Current Funded Research

Targeting Renal Urate Transport to Suppress Cystogenesis in ADPKD 

This research is studying how a newly discovered urate pathway inside kidney cells may affect cyst growth in ADPKD. The preliminary data suggests that regulating urate could be an alternative way to slow cyst growth without impacting thirst and frequency of urination which are the most common side effects of the ADPKD treatment tolvaptan. By understanding this process, drugs targeting the urate pathway could offer better treatments with fewer side effects for people living with ADPKD. To save drug development time, this study tests existing drugs (lesinurad and febuxostat). The results from this study aim to confirm an important treatment pathway for the future, that would offer fewer side effects, long-term use, and real slowing of the disease.

Fouad T. Chebib, M.D., FASN, is a professor of medicine, nephrologist, and physician-scientist at Mayo Clinic, Florida. He helped establish the Mayo Clinic Tolvaptan Clinic and has contributed to major ADPKD clinical trials and U.S. consensus guidelines. Additionally, Dr. Chebib directs the Mayo Clinic Florida PKD Foundation Center of Excellence and the Discovery and Translational PKD Research Lab.   

Dr. Chebib’s clinical and research focuses include clinical trials, molecular mechanisms of cystogenesis, precision imaging, gene therapy, and development of novel therapies for PKD. His lab is advancing innovative and AI-driven personalized therapies, an important step toward Dr. Chebib’s lifelong goal of eliminating the need for dialysis in ADPKD.   

 Gene Editing for ADPKD 

Current treatments for autosomal dominant polycystic kidney disease (ADPKD) can slow the disease progression, but they don’t fix the genetic cause and may have difficult side effects. This project is testing a new way to treat ADPKD by using CRISPR gene editing to fix changes in the PKD2 gene, one of the genes responsible for ADPKD. Dr. Chung’s lab plans to use tiny, kidney-targeted carriers called nanoparticles to deliver the gene-editing tools directly to the kidney cells where cysts start. If successful, this approach could reduce cyst growth, slow or stop disease progression, and lead to longer-lasting treatments with fewer side effects for people with PKD. Dr. Chung aims to open the door to a completely new class of therapies for PKD, ones that correct the disease rather than just manage it.

Eunji Chung, Ph.D., is an associate professor in the Department of Biomedical Engineering at the University of Southern California (USC) and the Dr. Karl Jacob Jr. and Karl Jacob III Early Career Chair. She’s the founding director of the USC Transformative Center for Nanomedicine and Drug Delivery, has various courtesy appointments at USC, and is an affiliated faculty member of the Norris Cancer Center and the Stem Cells department. Dr. Chung is a fellow of multiple medical societies; serves as associate editor for Bioactive Materials; and has received honors such as the K99/R00 NIH Pathway to Independence Award, AIChE 35 Under 35, NIH Director’s New Innovator Award (DP2), and more.   

Dr. Chung’s lab is interested in developing nano-to-macroscale biomaterials for medicine, with a particular focus on gene therapies using nanocarriers for PKD. Currently, her lab takes part in national centers and programs including the NIH U54 Kidney O’Brien Center, Chan Zuckerberg Initiative (CZI) Exploratory Cell Networks, and AHA Collaborative Sciences Award.  

 International Consortium for Intracranial Aneurysms in ADPKD 

 In patients with autosomal dominant polycystic kidney disease (ADPKD), up to 15% will develop bulges in blood vessels in the brain called intracranial aneurysms (ICAs) and have a seven-fold increased lifetime risk of bleeding in the space around the brain compared with the average non-PKD patient. Dr. Gilbert and colleagues will use a large collection of patient health data and genetic information from the International Consortium for Intracranial Aneurysms in ADPKD to study how screening affects the risk of serious bleeding and creates a score that uses both medical and genetic information to predict risk. This could help doctors decide which patients need screening or treatment the most, leading to better care and future research. 

Dr. Gilbert is a geneticist and co-principal investigator in the Human Genetic Research Group at the School of Pharmacy and Biomolecular Sciences at RCSI, Dublin. His Ph.D. and postdoctoral research investigated the population genetics landscape of Ireland and its links to neighboring populations in Britain, and extended this to diasporic populations such as those in Newfoundland, Canada. As a postdoctoral researcher, he started work applying population genetic approaches to disease genetics, investigating haplotype diversity in monogenic forms of kidney disease, and contributing to analysis of polygenic risk in kidney disease. His research group works at the intersection of population genetics and disease, applying population-genetic approaches to identify and study the history of disease variants, particularly in renal disease where he is a long-term collaborator with Peter Conlon, RCSI.  

Novel in vitro and in vivo Organoid Platforms for High-Fidelity ARPKD Modeling 

While there are two types of polycystic kidney disease (PKD), autosomal dominant (ADPKD), and autosomal recessive (ARPKD), the only FDA-approved drug available is for ADPKD. One challenge is that current animal and lab models don’t progress the same way that ARPKD progresses in people, which makes it harder to study the disease and test new treatments. This project will create two new human kidney models using stem cells: one model for testing possible drugs in the lab, and the other to grow ARPKD-like kidney tissue in live mice to better study the disease. Dr. Li’s team has previously built similar kidney models and shown they can recreate key features of PKD. These new models could give researchers better tools to understand ARPKD, find new treatment targets, and test future therapies.

