Identification of a New Drug to Treat Polycystic Kidney Disease
Abstract
This proposal is responsive to the FY21 Peer Reviewed Medical Research Program Discovery Award mechanism under the Topic Area of Polycystic Kidney Disease (PKD). Specifically, this project addresses the Area of Encouragement, Research on the underlying pathobiology and molecular mechanisms of polycystic kidney disease, including studies of genetic factors, cyst formation and growth, the role of cilia, and factors that modify disease progression and/or severity. Problem: Currently there is only one treatment, tolvaptan, available for patients with PKD, and patients undergoing tolvaptan therapy can suffer from serious adverse effects, which contribute to low patient compliance of tolvaptan. Further, the effectiveness of tolvaptan in slowing down the progression of PKD is far from ideal. Therefore, more effective treatments with less adverse effects are needed in the area of management of PKD. Solution: We propose that administration of nalfurafine, an orally active biased G-protein coupled kappa opioid agonist (KOA), could offer an improvement over the current standard of care for patient compliance and treatment outcomes since this drug has multiple mechanisms of action that can target PKD and has limited adverse effects. Nalfurafine could also be a suitable treatment for patients at the early stage of disease. PKD affects approximately 600,000 people in the U.S., costing the military and other federal programs more than $20 billion annually for related therapies, tests, dialysis and transplantation. Patients with PKD develop fluid-filled cysts in their kidneys, which appear as growing water-filled bubbles. The larger they become, the more pressure the cysts put on the surrounding healthy tissue, which, in response, becomes inflamed and tough. This destructive spiral leads to a pathological process known as renal fibrosis. The increasingly injured kidneys allow excessive metabolic waste to recirculate in blood, causing severe damage to the kidneys and other organs. In the end, patients must rely on dialysis or kidney transplantation to survive. Currently, tolvaptan is the only medication shown to slow the progression of PKD, but it is far from an ideal medication. Tolvaptan can cause serious side effects, including extreme thirst, frequent urination, and liver toxicity, and is infrequently used clinically due to this drug’s extremely expensive cost. Therefore, it is recommended only in patients at risk for fast progression of PKD. We propose that an oral drug called nalfurafine may present an alternative to the current treatment for PKD with vast improvements. Although not currently approved by the U.S. Food and Drug Administration, nalfurafine is an approved treatment in Japan for excessive itchiness in CKD patients undergoing hemodialysis. Several factors suggest that nalfurafine may be a more effective drug than tolvaptan for treatment of PKD. Like tolvaptan, nalfurafine causes an increase in urine output but acts differently since this drug decreases the blood levels of a critical hormone (vasopressin) shown to be involved in cyst growth in PKD patients. In contrast to tolvaptan, nalfurafine can also reduce inflammation, potentially countering damage caused by the cysts. Nalfurafine activates kappa opioid receptors but, unlike typical opioids, it does not cause the same devastating side effects such as sedation, addiction, dependence, or slowing of respiration. Nalfurafine has been approved for clinical use in Japan, demonstrating safety and commercial availability. Since nalfurafine is more tolerable than tolvaptan for patients to take and has multiple beneficial mechanisms of action to prevent cyst growth, we hypothesize that nalfurafine is a better drug to treat PKD than tolvaptan. To further investigate this hypothesis, a mouse model which highly mimics the disease progression in humans will be used to test two aims: (1) Determine the effects of nalfurafine on cyst formation and growth during the early stag
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210046
Entities
People
- Juan Gao
Organizations
- LSU Health Sciences Center New Orleans
- United States Army