Nephrologist Lloyd Cantley, MD, C.N.H. Long Professor of Medicine and professor of cellular and molecular physiology, has long had a scientific interest in polycystic kidney disease (PKD). Now he is taking this work to the next level. He is principal investigator of a $11.577 million study funded by the U.S. Department of Defense (DoD). The study, titled “Polycystic kidney disease: a disorder of glomerulotubular synchronization,” brings together five senior investigators at Yale, all leaders in their respective fields, to develop effective therapies for PKD.
“The most common form of PKD is autosomal dominant,” says Cantley. Autosomal polycystic kidney disease (ADPKD) is an inherited disorder in which clusters of cysts develop in the kidneys, causing them to lose function over time. It is the fourth leading cause of renal failure in the U.S., affecting some 600,000 people annually.
“You only need one copy of the gene to get the disease, so if either of your parents has it, you have a 50 percent chance of getting it.” The cysts that form in the kidneys, and sometimes in the liver, create a myriad of health problems, from hemorrhage and infection to massive organ enlargement. Symptoms typically begin in early adulthood, although cysts can be present from birth or early childhood. In most cases, kidney function eventually fails and patients need dialysis and a kidney transplant.
Mutations in one of two genes (PKD1 or PKD2) account for most cases of ADPKD. These mutations create cells that lack the normal function of the polycystin proteins, leading to an increase in kidney cell division, ultimately resulting in cyst growth and organ dysfunction. “Both types of mutations eventually lead to renal failure in many cases,” says Cantley. “The only medication approved to treat PKD provides a modest benefit, with many patients still progressing to renal failure. So there is a need and an opportunity to find more effective therapies.”
Cantley studies the mechanisms of renal tubule formation and repair. “In PKD, it’s the tubules that are defective.” he explains, adding that the failure to identify effective therapies for PKD stems from a lack of understanding of the effects of mutations on normal tubule biology. “By gaining a greater understanding of polycystins and what they do, we hope to develop a therapy that will not disrupt the tubules’ normal function, but rather disrupt this abnormal function caused by the mutation.”
The grant is part of the DoD’s Peer Reviewed Medical Research Program, which supports studies with direct relevance to military health. The program is highly competitive, funding only four projects a year. “DoD has identified priority areas for supporting research to help veterans and active military live a better, healthier life,” notes Cantley. “PKD is one of them, affecting both young people—the age of active military—and veterans. These awards are much larger than a standard grant. The concept is that you assemble a team of scientists, not just one or two, and the DoD will provide substantial resources to tackle a problem of significance to the military community.”
This project began conceptually as the result of a longstanding collaboration among Cantley and two other investigators: geneticist and PKD expert Stefan Somlo, MD, C.N.H. Long Professor of Medicine, professor of genetics, and chief of the Section of Nephrology; and Michael Caplan, PhD, MD, C.N.H. Long Professor and Chair of Cellular and Molecular Physiology and professor of cell biology. Cantley describes Somlo as “the paramount PKD researcher here at Yale, and to be honest, in much of the world.” Caplan is known for his studies of signaling pathways that are regulated by polycystins, and has especially focused on how these can be targeted for therapeutic benefit to patients. The trio identified a fourth investigator, adjunct professor Laura Niklason, PhD, MD, founder and CEO of a biotech company specializing in tissue engineering. Although not previously focused on studies of tubule biology, her pioneering work in developing bioengineered vascular-mimetics made her an ideal candidate to create bioengineered epithelial tubes to mimic kidney tubules.
The first grant application, made in 2019, received high ratings, but the DoD returned with a critique, saying it lacked a focused program around developing a therapeutic. “To them, that was a must,” says Cantley. An additional investigator with deep experience in drug development was recruited: Craig Crews, PhD, John C. Malone Professor of Molecular, Cellular and Developmental Biology, professor of pharmacology, and professor of chemistry. Cantley reapplied in 2020, and this time his application was accepted.
The team will first test their theories in vitro, with Niklason’s bioengineered tubes, toward the goal of identifying a therapeutic that Crews will develop further. Says Cantley: “Once we have an in vitro model, the next step is further studies in mouse models, ideally to obtain data for clinical trials. Our five-year target is to develop a pre-clinical compound that could be the focus for clinical trials.”