 Zhongwei Li, Ph.D., is an associate professor of medicine and of stem cell biology and regenerative medicine at the University of Southern California’s Keck School of Medicine. He’s the recent winner of the NIH Director’s New Innovator Award. As a stem cell biologist, Dr. Li’s research focuses on kidney development, regeneration, and disease. His lab develops and applies human pluripotent stem cell-based models, including kidney organoids and assembloids, to investigate disease mechanisms, discover new therapeutics, and advance regenerative medicine. His work has helped establish increasingly sophisticated human kidney models that more faithfully recapitulate kidney structure and function, creating new opportunities for studying kidney diseases, including polycystic kidney disease (PKD), and accelerating therapeutic discovery.  

The long-term goal of his research is to generate transplantable stem cell-derived kidneys as a renewable source of tissue for kidney replacement therapy. His work is supported by the National Institutes of Health (NIH), the California Institute for Regenerative Medicine (CIRM), the University Kidney Research Organization (UKRO), and the PKD Foundation. Dr. Li is the recipient of the NIH Director’s New Innovator Award (2022) and the Young Investigator Award from the Chinese American Society of Nephrology (2025).  

Establish a Zebrafish Platform for Discovering Genetic Modifiers of ADPKD

People with autosomal dominant polycystic kidney disease (ADPKD) experience a wide variety in the timing and severity of their symptoms. Researchers believe certain genes, called genetic modifiers, may affect when symptoms start and how fast the disease progresses. Current ways to find these genes can be slow, expensive, and hard to confirm.  

This project will study if changes to genes outside of the common PKD1 and PKD2 genes cause ADPKD to be more severe in some patients than others. To do this, the study uses zebrafish which are easy to work with, inexpensive, can be tested in large numbers, and can help researchers evaluate multiple genes quickly. This study will test about 50 genes and may identify up to five new genes that affect cyst growth, immune response, inflammation, and scarring in ADPKD. These findings could help researchers better understand disease progression and may lead to new treatments that delay symptoms and slow kidney failure. 

Xueying Lin, Ph.D., is an assistant professor in the Department of Biochemistry and Molecular Biology at Mayo Clinic, Rochester, and a member of the Mayo Clinic Translational PKD Center. Her research focuses on developing adult zebrafish as a relevant vertebrate model of cystic kidney disease and establishing efficient approaches, including F0-based genetic screening platforms, for the systematic identification of modifier genes regulating kidney cyst formation and cyst-associated pathogenesis. By leveraging the genetic tractability and cost-effective scalability of zebrafish, Dr. Lin’s work aims to uncover novel mechanisms underlying ADPKD progression and identify potential therapeutic targets.  

Uncovering How Polycystin Signals from the Primary Cilium

This research is studying how proteins called polycystins help keep kidneys healthy and what happens when they do not work correctly. 

Researchers are focusing on two important molecules, GLIS3 and NEK8, which may work like a brake and an accelerator that control cyst growth. Early results suggest that GLIS3 may help stop cysts from forming, while NEK8 may cause cysts to grow when polycystins are not working properly. 

By learning more about how these molecules affect cyst growth, researchers hope to find new treatment targets that address the root causes of ADPKD. This could lead to safer, more effective treatments that may stop or even reverse kidney cyst growth. 

Jeremy Reiter, M.D., Ph.D., is a professor at the University of California, San Francisco. His work focuses on how cells build antennae-like structures called cilia and how cilia function in intercellular communication. Dr. Reiter’s studies help reveal how cilia signal, how defective ciliary signaling causes ciliopathies (e.g., cystic kidney diseases), how ciliary defects contribute to diseases not normally considered ciliopathies (e.g., obesity), and how cilia function in postnatal tissues with a particular focus on how polycystins signal at kidney cilia and how disruption of those functions cause ADPKD.

Takamitsu Saigusa, M.D., is a faculty member and physician-scientist in the Division of Nephrology at the University of Alabama at Birmingham (UAB). His laboratory investigates how dietary protein sources modulate kidney cyst growth in polycystic kidney disease (PKD).  

Using murine models, Dr. Saigusa’s lab compares the effects of plant-based versus animal-based protein diets on metabolism, inflammation, and cyst progression. A major focus of his current funded research is to determine whether glucagon—released rapidly by the pancreas following protein-rich meals—travels to the kidney, activates the glucagon receptor (Gcgr), and promotes cyst growth. Using spatial transcriptomics in mouse models and human ADPKD organoids, Dr. Saigusa will define a shared Gcgr-regulated gene signature that drives cyst growth, and candidate therapeutic targets will then be tested directly in human PKD organoids. 

Sex-Specific Mechanisms in Kidney Cyst Formation

People with autosomal dominant polycystic kidney disease (ADPKD) can have very different symptoms, even when they have the same genetic change. Research shows that men often have more severe kidney disease, while women are more likely to develop liver cysts. 

This project will study the role of sex-specific hormones like estrogen in PKD. By learning more about these differences, researchers hope to better understand what causes cysts to grow and why the disease can be more severe in some people. This work could lead to more personalized treatments and better care for people living with PKD. 

