ARPKD affects roughly one in 20,000 children. The disease causes liquid-filled cysts to form in the kidney, and those cysts can appear even before a child is born. For newborns, they can be life-threatening, and for some patients the damage accumulates until the kidneys fail before adulthood. The segment of the kidney primarily affected is the collecting duct, the network of tubules responsible for draining urine from the organ. Because the disease is rare and its cellular origins are difficult to access in living patients, researchers have long lacked the experimental systems needed to watch the disease unfold at the cellular level, let alone to screen potential therapies against it. Li’s project is designed to close that gap.

The strategy rests on two complementary types of lab-grown biological systems, both derived from human stem cells. The first is the organoid, a three-dimensional structure grown from a type of progenitor cell that gives rise to the collecting duct system. In a Petri dish, these organoids self-organize into elongated tubules that closely mimic the architecture and function of human collecting duct tissue. The second is the assembloid, a more complex construct grown by combining collecting duct progenitor cells with cells that develop into the kidney’s filtering units, allowing two distinct compartments of the organ to be modeled together. With success, the project’s organizers say, these systems could become a major enabling factor for basic, translational and clinical research tackling ARPKD.

The power of the organoid approach lies in scale and speed. Because the structures are grown from human cells in culture, researchers can manufacture hundreds of thousands of them cost-effectively, according to Li. That opens the door to high-throughput drug screening, in which vast libraries of candidate compounds can be evaluated simultaneously against diseased tissue. Instead of testing one drug at a time in slow and expensive animal studies, scientists can rapidly identify the most promising molecules in vitro and then advance only the strongest candidates. For a disease as rare as ARPKD, where commercial incentives for drug development are limited, such a screening platform could dramatically lower the barriers to discovering new therapies.

The assembloid arm of the project addresses a different and equally stubborn problem in drug development: the failure of treatments that looked promising in the lab but collapsed in clinical trials. Li points to two major reasons such failures occur, kidney toxicity and the biological differences between animal models and human patients. His team’s plan is to grow diseased human kidney tissue in the form of assembloids and transplant it into mice, creating what researchers describe as a humanized model of the disease living inside an animal host. Drugs tested against that tissue would, in principle, yield far more accurate predictions of both efficacy and safety in human patients than conventional animal models can provide, because the target tissue itself would be human.

The project does not begin from scratch. Li’s research group has already developed a collecting duct organoid that closely mimics the structure and function of human tissue, and the team has shown that it can effectively model a related, more common condition: autosomal dominant polycystic kidney disease, or ADPKD. ADPKD accounts for about 90 percent of all polycystic kidney disease cases and is generally a milder illness that tends to emerge during adulthood rather than before birth. Having modeled ADPKD both in Petri dishes with collecting duct organoids and in mice with assembloids, the researchers now plan to apply the same principles to ARPKD, adapting systems they have already validated to a rarer and more severe form of the disease.

International collaboration supplies another key ingredient. Cell lines carrying ARPKD-related mutations were provided by the 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. These mutated cell lines serve as the starting material from which the diseased organoids and assembloids will be grown, embedding the genetic defects that drive cyst formation into the lab-grown tissue itself. Li has described the generosity of these colleagues as a perfect example of how the research community works together to help patients, a reminder that progress on rare diseases often depends on scientists sharing hard-won tools across institutions and continents.

The grant also reflects a deliberate strategic bet by the funder. The PKD Foundation, founded in 1982, is the only organization in the United States solely dedicated to finding treatments and a cure for polycystic kidney disease, and it is the largest private funder of research into the illness. Susan Bushnell, the foundation’s president and CEO, said that the field is seeing unprecedented momentum in PKD research and that the organization believes this is the right time to invest boldly in the scientists working to change the future of the disease. Because of the generosity of donors, she noted, the foundation is able to increase its investment in promising research that represents hope for the millions of people and families living with PKD.

For Li, the ARPKD project is one milestone within a much larger scientific mission. For nearly 15 years, he has worked on coaxing stem cells to produce kidney-like structures, with the long-term goal of engineering an artificial kidney for patients awaiting an organ transplant. The scale of that unmet need is enormous: kidneys account for about 80 percent of the demand for donor organs, and more than 90,000 people are on the kidney donation waitlist in the United States alone. Engineering a transplantable kidney, Li has said, is the ultimate goal of his career, but along the way, developing kidney-like tissue in which disease can be modeled and new therapies found offers the chance to meaningfully benefit patients with kidney disease now.

The significance of the work extends beyond a single rare disease. If collecting duct organoids and kidney assembloids prove reliable models for ARPKD, the same platforms could accelerate research into ADPKD and other disorders of the kidney’s tubular and filtering systems, and could sharpen the preclinical testing pipeline for any drug destined for the kidney. The approach also illustrates a broader shift in biomedical science, as human stem cell-derived tissues increasingly replace or supplement animal models whose biology often fails to translate to patients. For the families facing ARPKD, a condition that currently offers few answers, the grant represents something concrete: a funded, technically grounded path toward the models that drug discovery requires, built from the very cells where the disease begins.

Subject of Research: Development of human stem cell-derived organoid and assembloid models for autosomal recessive polycystic kidney disease research

Article Title: PKD Foundation provides support for kidney disease research by USC Stem Cell’s Zhongwei Li

Article References: PKD Foundation provides support for kidney disease research by USC Stem Cell’s Zhongwei Li. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: polycystic kidney disease, ARPKD, organoids, assembloids, stem cells, kidney disease, PKD Foundation, drug screening, collecting duct, USC Stem Cell, genetic disease, transplantation