Arginine-Polyamine Pathway Inhibitor for Treatment of ADPKD

Our overarching goal is to develop an orally-available, effective, and well-tolerated drug to treat ADPKD patients and where our drug lacks the liver toxicities associated with Tolvaptan. ADPKD is an important human disease affecting at least 350,000 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, by 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 cell signature was removed (Swenson-Fields et al. 2013, Karihaloo et al. 2011, Yang et al. 2018), then it appears that the arginine to polyamine pathway plays an important role in ADPKD. More recent metabolic profiling further confirmed that the arginine-polyamine pathway and its polyamine products were increased with development of disease in a validated model of ADPKD (Hopp et al. 2022). To test the idea that blocking the arginine-polyamine pathway could be therapeutic, we measured the ability of an inhibitor of polyamine synthesis to change the course of disease in the validated, orthologous and clinically relevant Pkd1RC/RC mouse model of ADPKD. As reported in Fields et al. (2019) and in our proposal, we significantly reduced cyst growth and kidney growth and improved other characteristics of ADPKD with DFMO treatment. More recently, we showed that DFMO treatment significantly lowered plasma BUN levels in addition to reducing kidney pathology, indicating that kidney function was improved, a clinically desirable result. Our results with DFMO compare very favorably to similar results obtained with Tolvaptan treatment in this same validated model (Arroyo et al. 2021). With this Proof-of-Concept in hand, we have now created more potent and patent pending composition-of-matter analogs of DFMO. In this project, we propose to create additional analogs of DFMO, profile them by measuring their effects on Glomerular Filtration Rates, total kidney volumes and cyst volume in Hopp’s validated model of ADPKD. Using this data, we will create a composite score and select the best compound that displays a favorable combination of attributes following initial safety profiling, pharmacokinetic/pharmacodynamics profiling, and polyamine reduction activities. The efficacy of the best compound will then be tested in the validated Pkd1RC/RC mouse model of ADPKD. The results of this testing will then permit us to move forward with GLP pre-clinical safety/toxicity studies and subsequent clinical trials for an ADPKD indication.