Targeted Gene Therapy Strategies for Autosomal Recessive Polycystic Kidney Disease

This research is working to develop new treatments for people with autosomal recessive polycystic kidney disease (ARPKD). Researchers are testing two types of gene therapy—one that could help many patients and another that could be customized for each person as a one-time treatment. 

A major challenge in treating ARPKD is getting treatment to the kidney cells where the disease starts. To do this, researchers will use tiny particles called nanocarriers to deliver the therapy directly to those cells. 

The treatments will be tested in lab-grown cells and animal models. Led by experts in drug delivery and kidney disease, this project brings together scientists and doctors with deep experience in PKD research. If successful, this research could lead to future clinical trials and new treatments that help people with ARPKD live longer, healthier lives. 

3D MRI Radiohistology for Precise Longitudinal and Simultaneous Assessment of Cysts and Fibrosis

Doctors currently don’t have very safe and accurate tools to find early kidney scarring or track how autosomal dominant polycystic kidney disease (ADPKD) is progressing. This project is testing a new MRI imaging agent called INL-101 that can help doctors see kidney scarring earlier and more clearly than current methods. 

Early studies showed that INL-101 can detect small changes in the kidneys and may be safer than standard MRI contrast agents. Researchers will continue testing it to prepare for future clinical trials. 

If successful, INL-101 could help doctors diagnose ADPKD earlier, track disease progression more accurately, and make better treatment decisions. It may also help people with other diseases that cause scarring in the kidneys and other organs. 

Jenny Yang, Ph.D., is a fellow of the National Academy of Inventors, Presidential University Scholar, Caldwell Marks Endowed Chair in Cancer Oncology and permanent regents’ professor at the University of Alabama at Birmingham, and founder and president of Inlighta Biosciences. Dr. Yang is a pioneer in establishing “calciomics,” to enable visualization of the roles of calcium in extracellular/intracellular Ca2+ signaling, and cell-cell communication through development of responsive calcium sensors.  

Dr. Yang’s work revealed key determinants for metal binding, selectivity, conformational changes, and dynamics. This research led to the development of transformative novel protein-based MRI contrast agents (ProCA) to enable biomarker-targeted MRI molecular imaging for drug discovery, early diagnosis, and patient selection for acute and chronic human diseases including polycystic kidney diseases. Today, Dr. Yang’s protein drug, ProAgio, is in multiple clinical trials targeting different types of cancer. She has been granted 40 patents (with more pending), published countless papers, given hundreds of talks, trained numerous members, and has received multiple awards for her groundbreaking research.

Design of Protein Binders Targeting PKD2 TOP Domain for Restored Channel Function

About 95% of autosomal dominant polycystic kidney disease (ADPKD) is caused by changes in two genes called PKD1 and PKD2. These genes help make proteins called polycystins, which keep kidney cells healthy. When these proteins don’t work correctly, ADPKD can develop. 

Right now, most treatments don’t fix these proteins. Instead, they try to slow the effects of the disease, like fluid buildup in kidney cysts. 

This study is trying to treat the root cause of ADPKD by fixing a problem in one version of a protein called polycystin-2. Researchers will test whether a drug can help this protein work normally again. 

If it works, the drug will be tested in animals to see if it can reduce cyst growth and kidney swelling. In the future, it could lead to new treatments for people with ADPKD. 

Vladimir Yarov-Yarovoy, Ph.D., is a professor, associate director of the Center for Precision Medicine and Data Sciences, and vice chair of the Department of Physiology and Membrane Biology at the University of California, Davis. Dr. Yarov-Yarovoy’s research interests and expertise include neuroscience, protein structure, and computational biology. The primary focus of his research group is on the computational design of subtype-specific ion channel modulators, structure-function studies of voltage-gated ion channels, and the development of computational methods for membrane protein structure prediction and design. Recent advances in computational protein design, determination of high-resolution ion channel structures, and discoveries of natural peptides that target them with high affinity, set a stage for computational design of novel ion channel modulators.

Base Editing as a Therapeutic Approach for Polycystic Kidney and Liver Disease

This research aims to treat the root cause of ADPKD, which is changes in genes that affect proteins called polycystins. Studies show that even a small increase in normal polycystin function can slow cyst growth. 

This project builds on early research using a gene-editing tool that can fix small genetic changes and reduce cysts in animal models. Researchers will work to make this approach safer and more effective in human kidney cells and improve ways to deliver it to the kidneys. 

The project will also test another approach that helps the body make more healthy polycystin from the working gene it already has. This could help more people, even if their exact gene change cannot be fixed. 

In the future, this work could lead to treatments that do more than slow ADPKD—they could target the cause of the disease and better treat both kidney and liver problems. 

While at Yale University, his studies demonstrated that activation of cellular chaperone pathways can restore PC1 maturation and reduce cystic disease severity in vivo, providing proof-of-concept for mutation-directed chaperone therapy approaches in ADPKD. More recently, Dr. Krappitz developed a clinically relevant PKD1 missense mouse model and led the first in vivo study demonstrating that adenine base editing can ameliorate cystic disease in ADPKD. In parallel, his laboratory is developing mutation-agnostic approaches aimed at increasing endogenous polycystin expression across broader patient populations. Dr. Krappitz collaborates closely with investigators at Yale University and Charité and is committed to translating mechanistically informed genetic therapies into meaningful treatments for patients with kidney and liver manifestations of PKD. 

