Current funded research
In 2021, we awarded new research funding to 11 outstanding PKD researchers. The goal of the Research Grant and Fellowship Programs will fund critical research to increase understanding of the genetic and pathological processes involved in PKD and to accelerate the development of potential therapies for PKD patients.
The review process
The Review Committee was comprised of the PKDF Scientific Advisory Committee (SAC), additional ad hoc scientists and experts in PKD, as well as a Stakeholder Review Panel made up of PKD patients and caregivers. Each application was assigned three independent reviewers who ranked the grants based on our Guidance for Reviewers that provided separate criteria for scientists and stakeholders. Read more about our Peer Review Process here.
Rankings were based on:
- significance to PKD research
- investigator strengths
- scientific environment
View more grant and fellowship awardees
2021 research grant awardees
We are excited to share with you the eight grants and three fellowships selected for funding in 2021 below.
2020 Dr. Vincent H. Gattone Research Award
Darren Wallace, Ph.D.
University of Kansas Medical Center
Targeting the periostin-integrin signaling pathway in PKD
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders affecting nearly 12 million people worldwide. ADPKD is characterized by relentless growth of numerous fluid-filled cysts causing kidney injury and fibrosis (scar tissue), leading to the progressive loss of kidney function. We discovered that kidneys of human ADPKD and autosomal recessive PKD (ARPKD), and PKD animal models have high expression of periostin, a molecule involved in tissue maintenance and repair and is highly expressed in fibrotic tissues. Periostin binds alpha(V)beta(3) [aVß3]-integrins (cell surface receptors that are linked to the cell’s cytoskeleton), leading to the activation of signaling pathways involved in repair, cell proliferation and survival. Periostin promotes the proliferation of human ADPKD cells, but not normal human kidney cells. This difference in the proliferative response is due to overexpression of aVß3-integrins by the cystic cells. Gene knockout of periostin in PKD mice significantly reduced renal cyst growth and fibrosis and extended the lifespan of the mice. Conversely, overexpression of periostin in the kidneys of PKD mice caused more rapid growth of cysts, fibrosis, and decline in kidney function. In preliminary studies, we found that an aVß3-integrin blocking antibody prevented periostin-induced proliferation of ADPKD cells. We propose that persistent overexpression of periostin and its receptor aVß3-integrin cause hyperactivation of aVß3-integrin signaling pathway causing misguided tissue repair that contributes to cyst growth and fibrosis, and that inhibition of the aVß3-integrin signaling pathway could be a therapeutic approach to slow the progression of ADPKD.
Darren Wallace is a Professor in the Department of Internal Medicine and a member of the Jared Grantham Kidney Institute at the University of Kansas Medical Center. Dr. Wallace earned his PhD from the Department of Molecular and Integrative Physiology and completed postdoctoral training in renal physiology and polycystic kidney disease at the University of Kansas Medical Center. His contributions to the PKD field include research on the molecular mechanisms involved in cAMP-dependent cell proliferation and Cl-dependent fluid secretion using primary cultures of human ADPKD cyst epithelial cells. Recently, his laboratory discovered that periostin, a matricellular protein, is highly overexpressed by cysts of ADPKD and ARPKD kidneys and it accumulates within the extracellular matrix adjacent to the cysts. Periostin binds to integrins on the cystic epithelial cells and stimulates repair mechanisms, including cell proliferation and matrix production, contributing to progressive cyst growth and fibrosis. Dr. Wallace is the Associate Director of the Kansas PKD Research and Translational Core Center and Director of PKD Biomarkers and Biomaterials Core, which is part of the national PKD Research Resource Consortium (PKD-RRC). He also served as a member of the PKD Foundation Scientific Advisory Committee from 2008 to 2019.
Erum Hartung, M.D.
Children’s Hospital of Philadelphia
Intracranial aneurysms and vascular abnormalities in ARPKD
Unlike the dominant form of polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD) has historically not been thought to cause an increased risk of intracranial aneurysms (ICA; outpouchings of arteries in the brain) or other problems with blood vessels (vascular abnormalities). However, there have now been six reported cases of ICA in children and young adults with ARPKD, and another two individuals reported with aneurysms in other parts of the body. In some cases, these aneurysms caused significant complications such as bleeding in the brain or even death. Despite the potentially devastating effects of ICAs and other blood vessel problems, we do not know how commonly they occur in individuals with ARPKD and whether they can be prevented, because to our knowledge there have been no prior systematic studies to investigate this issue. Our overall objective is to determine how common ICA and blood vessel abnormalities are in individuals with ARPKD, and to study potential risk factors for these problems, such as high blood pressure, abnormal function of the cells lining the blood vessels (endothelial dysfunction), and increased stiffness of the blood vessels. This study will yield important information to guide the care of individuals with ARPKD by helping to inform whether screening for ICA and other blood vessel problems is indicated, and by identifying potentially treatable risk factors to prevent vascular complications.
