GLPG2737, a CFTR Inhibitor, Prevents Cyst Growth in Preclinical Models of Autosomal Dominant Polycystic Kidney Disease.

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder that is characterized by the development of fluid-filled kidney cysts, which often lead to kidney failure. The vasopressin receptor 2 antagonist, tolvaptan, is the only approved treatment that slows the progression of ADPKD. There is an unmet need for treatment options for patients with ADPKD because tolvaptan has limited efficacy and non-negligible side effects. In vitro and in vivo data suggest that inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) may be a suitable approach to treating ADPKD. Here, we assessed the capacity of GLPG2737, a CFTR inhibitor, to inhibit cyst growth in preclinical models of ADPKD.

Methods: We investigated the ability of GLPG2737 to modulate CFTR activity in mouse kidney inner medullary collecting duct (mIMCD-3) epithelial cells by measuring chloride flux and to prevent cyst growth in mIMCD-3 cells, cells from human ADPKD kidney donors, and metanephric organ cultures (MOCs). We assessed cyst volume, kidney weight or volume, and blood urea nitrogen (BUN) in two mouse ADPKD models (Pkd1 kidney-specific knockout mouse model; Pkd1RC/RC mouse model) that received GLPG2737, tolvaptan, or their combination. Statistical tests used for data analysis were based on the normality and variance of the data.

Results: GLPG2737 inhibited chloride flux in mIMCD-3 cells with an IC50 of 2.41 µm. In a 3D assay, GLPG2737 inhibited cyst growth in both wild-type (IC50 = 2.36 µm) and Pkd1 knockout (IC50 = 2.5 µm) mIMCD-3 cells. Preincubation of human ADPKD kidney cells with 10 µm of GLPG2737, 10 µm of tolvaptan, or their combination prevented forskolin-induced cyst growth by 40%, 29%, and 70%, respectively. Furthermore, 10 µm of GLPG2737 inhibited cyst growth in MOCs, decreasing the cyst area by 67% and the number of cysts per area by 46% after 6 days of culture. In both in vivo models, GLPG2737, tolvaptan, or their combination improved the projected cyst volume. In the Pkd1RC/RC model, GLPG2737 also improved the total kidney volume normalized to tibia length (LnTKV) and BUN, while tolvaptan improved the LnTKV and fibrosis but did not lower BUN at sacrifice. The combination reduced all parameters measured in the Pkd1RC/RC model, including cyclic adenosine monophosphate content in the kidneys.

Conclusions: Our findings in preclinical models provide evidence of the therapeutic potential of CFTR inhibition and its possible combination with tolvaptan. The present work shows that targeting CFTR is a valid strategy to slow ADPKD progression.