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are still capable of trafficking to and functioning in the primary cilia, but in reduced number (13, 14, DeCaen unpublished data).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, but do interrupt PC2 ion channel activity, are sufficient to cause cystic kidney phenotypes in humans (15, 16). These two pieces of data lead to the hypothesis that dose-dependent loss of PC2 calcium channel activity in the primary cilia drives cystic kidney formation. This hypothesis is supported by human genetic data; PKD2 mutations are the most severe genetic modifiers of PKD1 mutations in ADPKD patients. Patients with PKD1 mutations who have a second mutation in PKD2 show much more severe disease than their parents, who have mutations in one or the other, in every case (17, 18, 19). This phenomenon is also true in mouse models: Mice with PKD1+/-: PKD2+/- phenotypes show much earlier cyst formation than PKD1+/- or PKD2+/- mice (20). These data indicate that conditions that decrease PC2 amount in the primary cilia, or PC2 channel activity, or both, ultimately reduce ion flux in the primary cilia, with conditions with the lowest flux causing the most severe clinical forms of ADPKD. The therapeutic hypothesis of this initiative is that a small molecule activator of the ion channel activity of PC2 will slow cyst growth and improve outcomes in patients with ADPKD type 1 and type 2. In validation of this target and approach, it is known that in mouse models of ADPKD type 2 with loss of function mutations or knockout of PKD2, overexpression of PKD2 6 rescues cystic kidney growth (21). In mouse models of ADPKD type 1, PKD1 knockout or induced loss of expression through a TetOff transgene also cause cystic kidneys in mice (22). Overexpression of PKD2 also rescues the cystic kid