Erum Hartung, MD, MTR is a pediatric nephrologist at Children’s Hospital of Philadelphia and an Assistant Professor of Pediatrics at the University of Pennsylvania. Her clinical and research focus is in polycystic kidney disease, particularly autosomal recessive polycystic kidney disease (ARPKD). She co-directs the Combined Kidney/Liver Program at CHOP, which specializes in the care of children with ARPKD and other genetic kidney/liver diseases and ciliopathies. Her research aims to accelerate the development of new treatments for ARPKD through observational and database studies to better define the natural history and complications of ARPKD, and through imaging studies to develop new biomarkers of kidney and liver disease progression.
Katharina Hopp, Ph.D.
University of Colorado Anschutz Medical Campus
Caloric restriction in PKD: Mechanisms mediating efficacy and impact on immune cell function
The Autosomal Dominant Polycystic Kidney Disease (ADPKD) patient community is still in dire need of new treatment options despite the FDA approval of JYNARQUE (tolvaptan), which merely delays cyst growth, impacts quality of life, and only aids a select group of patients (rapid progressors). Changes in kidney metabolism are a characteristic of ADPKD and preclinical studies targeting these abnormalities have shown efficacy in alleviating disease severity. Correlatively, body mass index (BMI) has been shown to be an important predictor of ADPKD progression. Hence, there is rising interest in a variety of caloric intake regimes as a potential therapy for ADPKD. Preclinical studies in mouse models have shown a profound reduction in cyst growth with daily reduction in food intake, i.e. caloric restriction (CR). While daily CR may have health benefits, beyond impacting kidney cyst growth, in overweight/obese ADPKD patients, it is not a viable therapeutic option for ADPKD patients with normal BMI as it provokes health risks such as bone loss, decreased immune function, or anemia, to name a few. Besides, it is also very challenging to adhere to a life-long reduction in food intake. Alternate regimes such as intermittent fasting (IMF, alternate-day CR) or time restricted feeding (TRF, restricting the number of hours for food intake) are being considered for a variety of diseases including ADPKD.
We compared CR, IMF, and TRF using a clinically relevant ADPKD mouse model and found that neither IMF nor TRF were as efficacious in halting cyst growth as CR. Indeed, our results show a remarkable efficacy of CR in slowing PKD progression, even more so than tolvaptan. Hence, it is critical to understand the cellular and molecular mediators of the CR response in order to identify pharmaceutical-based alternatives to CR, which would eliminate the need for life-long food restriction and health risks associated with continued weight loss. In this study, we will use a clinically relevant mouse model to understand detailed mechanisms of the CR response in ADPKD kidneys in a cell type specific manner. We will use sophisticated methodologies such as single cell RNA sequencing and metabolomics as well as bioinformatic approaches of data integration to build a catalog of changes in cell composition, function, and communication that are modulated by CR. In additional, we will focus on the role of immune cells in the CR response. The reason for this focus is twofold, one, recent studies by others and us show that immune cells are key modulators of PKD severity, and two, in cancer, a disease with many parallels to PKD, CR improves disease and therapy outcome in part by modulating immune cell function. These studies will facilitate identification of novel drug targets for (pre-) clinical testing, which would not be feasible in humans due to limited kidney tissue availability. This study addresses the PKD Foundation special consideration areas of “lifestyle interventions” and “PKD drug discovery”.
Jelena Klawitter, Ph.D.
University of Colorado Anschutz Medical Campus
Microbiota-Derived Bile Acids and Short Chain Fatty Acids as Markers of ADPKD
ADPKD is the most common hereditary kidney disease worldwide, characterized by bilateral kidney enlargement with numerous cysts and a variable rate of disease progression. Intrafamilial renal disease variability is a well-documented feature of ADPKD, making risk prediction at the level of the individual patient challenging, even among affected relatives. Modifying genes, epigenetic mechanisms and environmental factors, such as the here proposed gut microbiome, considerably influence the clinical course of the disease.
