Small Molecule Activators of Polycystin-2 to Treat Autosomal Dominant Polycystic Kidney Disease

Loss of function mutations in the genes PKD1 and PKD2 cause about 80% and 15% of autosomal dominant polycystic kidney disease (ADPKD) type 1 and type 2, respectively (1, 2, 3, 4, 5). Patients with ADPKD develop bilateral cystic kidneys, resulting in detectable decline in kidney function about 12 years prior to end-stage renal disease (ESRD), which occurs at median age of 58 (type 1) or 79 (type 2) (5). While the severity of disease progression is variable and dependent on genetic and environmental factors, the relative rate of progression of total kidney volume growth (TKV) and function decline can be reasonably predicted by a combination of clinical and genetic markers (5, 6, 7). Estimates on incidence and prevalence vary between 1:400 and 2.7:10000 based on study methodology, but best estimates suggest there are 300,000 patients in the U.S. living with ADKPKD (5, 8). Currently, no curative treatment exists for ADPKD; the aquaretic vasopressin receptor antagonist Tolvaptan was approved for ADPKD in 2018, however liver toxicity has limited its distribution (5). In addition, it does not address the primary defect present as a result of genetic mutation in ADPKD. No direct modulators of PKD2 activity are known to be in development. PKD1 and PKD2 encode polycystins (PC1 and PC2), which together form a complex and are found on the surface of primary cilia in epithelial cells of the kidney collecting duct. PC2, or TRPP2, functions as a calcium conductive ion channel (3). PC1 is postulated to have atypical GPCR-like function, and it aids in trafficking, stabilization, and activation of PC2 in the primary cilia through direct physical interaction between the c-terminal domains of PC-1 and PC-2 (9, 10, 11, 12). In the absence of PC1, PC2 ion channels are still capable of trafficking to and functioning in the primary cilia, but in reduced number (13, 14, DeCaen unpublished data). In addition, point mutations in PC2 which do not perturb PC1 or PC2 trafficking to the cilia,