Dissecting the Cystogenic Pathway Driving Polycystic Kidney Disease
Abstract
Topic Area: Polycystic Kidney Disease Research Problem: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common life-threatening, inherited disease, affecting ~1 in 1,000 Americans. It and other related Polycystic Kidney Diseases (PKD) are characterized by growth of fluid-filled cysts that destroy healthy kidney tissue. Treatment options for ADPKD are currently limited to a drug called tolvaptan. Tolvaptan delays renal failure with an average increase in life expectancy of 2.6 years. However, it may cause side effects of chronic thirst, frequent urination, and liver toxicity and is often discontinued for these reasons. There is no cure for PKD, and in ADPKD, more than half of patients develop kidney failure requiring kidney transplant and/or dialysis by their 60s. The high incidence of ADPKD means that patients constitute 10% of individuals in the US with kidney failure. This places a large burden on the healthcare system and greatly impacts patient quality of life. As such, there is a pressing need for new PKD treatments. Innovation: Through comparative analysis of mice engineered to model two distinct forms of human PKD, we discovered a shared factor that causes kidney cysts. Expression of this factor is negligible in healthy kidneys but switches on in PKD. By removing this factor prior to disease development, we prevented cysts from forming. Importantly, removal of this factor in healthy kidneys had no ill effect. Significantly, we discovered this key factor turns on a process often active in cancer, which reinforces the disease. We also successfully reduced disease severity by disrupting this process with a cancer drug. We have since identified several additional proteins that connect these processes and seek to analyze this new disease pathway to find the best way to prevent human disease. Applicability and Impact: PKD is ultimately treated by dialysis and kidney transplant, with Tolvaptan being the only (albeit imperfect) drug treatment capable of slowing ADPKD progression. Our unique approach has led to discovery of a new pathway that causes cyst growth. Furthermore, experimental inhibition of this pathway has prevented disease in two distinct PKD animal models. Due to commonality of this pathway with cancers, identification of contributing factors causing cyst growth has the potential to expand the therapeutic repertoire available for treating PKD because many are the target of FDA-approved drugs for other indications. Because of the limited therapies currently available, even a single new therapeutic compound has the potential to increase the quality of life for PKD patients and reduce the burden on the healthcare system.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110164
Entities
People
- Denny L Cottle
Organizations
- Monash University
- United States Army