Despite tolvaptan’s approval, there is still critical need for identification of biomarkers and therapeutic targets for treatment of ADPKD. Liver is the most affected extrarenal organ in ADPKD and unfortunately tolvaptan has been shown to induce serious and potentially fatal liver injury. Gut microbiome and related gut-kidney-liver axis has been recognized as a main regulator of innate and adaptive immune systems. Despite the importance of gut microbiome in regulating inflammation and cellular injury, no studies have yet systematically evaluated microbiota-derived metabolites in ADPKD patients.
This proposal will be the first to validate bile acids (BAs) and short-chain fatty acids (SCFAs) as biomarkers of ADPKD severity and progression as measured by the change in total kidney volume and renal function. For this purpose, we will use samples already collected during HALT-PKD trials. BAs and SCFAs are chemically stable at low temperatures and HALT-PKD database contains information on considerable renal and cardiovascular clinical measures.
In the second part of this proposal, we will assess the potential of a simple resistant starch-based dietary intervention to slow down the progression of PKD in a PKD1RC/RC mouse model.
Our proposal will address the existing gap in knowledge about the role of microbiome metabolites in ADPKD. Collectively, our preliminary data suggest that ADPKD induces an imbalance in the hydrophobic BAs (accumulation) and SCFAs (depletion). In this scenario, intervention strategies such as the proposed dietary intervention with SCFA-producing resistant starch should be beneficial to re-establish the lost microbiota balance.
Jelena Klawitter, Ph.D. is an Associate Professor of Anesthesiology and Renal Medicine at the University of Colorado, Anschutz Medical Campus in Aurora. For the past 19 years, she has been investigating the mechanisms of cellular reprogramming first in malignant and later in cardiovascular diseases. In the past 9 years, since joining the PKD research group at UC Denver, Dr. Klawitter has participated in the group’s biomarker development efforts to understand the mechanisms underlying varying progression rates in patients with ADPKD. For Her laboratory utilizes a combination of lipidomic, metabolomic and proteomic approaches to explore the role of oxidative stress and inflammation, endothelial and mitochondrial dysfunction and recently that of the dysregulated microbiome in the development and progression of PKD.
Ronak Lakhia, M.D.
University of Texas Southwestern Medical Center
Role of intracellular cholesterol in ADPKD
Autosomal dominant polycystic kidney disease is the most common monogenetic disorder in the United States and has no cure. Though significant progress has been made, we still do not have a complete understanding of the pathogenesis of this disorder. Understanding how kidney cysts develop and grow is necessary to identify new areas for drug development for the treatment of ADPKD. Recently, studies have highlighted the role of metabolism in modulating cyst growth. In particular, the effect of aberrant glycolysis and impaired fatty acid oxidation has been described in ADPKD. Whether other metabolic pathways play a role in cyst growth is not known. Cholesterol is an integral component of the cell membrane, serves as a signaling molecule and requires a significant amount of energy for synthesis. We have discovered that the synthesis of cholesterol may be reduced in the kidneys of mouse models of PKD. Moreover, our preliminary data suggests that inhibiting the synthesis of cholesterol in the kidney promotes cyst growth, whereas promoting cholesterol synthesis slows cyst growth. This leads us to hypothesize that the cholesterol biosynthesis pathway is downregulated in ADPKD and enhancing the synthesis of cholesterol in the kidney may slow cyst growth. To answer this question, we will first determine whether cholesterol biosynthesis is indeed reduced in the kidneys of mouse models of ADPKD. Then we will determine whether modulating cholesterol biosynthesis affects cyst growth in aggressive and long lived mouse models of ADPKD. By performing a comprehensive metabolic and phenotypic analysis, we will establish that cholesterol biosynthesis is a newly discovered modulator of cyst progression. These studies have the potential to add a dramatic new dimension to the understanding of metabolic rewiring in ADPKD and will pave the way for future studies to study the cholesterol biosynthesis pathway in detail to identify novel drug targets for the treatment of ADPKD.
Dr. Ronak Lakhia is an Assistant Professor of Medicine in the Division of Nephrology at the University of Texas Southwestern Medical Center in Dallas. She completed medical school at the University of Texas Southwestern Medical Center in Dallas and internal medicine residency at Baylor College of Medicine in Houston, TX. She then returned to UT Southwestern to pursue nephrology clinical and research fellowship at UT Southwestern and was appointed to the faculty at the completion of her training. Her research program focuses on understanding the role of metabolic and epigenetic aberrancies in the pathogenesis of ADPKD. In addition, Dr. Lakhia leads the PKD Clinic at UT Southwestern.
*Co-funded by PKD Australia
Melissa Little, Ph.D.