Refining ADPKD Risk Prediction: The Utility of Machine Learning Approaches

Autosomal dominant polycystic kidney disease (ADPKD), characterized by fluid-filled cysts growing in the kidneys, is the most common cause of genetic kidney disease leading to kidney replacement therapy. However, the disease does not progress in the same way for everyone. Some people present a rapid decline in their kidney function, while others remain stable for many years. This makes it hard for physicians to predict the risk of progression for each person and to know who could benefit from treatment. As new treatments emerge, many of which can be costly and not without side effects, it is crucial to identify people at high risk who could potentially benefit from them. Our project aims to improve the prediction of the course of ADPKD by combining several types of tools: medical data, advanced imaging of the kidneys, and a wide range of genetic information. We will study about 2,000 people with ADPKD using modern tools like artificial intelligence to identify patterns that may be missed by traditional methods. In addition to kidney size and single gene tests, we will also analyze complex genetic patterns and new types of imaging data to better understand this risk. In the end, our goal is to create a tool that helps physicians to give more personalized advice: who is likely to progress and needs to start treatment early, and who can avoid unneeded medication. Ultimately, this will lead to better care, reduce unnecessary exposure to medication side effects, and support smarter use of healthcare resources. 

A Pilot Study for Managing Depressive Symptoms in Autosomal Dominant Polycystic Kidney Disease

Depression is common in chronic conditions such as ADPKD. We know that having depression can accelerate loss of kidney function in chronic kidney disease. In this proposal we will first evaluate whether or not having a diagnosis of depression affects the loss of kidney function in our ADPKD patients at Mayo Clinic. Given that depression is common in ADPKD, we will also conduct a small pilot study comparing 2 different non-medication techniques for treating depression, either digital neurotherapy or capacity coaching to see if we are able to improve symptoms of depression and pain in those with ADPKD. Digital neurotherapy is a web-based treatment somewhat similar to playing a video game, that improves the connections within various parts of the brain thus helping the brain function better. Capacity coaching teaches resilience in managing both the disease and treatment burden associated with ADPKD. This clinical trial will be conducted virtually making it accessible to those at remote distances from Mayo Clinic. 

Dr. Neera Dahl is a Professor of Medicine in the Division of Nephrology and Hypertension at Mayo Clinic Rochester. She is a member of the Scientific Advisory Committee for the Polycystic Kidney Disease Foundation, and Director of the PKD Center of Excellence at Mayo Clinic Rochester. Dr. Dahl is an Associate Director of the Mayo Clinic Translational PKD Center and co-chair of the KDOQI ADPKD Workgroup on the KDIGO Guidelines for ADPKD.

Developing a Vascularized Human Kidney Organoid Model for ARPKD Research and Therapeutic Screening

Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic condition that causes fluid-filled cysts to form in the kidneys from a young age, often leading to kidney failure early in life. Our research aims to create a better way to study and treat this disease by using tiny, three-dimensional “mini-kidneys” grown in the lab. These mini-kidneys, called organoids, are made from the urine of ARPKD patients. Using a novel method developed in our lab, we collect cells that naturally shed into the urine, expand them, and grow them under specialized 3D conditions to form patient-specific kidney organoids. Using urine a source for organoids makes this process entirely non-invasive . Once we have these ARPKD organoids, we aim to establish a large collection and build a biobank – a living organoid library that reflects the variety of disease presentations seen in ARPKD. Moreover, to make these models more realistic, we add engineered blood vessels into organoids so they now harbor a perfusable vascular network and behave more like a real human kidney. This vascularized ARPKD organoid system allows us to study how cysts form and expand, and how diseased kidney cells communicate with each other. With this platform, we can analyze each organoid by multi-omics to identify key changes in genes and proteins that drive cyst growth and disease progression. Based on the changes we then test existing drugs and their combinations to see if they can be repurposed to shrink or prevent cysts in our lab-grown ARPKD models. Alternatively, if such do not exist for the molecular aberrations observed we will start planning new approaches. By combining patient-derived organoids, blood vessel networks, and molecular analysis, we hope to discover new treatments that can slow or stop ARPKD progression and ultimately improve outcomes for children and families facing this challenging disease. 

Prof. Benjamin Dekel leads a pioneering research program at the Pediatric Stem Cell Research Institute and the Division of Pediatric Nephrology, Sheba Medical Center, dedicated to advancing the understanding and treatment of autosomal recessive polycystic kidney disease (ARPKD). The Dekel lab utilizes innovative patient-specific kidney organoids, non-invasively derived from urine samples of multiple donors, to establish a biobank, complemented by engineered vascular networks to closely mimic the kidney’s physiological environment. By integrating innovative laboratory techniques, cutting-edge bioinformatics, and advanced vascularization technologies, the lab seeks to uncover critical mechanisms underlying ARPKD, identify novel therapeutic targets, and facilitate precision medicine approaches to ARPKD and related cystic kidney diseases.

