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：DFMO 治疗常染色体显性多囊肾病 (ADPKD) ADPKD 是一种重要的人类疾病，影响着 60 万不同种族和民族的美国人约占所有终末期肾病 (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特征（Colton 等等人。 2006，Kan 等人。 2015）。由于 ADPKD 和症状中报告了类似的 M2 免疫特征当 M2 免疫特征被移除时，效果得到改善（Swenson-Fields et al. 2013，Karihaloo et al. 2011，杨等人。 2018），这些数据支持精氨酸到多胺途径在 ADPKD。为了验证这个想法，我们测量了二氟甲基鸟氨酸的能力，它是一种抑制剂多胺合成，改变 ADPKD 直系同源 Pkd1RC/RC 小鼠模型的病程。据菲尔兹等人报道。（2019），我们显着减少了囊肿生长和肾脏生长，并改善了其他 DFMO 治疗 ADPKD 的特点。我们与 DFMO 的结果与类似结果相比非常有利在同一模型中使用托伐普坦治疗获得的结果（Hopp 等人，2015）。使用不同的精氨酸-多胺途径的抑制剂和 ADPKD 的不同小鼠模型，杨等人。 (2018) 的囊肿和肾脏体积的减少与 Fields 类似等人。（2019）并发现肾功能有所改善。有了这些积极的有了现有的数据，我们现在建议确认或拒绝精氨酸的重要性- ADPKD 的多胺途径（图 1）。由于 Pkd1RC/RC 小鼠在 9 个月大时表现出肾功能下降，我们建议用 DFMO 治疗 9 个月以抑制 ODC，与正缬氨酸 (Nva) 一起抑制精氨酸酶，与氨基胍 (AG) 一起抑制精氨酸酶抑制诱导型一氧化氮合酶 (iNOS) 并测量结果，包括肾功能、代谢物和酶水平的测量。等待结果从这些实验中可以看出精氨酸的重要性或不重要性 ADPKD 的多胺途径是否得到证实，这是一个关键的决定推进我们针对 ADPKD 的 DFMO 临床计划的要点。