Murdoch Childrens Research Institute
In vitro modelling of autosomal recessive polycystic kidney disease
Autosomal recessive polycystic kidney disease (ARPKD), caused by mutations in the PKHD1 gene, is a devastating kidney and liver disease affecting babies and children. Most babies are born unable to produce any urine which also affects lung development. These babies require prolonged intensive care, breathing support and dialysis from birth. They often remain in hospital for the first 4-6 months of life and remain on dialysis until kidney transplantation. Milder cases can present later but ultimately require dialysis and transplantation in childhood or young adulthood. Furthermore, 10-20% of patients will also require liver transplantation in childhood. Little is understood about how PKHD1 functions within the kidney and how PKHD1 mutation leads to cysts. Consequently, there are no established treatments for ARPKD.
Researchers often study genetic diseases in animals as a surrogate model for human disease. However, animals with PKHD1 mutations don’t develop kidney cysts like human ARPKD patients. PKHD1 therefore has unique functions in humans and needs to be studied using human kidney cells. Obtaining kidney cells from paediatric ARPKD patients by kidney biopsy is impractical and unethical.
Our laboratory is one of few in the world generating stem cells from patients with kidney disease and turning them into 3D mini-kidneys in a dish (called organoids). We have developed a new method to grow collecting duct (CD) cells, which are the cells that develop cysts in ARPKD. When we grow CD organoids from stem cells carrying PKHD1 mutations, they form large cysts. This represents an opportunity to study ARPKD in a human model without having to biopsy a human kidney.
In this proposal we will compare healthy and ARPKD-patient kidney organoids to better understand how defects in PKHD1 lead to cyst formation. In the short term, this will help us to understand the function of PKHD1 and possibly also allow the testing of treatments to reduce cyst growth. To move towards drug screening, we will miniaturise our cultures using a robotic cell handling and imaging platform. This will allow us to create almost 400 kidney models on one plate the size of a cell phone. Showing we can test drugs in this way will provide the foundation for future work screening potentially thousands of potential therapies to see which works best at reducing cyst growth in the ARPKD organoids. As such, this may lead to the development of the first treatments for ARPKD. The long term hope is to be able to grow an individual patient’s kidney cells within this system and find the best treatment for their particular PKHD1 mutation. This type of ‘personalised therapeutics’ would be a world first. In the long term this approach may also be applied to other diseases of the collecting duct, including ADPKD.
Albert Ong, Ph.D.
University of Sheffield
Urine extracellular vesicle miRNAs as prognostic biomarkers and to identify new therapeutic targets in ADPKD
The course of ADPKD can vary considerably between individuals even within the same family and there is a clinical need to identify those with more rapidly progressive disease who would benefit from early treatment (eg tolvaptan) or more intensive management. Extracellular vesicles are tiny microscopic particles that actively exported by most cells in the body including the kidney. They may be a common way through which cells communicate with each other since they contain both protein and genetic messengers including small ribonucleic acid (RNA) molecules. By isolating these particles in urine, we could potentially ‘sample’ the kidney without the need to do a needle biopsy (‘liquid biopsy’). In this study, we will examine whether the small RNA content of urine vesicles could be used to more accurately predict kidney lifespan, decide treatment options and provide clues for developing novel drugs. This is because tolvaptan is associated with rare cases of liver toxicity and is poorly tolerated in some patients. These features indicate that more effective, safer and better tolerated treatments are still needed.
Albert Ong is Professor of Renal Medicine, Head of Academic Nephrology and Deputy Director for Clinical Academic Training at the University of Sheffield, UK. He graduated in medicine from the University of Oxford and completed postgraduate training at University College London and Oxford. His interest in ADPKD began in the laboratory of Dr Peter Harris through a post-doctoral Kidney Research UK Senior Fellowship at the Weatherall Institute of Molecular Medicine, Oxford. Later, he successfully established a new research group and investigational program on ADPKD at Sheffield underpinned by a long-term Research Leave Award from the Wellcome Trust. His research goals are to define the molecular basis of cyst formation, initiate drug discovery and stimulate translational research in ADPKD. Dr Ong also directs the Sheffield Renal Genetics Service which serves to provide expert diagnosis and management for patients with ADPKD and other forms of inherited kidney disease. He is Chief Investigator of the CYSTic consortium and currently serves on the steering committees of the European ADPKD Forum, SONG-PKD initiative, the STAGED-PKD study and as External Faculty for the Mayo Clinic Translational PKD Centre (USA).
Kurt Zimmerman, Ph.D.