Bempedoic Acid as a Novel Therapy for Polycystic Kidney and Liver Disease

New ADPKD treatment strategies are desperately needed, including therapies targeting both kidney and liver cystic disease (PKD and PLD). Tolvaptan, the only FDA-approved drug for ADPKD, slows PKD progression but does not affect PLD, and side effects limit its tolerability, including thirst, frequent urination, and rare liver toxicity that requires close clinical monitoring. In this project we will test repurposing of bempedoic acid (BA), FDA-approved to treat high cholesterol, as a new potential therapy in the PCK rat model featuring both PKD and PLD. We recently showed that BA was effective in the treatment of ADPKD in mouse kidneys where it inhibited cyst growth and improved energy usage in ADPKD cells. Importantly, we found that in ADPKD mouse liver tissue, BA improved the health of mitochondria (major energy-generating structures in cells) while dramatically inhibiting liver cell death both in mice treated with BA alone or together with tolvaptan. Based on these exciting findings, we hypothesized that repurposing BA as a therapy for ADPKD would be beneficial in improving both liver and kidney disease manifestations and may limit tolvaptan-induced liver cell stress and injury. For this project we will investigate the dose-dependent effects of BA alone and its potentially additive effects in combination with tolvaptan on kidney and liver cystic disease features at early and late disease time points and the effects of BA on markers of tolvaptan-induced liver stress and injury in the PCK rat model. Results obtained from this study will complement and help inform pending ADPKD clinical trials. 

Effective July 2025, Dr. Hallows is transitioning from the University of Southern California (USC) to the University of Vermont (UVM), where he will be Professor of Medicine and Chief of Nephrology for the UVM Health Network. After completing his undergraduate training at Brown University, Dr. Hallows earned his PhD and MD degrees from the University of Rochester. He then went on to complete residency in internal medicine and then a fellowship in nephrology at the Hospital of the University of Pennsylvania. After spending a year as an instructor at the University of Pennsylvania, Dr. Hallows moved to the University of Pittsburgh as an assistant professor, then associate professor of medicine. He moved to the Keck School of Medicine of USC in 2015 where he has served as Chief of the Division of Nephrology and Hypertension, Director of the USC/UKRO Kidney Research Center, and more recently Director of the USC Keck PKD Clinic, a PKD Foundation Center of Excellence. Dr. Hallows’ broad research interests are in studying the metabolic control of kidney epithelial salt and water transport mechanisms with applications to therapeutics for various kidney diseases, including ADPKD. In the ADPKD field, he has spearheaded preclinical, translational, and clinical studies relevant to dysregulated metabolism, new therapeutic target identification, and the repurposing of metformin, bempedoic acid, and other FDA-approved drugs for ADPKD. He was Co-PI of the Dept. of Defense (DoD)-funded ADPKD clinical trial (TAME-PKD), where he led the biomarker discovery aims of the grant. He is currently the overall PI for an approved DoD-funded placebo-controlled multicenter clinical trial that will be launched to investigate bempedoic acid as a new ADPKD therapy (BEAT-PKD). 

Activation of endogenous renal exercise mimetics to treat ADPKD in mice.

Polycystic kidney disease (PKD) is a genetic condition where fluid-filled cysts grow in the kidneys, eventually leading to kidney failure. Studies have shown that being overweight and overeating can make PKD worse, while healthy habits like regular exercise and reduced calorie intake may help slow the disease. However, maintaining these lifestyle changes over a lifetime can be difficult for many people. 

Our research aims to find a way to mimic the effects of exercise and calorie restriction using medicine. In other words, we’re looking for a drug that can “trick” kidney cells into acting as if the person is exercising—even when they aren’t. This could help slow the growth of cysts and protect kidney function. 

One drug we are testing, called AICAR, activates a part of the cell’s metabolism that is usually turned on during exercise. In early studies using a mouse model of PKD, AICAR helped kidney cells burn energy more efficiently. By boosting the activity of mitochondria—the energy-producing “powerhouse” of the cell—we believe we can reduce the energy available for cysts to grow. 

This project builds on years of promising research and is led by a team with deep experience in kidney disease and metabolism. Our goal is to develop new therapies that can improve the lives of people with PKD by slowing disease progression in a way that doesn’t depend solely on diet and exercise. 

Dr. Miguel A. Lanaspa is an experienced investigator with a strong background in metabolism and nutrient sensing, with a focus on fructose, glucose, and purine metabolism in the context of obesity, diabetes, and kidney disease. His recent interest in polycystic kidney disease (PKD) stems from emerging data linking metabolic dysregulation to cyst growth. Leveraging his expertise in metabolic pathways, Dr. Lanaspa is now investigating how alterations in glucose and purine metabolism may contribute to PKD progression, with the goal of identifying novel therapeutic targets. 

Role of netrin-1 in cyst growth

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, affecting about 600,000 people in the U.S. and 4 to 6 million worldwide. In this disease, genetic mutations—mostly in a gene called PKD1—cause kidney cells to behave abnormally. Instead of functioning normally, these cells grow excessively and form numerous fluid-filled sacs called cysts. Over time, these cysts grow larger and damage the kidneys, often leading to kidney failure. In fact, ADPKD is responsible for 7–10% of patients who end up needing dialysis to survive. Currently, there is only one FDA-approved medication, Tolvaptan, but its side effects can make long-term use difficult. A key challenge in developing better treatments is that scientists still don’t fully understand what causes these cysts to grow. 

