The PKD Foundation has awarded a two-year grant totaling $240,000 to support research by USC Stem Cell faculty member Zhongwei Li, PhD . The goal of the project is to establish new lab models that will advance understanding of, and treatment for, a rare genetic condition called autosomal recessive polycystic kidney disease (ARPKD).
Founded in 1982, the PKD Foundation is the only organization in the United States solely dedicated to finding treatments and a cure for polycystic kidney disease, and the largest private funder of research into the illness.
“Today, we are seeing unprecedented momentum in PKD research, and we believe this is the right time to invest boldly in the scientists working to change the future of this disease,” said Susan Bushnell, president and CEO of the PKD Foundation. “Because of the generosity of our donors, we are able to increase our investment in promising research that represents hope for millions of people and families living with PKD.”
ARPKD affects about 1 in 20,000 children, causing liquid-filled cysts to form in the kidney. The cysts, which can appear before birth, are life-threatening to newborns and can result in kidney failure for some patients before they reach adulthood.
“The PKD Foundation really serves patients,” said Li, an associate professor of medicine and of stem cell biology and regenerative medicine at the Keck School of Medicine of USC . “They offer vital resources to study ARPKD, which can lead to new therapies. The Foundation is doing a great thing, and we’re deeply grateful.”
There are no Food and Drug Administration-approved treatments and no reliable biological models that scientists can use to study the disease. Li aims to change that.
He is cultivating scientific models for ARPKD based in two types of biological systems grown from human stem cells. The first is the organoid, which is derived from a type of progenitor cell that gives rise to the collecting duct system that drains urine from the kidney. The second is the assembloid, which is grown from collecting duct progenitor cells combined with cells that develop into the kidney’s filtering units. With success, the project will be a major enabling factor for basic, translational and clinical research tackling ARPKD.
“We need advanced models to understand the disease and eventually help patients,” Li said. “Organoids have advanced rapidly in the past decade, and now we can generate kidney-like structures. We want to make sure that families facing ARPKD benefit from these advances.”
ARPKD primarily affects the collecting ducts. One objective of the project is to generate collecting duct organoids that develop ARPKD-style cysts. Grown in Petri dishes, these model structures could be the source of fundamental insights into the disease. They also could be used in experiments that quickly test huge varieties of potential treatments.
“The advantage of modeling something in vitro is that we can manufacture hundreds of thousands of organoids cost-effectively,” Li said. “With high-throughput drug screening, we can evaluate many candidate therapies at once, which is certainly helpful for drug discovery.”
The second objective is creating assembloids that model ARPKD, which would not only be studied in a lab dish, but also transplanted into mice.
“Two big reasons why drugs fail in clinical trials are kidney toxicity and the differences between animal models and human patients,” Li said. “If we grow diseased human kidneys in mice and test drugs, that will give us far more accurate predictions of drug efficacy and safety.”
The project builds on recent successes from Li’s research group.
The team has developed a collecting duct organoid that closely mimics the structure and function of human tissue. And they’ve shown that they can effectively model a related disease, the more-common autosomal dominant polycystic kidney disease (ADPKD). ADPKD, which accounts for about 90% of PKD cases, is a milder version of the disease that tends to develop during adulthood.
After modeling ADPKD both in the Petri dish with collecting duct organoids and in mice with assembloids, the researchers plan to apply the same principles to model ARPKD.
Another key ingredient is international scientific collaboration. Cell lines with ARPKD-related mutations were provided by two researchers who developed them, Yun Xia, PhD , of Singapore’s Agency for Science, Technology and Research and Ryuji Morizane, MD, PhD , of Harvard Medical School.
“The generosity of these colleagues is a perfect example of how the research community works together to help patients,” Li said.
Coaxing stem cells to produce kidney-like structures has been part of Li’s larger mission for nearly 15 years. He has dedicated his efforts to generating an artificial kidney for patients awaiting an organ for transplantation. Kidneys account for about 80% of the demand for donor organs, and more than 90,000 people are on the kidney donation waitlist in the U.S. alone.
“There’s a huge unmet need, so engineering a transplantable kidney is the ultimate goal of my career,” he said. “Along the way, developing kidney-like tissue in which we can model disease and find new therapies gives us the chance to meaningfully benefit patients with kidney disease.”