University of Oklahoma Health Sciences Center
Targeting Trem2+ kidney resident macrophages to slow cyst growth
The current idea in the field is that macrophages promote cyst growth. However, the majority of data supporting this idea comes from rapidly progressing mouse models that do not accurately reflect the rate or timing of cyst growth observed in PKD patients, where cyst growth typically begins in teenage years and progresses over several decades. In this study, we address this concern by analyzing macrophages that are present in two slowly progressing models of cystic disease that mimic the timing and rate of cyst growth observed in patients. The macrophages from these models are compared to macrophages from commonly used, rapidly progressing cystic models and non-cystic control mice. Using this approach, we identify a single population of macrophages that are present only in the slowly progressing models of cystic disease but are absent in the rapidly progressing model of cyst growth and control mice, suggesting that these macrophages may restrict cyst growth. The goal of this study is to test the hypothesis that macrophages found only in slowly progressing models of cystic disease slow cyst growth and to test the idea that treatment with a therapeutic antibody, which is currently in clinical trials for other diseases, can be used to further activate these macrophages to further reduce cyst growth.
Alysia Cox, Ph.D.
University of Southern California
Targeted mRNA Nanomedicine for Autosomal Dominant Polycystic Kidney Disease
Polycystin-2 (PC2) is a protein that is needed for normal kidney function. It is encoded by the Pkd2 gene. Around 21,000 Americans have PKD2 mutations that reduce PC2 levels, causing autosomal dominant polycystic kidney disease (ADPKD). This disease involves uncontrolled kidney cell growth and development of cysts that can destroy the organ. Symptoms include high blood pressure, kidney stones, urinary tract infections, and pain. Patients are also more likely to have a stroke. The only treatment available is Tolvaptan. However, this drug can cause severe side effects including liver damage and can only modestly slow disease progression.
To address this problem, we aim to design a new treatment using nanoparticles to deliver Pkd2 mRNA. mRNA is the molecule that produces proteins based on the “instruction manual” that exists in our genes. We will deliver mRNA that produces PC2 by attaching it to nanoparticles called micelles. These micelles will be made of lipids that are similar to the fats that naturally occur in our bodies, making them safe to use. We will also add peptides, small portions of proteins, to the nanoparticles that can react with kidney cells involved in ADPKD. By using these peptides, we can ensure that the mRNA therapy goes directly to the kidney and does not harm other organs.
To achieve this goal, we will test our nanoparticle therapy on healthy and diseased kidney cells from mice and humans in vitro. We will use test nanoparticle concentrations to assess the ideal dose for therapy and safety. We will use our results to optimize the nanoparticle formulation if it does not work as we expect. After we improve our nanoparticle, we will inject it into mice that have ADPKD. After the 4-week treatment, we will examine the mouse kidneys for cysts and will check other organs for signs of toxicity. We expect that the nanoparticles will stop cysts from growing.
If successful, this will be the first effective treatment to stop ADPKD. This could allow patients around the world to live longer and healthier lives, without needing kidney transplants.
Alysia Cox, Ph.D., is a postdoctoral fellow working in the Department of Biomedical Engineering in University of Southern California. Her work focuses primarily on the use of targeted micelles to deliver drugs or RNA therapeutics to the kidney, in order to improve therapeutic efficacy and reduce off-target side effects in ADPKD treatment. Her PhD work in the University of Milano-Bicocca, Italy, as a Marie-Sklodowska Curie fellow examined nanoparticle-protein interactions with the blood brain barrier, and the use of physiological proteins to target nanoparticles for the treatment of neurological disorders.
Kotdaji Ha, Ph.D.
University of California San Francisco
Physiological Regulation of the polycystin complex
Primary cilia are small sensory organelles found on a majority of cells and neurons. Proper function of cilia and the polycystin complex is necessary to regulate diverse cellular in renal environment. Two proteins, PC-1 and PC-2 form the polycystin complex by forming a heteromeric channel to permeate positively charged ions on the ciliary body. Mutations in PC-1 protein and PC-2 ion channel can lead to Autosomal Dominant Polycystic Kidney Disease (ADPKD), a common cause of monogenic end stage of renal disease and cilia-related disorder. It is currently unknown how mutations in PC-1 cause ADPKD and whether dietary changes in cholesterol additionally regulate the polycystin complex. In this proposal I will leverage ciliary electrophysiology, biochemistry, and imaging analysis to 1) dissect the mechanism of PC-1 in modulating the polycystin complex and 2) asking if nutrients such as cholesterol and its metabolism is required for proper polycystin function.