Our research focuses on a protein called netrin-1, which is known to play a role in cell proliferation, cell migration, and tumor growth. Our laboratory recently discovered that netrin-1 is significantly increased in the kidneys of animal models with ADPKD. When we increased netrin-1 levels in mice, their kidney cells grew more rapidly and formed more cysts. On the other hand, when we blocked netrin-1, cyst growth slowed down in ADPKD animal models. This suggests that netrin-1 plays a major role in worsening ADPKD. However, we still don’t know exactly how it does this. The long-term goal of our project is to better understand how and when netrin-1 contributes to cyst growth and PKD progression. Successful completion of our proposed studies will increase our understanding of the role of netrin-1 in cyst growth and provide the pre-clinical foundation needed to identify netrin-1 as a novel therapeutic target for the treatment of PKD. 

Riyaz Mohamed, PhD, is a Research Scientist in the Department of Physiology at Augusta University in Augusta, Georgia. He has extensive training and expertise in cardiovascular and renal physiology and pathophysiology, with a particular focus on kidney injury/regeneration and hypertension. Dr. Mohamed’s research centers on characterizing signaling pathways and identifying therapeutic targets by utilizing a broad range of biochemical, cellular, immunological, molecular biology techniques and whole animal physiology. Dr. Mohamed earned his PhD in Biochemistry from the University of Mysore, India, and completed a postdoctoral fellowship in vascular biology and renal physiology at Augusta University. His long-term research interests involve understanding the complex relationships between hypertension, acute kidney injury (AKI), and the progression to chronic kidney disease (CKD), as well as exploring the cellular mechanisms underlying polycystic kidney disease (PKD) in both males and females. Recently, Dr. Mohamed’s studies have focused mainly on elucidating the cellular and molecular mechanisms driving PKD progression. Dr. Mohamed recently published that neuronal guidance cue netrin-1 is significantly upregulated in the kidneys of rodent models of PKD. Overexpression of netrin-1 in renal tubules promotes tubular epithelial cell proliferation, stimulates cyst growth, and activates signaling pathways known to be involved in human PKD. Conversely, suppression or neutralization of netrin-1 was found to reduce cyst growth in both aggressive and slowly progressive PKD mouse models. Dr. Mohamed’s current grant application aims to address a critical knowledge gap by investigating the functional role of netrin-1 in cyst development and PKD progression. This research will help uncover the underlying mechanisms by which netrin-1 promotes cyst growth and will provide a preclinical foundation for targeting netrin-1 and its receptor as a novel therapeutic strategy for PKD. 

Signaling components of the polycystin pathway in cilia and extracellular vesicles

Understanding hidden communication in Polycystic Kidney Disease (PKD) is a serious genetic condition where fluid-filled cysts grow in the kidneys, often leading to kidney failure. It’s caused by problems in two specific genes, PKD1 and PKD2, which produce proteins called polycystins. How changes in these proteins actually lead to cysts is still a mystery. Our research focuses on understanding how polycystins normally help cells “talk” to each other. We study this using a tiny transparent worm called C. elegans, which shares many biological features with humans. Think of C. elegans as a simple but powerful model that helps us zoom in on the fine details of how cells work, faster and at a much lower cost than in mice or humans. In C. elegans and humans, cells shed polycystins on tiny bubbles called extracellular vesicles (EVs). These EVs carry signals that may play a key role in starting or worsening PKD. Using advanced imaging and genetic tools, we’re now uncovering what exactly these vesicles carry and how those signals go wrong in disease. By figuring out the basic principles of polycystin EV cell-to-cell communication, our research lays the scientific groundwork that larger clinical projects can build on, bringing us closer to better outcomes for patients and families living with PKD. 

Dr. Inna Nikonorova is an Assistant Research Professor in the Department of Genetics at Rutgers University, where she explores the molecular roots of polycystic kidney disease using an unexpected but powerful model, the tiny nematode Caenorhabditis elegans. Her work has led to the identification of conserved signaling components in the polycystin pathway and opened new ways for the dissection of polycystin function on extracellular vesicles, tiny membrane-bound organelles that cells use to communicate, and which may hold the key to understanding disease progression. Dr. Nikonorova earned her undergraduate degree in Biochemistry and Molecular Biology from Lomonosov Moscow State University in Russia and her Ph.D. in Cellular and Molecular Pharmacology at Rutgers University. She studied the molecular regulation of ion channel production and then trained in mouse models of liver health as a postdoctoral researcher in Nutritional Sciences. With this multi-disciplinary background, Dr. Nikonorova is poised to solve complex biomedical questions with the ultimate goal of improving outcomes for patients with polycystic kidney disease. 

Dr. Patricia Outeda is an Assistant Professor in the Division of Nephrology at the University of Maryland, Baltimore, and Director of the Mouse Models and Biobank Core at the NIH-funded Maryland Polycystic Kidney Disease Research and Translation Core Center (MPKD-RTCC). She received her PhD from the School of Medicine at the University of Santiago de Compostela in Spain and completed postdoctoral training at Johns Hopkins University and the University of Maryland. Dr. Outeda’s research is dedicated to understanding the molecular mechanisms of polycystic kidney disease (PKD), with a specific focus on both autosomal dominant (ADPKD) and autosomal recessive (ARPKD) forms. She has developed and characterized innovative Pkd2 and Pkhd1 mouse models that have become essential tools for studying disease progression and testing potential therapies in preclinical trials. 
Since 2020, she has served as co-chair of the In Vivo Models Subcommittee of the PKD Research Resource Consortium (PKD-RRC), where she plays a key role in standardizing and expanding access to PKD mouse models across the research community. 

