Drug Inhibition of KCa3.1 Channel KCNN4 as a Strategy to Retard Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease
Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is considered the most common of the life-threatening hereditary diseases. Only a single genetic mutation in one of the two genes, PKD1 or PKD2, is needed to cause the disease. Such a mutation is found in 1 of every 500-1000 individuals, and 50% of individuals with the mutation will develop kidney disease that ultimately requires treatment by dialysis or by renal transplantation. ADPKD accounts for ~10% of the end-stage renal disease population in the United States. Each family has a unique mutation in one of the two ADPKD disease genes. The mechanisms by which all these mutations lead to development of PKD remains unclear. Also unclear is why only 50% of mutation carriers develop disease and why affected individuals within a single family can exhibit highly variable disease severity. Doctors do not have any Food and Drug Administration-approved treatment for ADPKD to offer patients in the United States. Tolvaptan has been approved in Europe for treatment of ADPKD, but concerns remain about liver toxicity, and the uniformly experienced, greatly increased urine volume can cause considerable interference with activities of daily life in otherwise healthy disease carriers. We propose to investigate a novel mechanism that contributes to the slow enlargement of cysts in the kidneys of ADPKD patients. This slow cyst enlargement is believed primarily responsible for the eventual loss of normal function in adjacent non-cystic kidney tissue ultimately leading to end-stage renal disease. A drug to slow cyst enlargement holds promise to delay total kidney enlargement and to delay the disease-associated decline in renal function. If that delay can be sufficiently prolonged, then patients with enlarged cystic kidneys caused by ADPKD will be able to live out their lives without need for dialysis or kidney transplant. Cysts enlarge by secreting salt and water into their central sacs (called lumens). The water transport requires the accompanying salt, and the salt transport requires the cells that surround each cyst to be able to freely recirculate potassium ion on the side of the cyst cell away from the cyst lumen. Some time ago we discovered a drug that potently and specifically blocks that process of potassium ion recirculation. A related drug, senicapoc, was created and shown to be nontoxic in patients with several non-kidney diseases. We now propose experiments in three mouse models of ADPKD to test the hypothesis that senicapoc can eventually be developed as an effective and well-tolerated treatment to delay cyst enlargement in human ADPKD patients. Our experiments will compare the three mouse models to similar mice in which the protein target for senicapoc, the potassium channel KCNN4, has been inactivated by genetic engineering. Our preliminary results indicate that progression of polycystic disease in these latter mice is indeed slowed. After completion of the mouse genetic experiments, we will test whether senicapoc treatment of mouse models of ADPKD with normal expression of their native KCNN4 potassium channel protein will retard progression of polycystic disease to the same extent as in mouse models of ADPKD that are genetically deficient in KCNN4. If senicapoc can completely or partially reproduce the slowing of disease produced by genetic deletion of the senicapoc target protein KCNN4, then senicapoc will be considered a good candidate for development as a potential drug for human ADPKD patients. We will also perform experiments with mouse kidney tissue in organ culture and with human cyst-forming epithelial cells originally derived from patients with ADPKD. In these experiments, we also will compare the effect of genetic deletion or decrease in expression of senicapoc target KCNN4 with simple exposure of the tissue and cultured cells to the drug senicapoc. Here, too, if senicapoc can slow the formation of cysts in experimental tissue and cel
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810463
Entities
People
- Seth Alper
Organizations
- Beth Israel Deaconess Medical Center
- United States Army