Research Awards Recipients

Co-Applicant(s):  Darren Yuen

Lay Abstract

Despite recent advances in care, kidney failure remains a major health problem. We urgently need new treatments to prevent the development of kidney failure. Unfortunately, even if a new discovery is made in the lab, the pathway from discovery to the availability of a new treatment is very long and fraught with failure. This pathway can often take 15-25 years, and even if a medication makes it as far as being tested in patients, it only has a 1 in 10 chance of success. In the current proposal, we will circumvent these major and lengthy obstacles by testing a medication already used in patients for another reason. This is called drug repurposing and the medication that we will test is called istradefylline. Istradefylline is a medication that was approved by the United States Food and Drug Administration in 2019 for the treatment of Parkinson’s disease. It is safe, has few side effects, is taken once daily by mouth and, importantly, it can be used without increased risk in people with kidney disease. Istradefylline works by blocking a protein on cells called the adenosine A2A receptor (or A2A for short). We recently discovered that A2A is important in the development of kidney failure. Irrespective of its original cause, when kidney disease progresses to kidney failure it does this through scarring of the kidney, which is also called ‘fibrosis’. To look for potential treatment opportunities for kidney scarring, we took individual single scar-forming cells from diseased kidneys and we looked at what proteins were on their surfaces that could be targeted by new treatments. One of those proteins was A2A. A2A is one of four proteins on cell surfaces that are called adenosine receptors. Interestingly, many people consume an adenosine receptor blocker every day without knowing it. That blocker is caffeine. When we put caffeine in the water that mice with kidney disease drank, it reduced the amount of kidney scarring that developed. The problem is that caffeine blocks all the adenosine receptors, not just A2A. While we were searching for a specific A2A blocker to test, we came across istradefylline, which is very specific for A2A and which was recently approved in the U.S. for the treatment of Parkinson’s disease. In the current proposal we will study whether removing just A2A from kidney scar-forming cells slows kidney disease development, and we will test to see whether istradefylline reduces kidney fibrosis in experimental models, mimicking the way it might be used in people with kidney disease. If the experiments are successful, the data should be sufficient to support moving directly into a clinical trial of istradefylline as a treatment for kidney fibrosis, overcoming most pre-existing drug development hurdles.