Research Project
10080836
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.