A flow nanocytometry based assay for the diagnosis and monitoring of ADPKD

This application will develop a technique to diagnose autosomal dominant polycystic kidney disease (ADPKD) using a urine sample. No needles, MRI, or ultrasound scanning! The test will be able to tell who in an affected family has the disease and how bad the disease will be before cysts develop in the kidney. This will allow a physician to start treatment before the kidney has become damaged and thus preserve renal function. This test relies on the finding that the proteins encoded by the PKD1 and PKD2 genes, polycystin-1 and polycystin-2 are both present on tiny structures present in urine termed extracellular vesicles (EVs). We have made antibodies to these proteins that can be modified to glow brightly when illuminated by laser light. We will use a machine called a flow Nanocytometer (Kinetic River) that can detect EVs in the urine and can measure how much polycystin-1 antibody is attached to the EV as it passes an intense laser. The degree to which the EV glows indicates the amount of polycystin-1 on the EV as well as the number of EVs per unit volume of urine. The number of polycystin-1 positive EVs per milliliter of urine is low in people with ADPKD and the lower the number of EVs the worse the disease will be. The results are available immediately and the test will be inexpensive compared to MRI or ultrasound. Hopefully, this will allow future generations to be diagnosed early and their disease stopped before kidney damage sets in. 

Development of gene therapy for polycystic liver disease 

The research team at UCSF is working on reversing cysts in the liver, and the negative effects they can have on liver function and health, by gene therapy. For this, the researchers are using AAV vectors, which are FDA approved for liver-directed gene therapy of bleeding disorders. They took the first hurdle by targeting AAV vectors to the cells that form the biliary system, which are also the source of liver cysts. They will now test in mice whether liver cysts caused by a gene defect found in humans can be reversed by delivering a normal copy of that gene with AAV vectors. To make gene therapy of liver cysts as useful as possible, the researchers need to overcome another hurdle, which is that in humans many defects occur in genes that are too large to be delivered with AAV vectors. For this, they will build on other researchers’ work that showed that liver cysts can be reversed by inactivating genes that execute the effects of the defective gene. Using their AAV vectors, the researchers will screen a large group of these candidate genes for those whose inactivation most efficiently and safely reverses liver cysts in mice. In summary, the researchers aim to establish the know-how and tools for gene therapy of liver cysts impairing liver function and health. 

Pharmacological reprogramming of the epithelial and stromal compartments to treat PLD

Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) develop cysts in their kidneys, but 9-in-10 patients also live with cysts in their livers (called polycystic liver disease; PLD). Like water balloons, cysts fill with liquid and swell. This makes livers bigger, causing them to press on other organs in the body, resulting in pain and discomfort. Like water balloons, cysts can burst leading to infections if not treated quickly. Because of this, patients with PLD experience a poor quality of life. 

Despite liver cysts being often found in patients with ADPKD, research to understand how liver cysts form has been neglected, meaning there are no approved therapies to treat PLD. There is a desperate need within the PKD-patient community to develop therapies that can shrink liver cysts or stop them from forming in the first place. We know from other human diseases that different types of cells contribute to disease: tumors, for example, not only contain cancer cells but also immune cells whose normal job is to fight infection. Using medicines that both kill cancer cells and turn-on nearby immune system cells to attack the cancer has revolutionized how cancer patients are treated. This project will focus on studying how medicines that are currently used to treat patients with cancer can be used to stop cyst cells growing, while also telling nearby immune cells to discourage cyst growth. 

Scott Waddell completed his PhD with Luke Boulter & Pleasantine Mill at the MRC Human Genetics Unit at the University of Edinburgh (UK). During his doctoral studies, Scott investigated the role of primary cilia in hepatobiliary diseases, which led him to research the cellular and tissue dynamics underpinning polycystic liver disease (PLD). 
 
PLD is the most common extra-renal manifestation in Autosomal Dominant Polycystic Kidney Disease (ADPKD), yet research into PLD is largely neglected. Further research is required to understand what promotes cyst development and progression in the liver such that new therapeutics can be discovered. 
 
Scott has previously shown that hepatic cyst cells modulate and signal through the surrounding extracellular matrix to promote cyst growth. In his PKD Foundation-funded project, he will continue to investigate the intracellular response to a cyst-associated matrix, as well as investigate how different cells of the cyst microenvironment use common signaling pathways to promote PLD progression. 