Aim1: Define physiological role of PC-1 in the polycystin complex. This aim will be accomplished by leveraging multiple PC-1 pathogenic mutations and following biological activity. Using a combination of electrophysiology and in vitro imaging, I recently observed proximal domains of PC-1 N terminus, LRR and CTL act as the essential region that activate the polycystin complex on the cell or ciliary membrane. Additionally, I determined that a mutation in LRR resulted in impaired channel activity. Collectively these data demonstrate the importance of PC-1 function on the cell membrane, however it is still unclear whether trafficking or misfolding of the mutant protein perturb channel function. In this aim I will determine the characteristics of pathogenic mutant in LRR and CTL by conventional or ciliary electrophysiology and trafficking using imaging analysis, and biochemistry.
Aim 2: Elucidate the association between cholesterol metabolism and regulation of the polycystin complex. Perturbed cholesterol metabolism has been resulted in the cystic phenotype. Here I will ask if the oxysterol present on renal cilia behaves as an agonist to activate the polycystin complex by performing both ciliary patch clamp and affinity assays. Understanding how cholesterol affects the kidney at the level of the cilia is important because because it will shed light on lipid-mediated regulation of the polycystin complex at molecular level.
The aims outlined in this proposal will lead to novel and fundamental insights into how pathogenic mutants in the proximal region of PC-1 subunit affect channel dynamics. Furthermore, understanding the relationship between cholesterol and the polycystin complex is imperative for the development of novel therapeutics to treat ADPKD. Should I be awarded ADPKD postdoctoral Research fellowship, it will not only help my current research, but also be a great motivation to start an independent research in the cilia and renal physiology.
Cynthia Sieben, Ph.D.
Pathogenicity and pathomechanisms of variants across the ADPKD spectrum
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most commonly inherited genetic diseases, and is associated with a broad spectrum of disease severity. The most dramatic extremes span from mild PKD into old age without kidney failure, to severe PKD in utero resulting in prenatal death. Some diversity can be explained by the gene mutated, mutation severity, and whether the individual has inherited a single mutation from one or both parents. The typical form of ADPKD is adult onset and results from inheritance of a single mutation, however, occasionally two mutations to the same gene, inherited from both parents, can result in severe very early onset ADPKD. Although, we have gained some understanding of the mechanisms driving clinical heterogeneity, complex genetic inheritance and uncertainty regarding the impact(s) of particular mutations on the function of the disease gene and synthesized protein limit our ability to provide confident diagnostic and prognostic information to physicians and patients. The increase in global DNA sequencing methods, like whole-exome sequencing, provides a wealth of information, but further demonstrates the need for new methods to determine the significance of particular mutations. For these reasons, further development of these tools is important not only for ADPKD, but also more broadly. Here, we aim to improve our current complex manual technique for determining the significance of substitution mutations in the ADPKD genes, PKD1 and PKD2 (~94% of ADPKD cases), by comparing our in-house method to newly developed automated prediction tools. In addition, we will assess the impacts of these mutations on known features of the PKD1 and PKD2 gene products, polycystin 1 and 2 (PC1 and PC2) in cultured human kidney tubule cells in an effort to identify common disease mechanisms. Further, we plan to evaluate the therapeutic potential of one such common mechanism identified in our previous studies and found more broadly applicable to a range of mutations in our preliminary analyses for this proposal, improper maturation and subcellular localization of PC1 due to misfolded mutant PC1 or PC2. Here, we will use chaperone therapy to improve PC1 and PC2 folding conditions in an effort to enhance or rescue proper maturation and subcellular trafficking of PC1. We will initiate these studies first in cultured cells to assess the applicability and efficacy of the treatment across a number of different PKD1 and PKD2 mutations, and then will employ successful compounds for preclinical trials in an ADPKD mouse model containing a patient mutation (Pkd1 RC/RC). These studies will aid in our understanding of the genetic complexity and disease mechanisms associated with ADPKD, and will assess the therapeutic benefit(s) of targeting one common disease mechanism, providing diagnostic, prognostic, and potentially therapeutic value to ADPKD patients.
Dr. Cynthia J. Sieben is a Postdoctoral Research Fellow in the laboratory of Dr. Peter Harris, in the Department of Medicine, Division of Nephrology & Hypertension Research at the Mayo Clinic in Rochester, Minnesota. She received her Ph.D. from the Mayo Clinic Graduate School of Biomedical Sciences in January 2020, after completing her thesis work investigating the mechanisms associated with cancer and aging, by modeling the progeroid, neoplastic syndrome, mosaic variegated aneuploidy (MVA) in mice. Dr. Sieben has had a long-standing interest in elucidating the mechanisms of human disease. She developed this interest prior pursuing her Ph.D., while working as a research technologist in PKD research, involving the: (i) characterization and identification of genes associated with the syndromic PKD form, Meckel syndrome (MKS), and (ii) investigation of ADPKD gene function, pathomechanisms, and therapeutic testing. After completing her Ph.D., elucidating the mechanisms associated with natural aging, progeria, and cancer, Dr. Sieben has chosen to return to PKD research. Her current primary research project aims to increase our understanding of the genetic complexity and pathomechanisms of ADPKD.
