adult Affect American Anabolism Animal Disease Models Animal Model Apoptosis Arginine Autosomal Dominant Polycystic Kidney Autosomal Recessive Polycystic Kidney Biochemical Pathway Blood Blood Urea Nitrogen Brain Diseases Cancer Patient Carboxy-Lyases Characteristics Chronic Kidney Failure Citrulline Clinical Clinical Research Clinical Trials Control Animal Creatinine Cyst DL-alpha-Difluoromethylornithine Data Dichloromethylene Diphosphonate Disease Disease Outcome Dose End stage renal failure Enzymes Epithelial Cell Proliferation Epithelial Cells Excision FDA approved Fibrosis Future Genes Growth Growth Factor Hand Human Immune Immune System Diseases Inflammation Intercept Kidney Kidney Diseases Knockout Mice Liver Longevity MYC gene Malignant Neoplasms Measures Metabolic Metabolism Modeling Mus NOS2A gene Neoplasms Nephrons Neuroblastoma Nitric Oxide Synthetase Inhibitor Oral Ornithine Outcome Outcome Measure Pathway interactions Patients Pharmaceutical Preparations Phase Pilot Projects Play Polyamines Polycystic Kidney Diseases Production Progression-Free Survivals Proteins Quantitative Reverse Transcriptase PCR Renal function Reporting Role Safety Serum Small Business Technology Transfer Research Source Stress Testing Time Urine Water Weight Western Blotting Yang aminoguanidine arginase base brain dysfunction cell growth cell type experimental study human disease immunocytochemistry improved indexing inhibitor/antagonist macrophage meetings mouse model norvaline overexpression programs racial and ethnic renal epithelium response symptomatic improvement tolvaptan uptake

项目摘要

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.

摘要：常染色体显性多囊肾脏疾病（ADPKD）的DFMO治疗 ADPKD是一种重要的人类疾病，影响了60万种种族和种族的美国人背景和大约占所有末期肾脏疾病（ESRD）的10％。我们发现免疫 - 精氨酸代谢在脑部疾病中的代谢重编程是基于M2-免疫的精氨酸在多胺途径的精氨酸酶过表达中部分定义的签名（Colton et al。 2006年，Kan等。 2015）。由于在ADPKD和症状中报道了类似的M2-免疫特征去除M2-免疫特征时会有所改善（Swenson-Fields等人，2013年，Karihaloo等人，2011年，2011年，杨等。 2018年），这些数据支持多胺途径的精氨酸在 ADPKD。为了测试这个想法，我们测量了二氟甲基氨酸的能力，这是多胺合成，以改变ADPKD的直系同源PKD1RC/RC小鼠模型中的疾病进程。如Fields等人的报道。（2019年），我们大大降低了囊肿的生长和肾脏的生长并改善了其他 DFMO处理的ADPKD的特征。我们使用DFMO的结果非常有利在同一模型中用Tolvaptan处理获得的结果（Hopp等，2015）。使用其他精氨酸聚胺途径的抑制剂和ADPKD的不同小鼠模型，杨等。（2018）显示出类似减少的囊肿和肾脏量与田野的减少等。（2019年），发现肾功能的改善。这些积极数据掌握的数据，我们现在建议确认或拒绝精氨酸的重要性多胺途径通往ADPKD（图1）。由于PKD1RC/RC小鼠在9个月的表演中肾功能降低，我们建议用DFMO治疗9个月以抑制 ODC，用诺瓦林（NVA）抑制精氨酸酶，以及氨基瓜氨酸（Ag）至抑制诱导型一氧化氮合酶（iNOS）和测量结果肾功能，代谢物和酶水平的度量。等待结果从这些实验中，精氨酸的重要性或不重要性多胺通往ADPKD的途径将被确认是否确认，这是一个关键决定在ADPKD中使用DFMO的临床计划前进的要点。