Refining ADPKD Risk Prediction: The Utility of Machine Learning Approaches

Autosomal dominant polycystic kidney disease (ADPKD), characterized by fluid-filled cysts growing in the kidneys, is the most common cause of genetic kidney disease leading to kidney replacement therapy. However, the disease does not progress in the same way for everyone. Some people present a rapid decline in their kidney function, while others remain stable for many years. This makes it hard for physicians to predict the risk of progression for each person and to know who could benefit from treatment. As new treatments emerge, many of which can be costly and not without side effects, it is crucial to identify people at high risk who could potentially benefit from them. Our project aims to improve the prediction of the course of ADPKD by combining several types of tools: medical data, advanced imaging of the kidneys, and a wide range of genetic information. We will study about 2,000 people with ADPKD using modern tools like artificial intelligence to identify patterns that may be missed by traditional methods. In addition to kidney size and single gene tests, we will also analyze complex genetic patterns and new types of imaging data to better understand this risk. In the end, our goal is to create a tool that helps physicians to give more personalized advice: who is likely to progress and needs to start treatment early, and who can avoid unneeded medication. Ultimately, this will lead to better care, reduce unnecessary exposure to medication side effects, and support smarter use of healthcare resources. 

 IFT172 as a minor ADPKD gene and identifying disease modifiers 

Autosomal Dominant Polycystic kidney disease (ADPKD) is one of the most common inherited kidney diseases, often leading to kidney failure. ADPKD is mostly caused by changes in the PKD1 and PKD2 genes, but in this project we aim to look beyond those genes to study other lesser-known genes that can cause or modify ADPKD. 

One focus of this project is on a group of genes that encode intraflagellar transport (IFT) proteins, especially those in the B complex, which help cells form tiny hair-like structures called cilia, which are essential for normal kidney development. Particularly, our preliminary analysis indicates that genetic changes in the IFT-B gene IFT172 can cause ADPKD. We will use mouse models of IFT172 to see how loss affects cilia and the Pkd1 disease course. We will also study if other IFT-B genes are associated with ADPKD. 

Another part of the project involves less understood ADPKD genes, such as ALG8, ALG9, GANAB, and DNAJB11. A question we aim to address is why some individuals with changes in these genes develop multiple kidney cysts and severe symptoms, while others have only mild disease or even no cysts. To explore this, we will analyze large genetic databases and clinical data to identify other genetic factors that modify disease severity. We will also use mouse models of these modifying genes to mimic genetic interactions. By understanding these genetic modifiers, we aim to identify high-risk individuals earlier and discover new treatment targets. 

Dr. Doaa E. Elbarougy is a postdoctoral fellow at the Mayo Clinic’s Translational Polycystic Kidney Disease Center, under the mentorship of Dr. Peter Harris. Her research utilizes population-based biobanks to identify novel genetic causes and modifiers associated with Autosomal Dominant Polycystic Kidney Disease. She received her medical degree from Al-Azhar University in Egypt and then joined Mayo Clinic for training in PKD genetics. She is committed to a career as a physician-scientist, aiming to advance understanding of polycystic kidney diseases and improve patient outcomes.

Polycystic Kidney Disease (PKD) is a common genetic disorder that causes fluid-filled sacs, called cysts, to grow inside the kidneys. Over time, the growth of these cysts causes the kidneys to become very large and they damage healthy kidney tissue. Patients may pain, high blood pressure, and even kidney failure, requiring renal replacement therapy such as dialysis or renal transplantation. Currently, the only drug treatment that is available to slow the disease, comes with side effects that many patients are unable to tolerate. There is a pressing need for better, more targeted therapies. 

My research is focused on finding a better way to slow PKD progression. 

We discovered a protein called periostin that acts like a “bad signal” in PKD kidneys. This protein tells the kidneys to stay inflamed, creating more scar tissue. Another protein listens to that signal and makes things worse. Together, they help the cysts to grow and the kidneys to become damaged. We use advanced tools to determine if blocking these proteins in human PKD kidney cells and in PKD mouse models slow down or even stop the damage before it becomes permanent. If we succeed, this could lead to a new treatment that protects kidneys, reduces the need for dialysis, and gives people with PKD a better future. Ultimately, this research could pave the way for precision therapies that target the root causes of the disease, offering hope for ADPKD patients and others suffering from fibrosis-related conditions. This work brings hope not just for managing PKD, but for truly fighting back against it. 

Mayo ADPKD Mutation Database

In other genetic diseases, such as cystic fibrosis, all patients are routinely molecularly screened so that families know their disease causing mutations. At present this does not happen for ADPKD, partly because the value of the data for diagnostics and prognostics is not generally recognized, and because molecular testing is specialized and expensive due to the complex genomic situation of the PKD1 gene. However, as specialized next generation sequencing panels for ADPKD become available and there is more competition to offer testing, the price of testing is likely to decrease. In addition, the value of the patient knowing their specific mutation is likely to be more widely appreciated as the prognostic value of this data is realized, and genetic data is increasing used to select patients for treatment and clinical trials. In cystic fibrosis, therapies geared to specific mutations are being developed. ADPKD is more complex because of the high level of family specific mutations, but mutation focused treatment strategies are still likely to be tested in this disorder in the next few years. For instance, chaperone treatment may be of value for some missense substitutions and read-through drugs help patients with nonsense mutations, while therapies to overcome splicing defects have also been proposed. Hence, the database will play an increasingly important role as a repository of the accumulating genetic data (paired with clinical and in vitro data), allowing the penetrance of specific mutations to be better determined. In addition, it will function as a source of information about patients that (through their nephrologist) can be selected for treatments and specific clinical trials, including targeting specific mutation groups.

Visit Mayo ADPKD Mutation Database website