2020 research grant awardees
Read below about the eight grants and one fellowship selected for funding in 2020.
2020 Dr. Vincent H. Gattone Research Award
Harrison Kim, Ph.D.
University of Alabama at Birmingham
Developing early prognostic imaging biomarkers of ADPKD based on dynamic changes in cyst growth rates.
Total kidney volume has been used as an indicator of autosomal dominant polycystic kidney disease (ADPKD) severity. However, its accuracy in predicting ADPKD activity may be suboptimal in the early stage of the disease. Also, since total kidney volume increases relatively slowly over time, it may take several years to determine whether ADPKD is favorably responding to therapy. Therefore, we sought an alternative to monitor the early activity of ADPKD. In our initial studies, we tracked the changes in volumes of individual kidney cysts over time and noted that these changes are surprisingly variable between cysts and that they also differ over time. We have developed a new computer software package to monitor these changes. We suggest that the pattern of individual cyst-volume change may serve as a better indicator of early ADPKD activity. We have demonstrated the feasibility of this approach with a small group of ADPKD patients and would like to validate it in a larger population in the proposed study. If successful, this novel approach will improve identification of high-risk ADPKD patients, optimize treatment decisions, and foster development of future therapies for ADPKD.
Harrison Kim is an associate professor in the Department of Radiology for the Division of Advanced Medical Imaging Research at the University of Alabama at Birmingham (UAB). Dr. Kim’s research vision is to globally standardize quantitative imaging of various diseases including polycystic kidney disease (PKD), which will facilitate automatic prognosis and therapy monitoring for patients. Automatic clinical decisions will drastically reduce both the turnaround time and medical expenses for patients. His research mission is to develop hardware and software tools along with this endeavor and validate those tools in multi-institutional clinical trials. In the proposed study, Dr. Kim will develop a novel prognostic imaging biomarker for PKD, which will be used for early therapy adjustment.
Eduardo Chini, M.D., Ph.D.
The Effect of Dietary Methionine Restriction on Pathogenesis of ADPKD and Therapeutic Implication of FGF21 Analogues
Polycystic Kidney Disease (ADPKD) is a common genetic cause of renal failure and is responsible for 5-10% of patients with end stage renal disease (ESRD). The disease is characterized by accumulation of fluid filled kidney cysts that ultimately leads to kidney failure. At present, only FDA approved treatment for ADPKD has relatively moderate effects. Therefore, treatment options for ADPKD patients are largely supportive, including dialysis and renal transplantation. We have previously observed that a decrease in food intake can prevent the development of ADPKD in animal models. Now our preliminary data shows that dietary restriction of single amino acid, methionine has beneficial effects in this cystic disease. We hope that understanding the effects of dietary methionine restriction in ADPKD will lead to the development of effective therapies for this cystic disease.
Dr.Chini is a native from Brazil and has been a clinician investigator at Mayo Clinic for 20 years. His clinical work is focused on the perioperative care of kidney and liver transplant patients. The research in Eduardo Chini laboratory is in the fields of metabolism, nutrition, pharmacology, with implications for cancer, obesity, aging, and kidney disease. In particular, Dr. Chini is interested in metabolism and molecular nutrition. In PKD Dr. Chini’s laboratory was the first one to demonstrate a key role for caloric intake on the pathogenesis of this disease. Furthermore, He and his colleagues have also explore mechanistic implications of caloric restriction in ADPKD and the role of specific macronutrients in this disease. Dr. Chini laboratory is also exploring the nonoxidative and oxidative roles of NAD (as a signaling molecule and energy coin in cells). Dr. Chini’s laboratory has done seminal work on NAD catabolism, including the description of the main enzyme responsible for the degradation of this molecule in mammalian tissues. Dr. Chini is the director of the molecular nutrition platform at the Kogod Center on Aging and director of the mitochondrial research center at Mayo Clinic.
Xiangqin Cui, Ph.D.
Machine Learning for Predicting eGFR Decline in the CRISP Cohort of ADPKD Patients
The rate of disease progression is highly variable among individual ADPKD patients. The recent approval of the first ADPKD therapeutic for patients with a high risk for renal function decline has made identification of such high-risk patients even more critical. Unfortunately, existing models for prediction of renal function decline perform well only in large groups of ADPKD patients, but their accuracy in individual patients is far from optimal. The models developed so far are regression models, which are beneficial for identifying risk factors and providing average renal function decline trajectories for patient subpopulations. However, they are not focused on predicting future renal function in an individual patient. Recently-developed groundbreaking Machine learning/Artificial intelligence (AI) methods are far more patient-oriented and have already transformed the prediction of diverse medical outcomes. Therefore, we propose to develop Machine learning models for predicting renal function in individual ADPKD patients, using the data from one of the best-characterized ADPKD studies (the CRISP study). We will examine various Machine learning methods and compare them with the traditional regression-based methods in prediction accuracy at the individual patient level. We will also test the hypothesis that the contribution of some expensive variables, such as genetic mutations and some advanced imaging data, can be offset by the collection of a large number of routinely obtained clinical variables. We propose to validate the CRISP-based Machine learning prediction models in other cohorts of ADPKD patients, such as the HALT cohort, the Kaiser Permanente cohort, and the VA cohort that we are constructing.
Dr. Cui is currently a Research Associate Professor in the Department of Biostatistics and Bioinformatics at Emory University. Dr. Cui earned her PhD in Genetics from Iowa State University. She was then trained in statistical genetics and bioinformatics at the Jackson Lab as a postdoctoral fellow. In 2004, she joined the Department of Biostatistics at University of Alabama at Birmingham as a faculty member focusing on analytical method development and collaborations in studies employing various high throughput omics technologies. Her interest in PKD research started from mapping modifier genes in mice during her postdoctoral training in collaboration with Dr. Lisa Guay-Woodford and Dr. Michal Mrug. The collaborations continued in the years after she moved to UAB and resulted in multiple publications in PKD basic research. In 2019, Dr. Cui moved to Emory University to lead the Data Analytics Core in the Atlanta VA Medical center and her research focus shifted toward studies based on VA electronic medical records and intervention trials.
Maria Irazabal, M.D..
Role of NOX4, mitochondria and related biomarkers in Autosomal Dominant Polycystic Kidney Disease
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a devastating genetic disorder that causes numerous cysts in the kidneys, and remains a leading cause of renal failure. However, the only FDA-approved therapy for ADPKD (tolvaptan) is limited to slowing-down disease progression, and has associated side effects. Furthermore, the mechanisms that contribute to cyst formation and further damage to the kidney are still uncertain. A better understanding of these processes may assist in development of new therapies with fewer adverse effects and improve the quality of life of these patients.
Another critical problem in the care of patients with ADPKD is that the rate of disease progression varies widely among individuals and markers of renal function don’t change until late stages, representing a major challenge for following these patients, identifying a treatment response or predicting the progression of the disease. Therefore, there is a pressing need for identifying early biomarkers of disease severity/progression and additional targets for therapeutic interventions.
Oxidative stress is the imbalance between the production of harmful free radicals and antioxidants and a major contributor of renal damage in other kidney diseases, but its role in ADPKD is unclear. This proposal will explore for the first time the role of oxidative stress damage in ADPKD and related biomarkers. The findings resulting from this study are likely to have important clinical implications by: advancing the understanding of the mechanisms of renal damage in ADPKD, identifying novel early biomarkers, and highlighting additional processes that could be target for therapeutic intervention.
Dr. Irazabal earned her medical degree from Universidad de la Republica in Montevideo, Uruguay, and completed her research fellowship in renal physiology and polycystic kidney disease at the Mayo Translational PKD Center, Mayo Clinic in Rochester, Minnesota. Her contribution to the field of PKD research includes the development of an imaging classification for autosomal dominant polycystic kidney disease (ADPKD) patients, which is broadly used for selecting which patients with ADPKD to treat. Dr. Irazabal is currently an Assistant Professor and a faculty member at the Mayo Translational PKD Center and her research program focuses on identifying mechanisms contributing to disease severity and progression while identifying early biomarkers in ADPKD. Her research includes in-vitro as well as pre-clinical translational and clinical studies in ADPKD. Specific areas of interest include redox signaling, mitochondrial abnormalities and energetic dysregulations, as well as the contributions of the intra-renal microvasculature to disease severity and progression.
Roman-Ulrich Müller, M.D. and Thomas Weimbs, Ph.D.
University of Cologne and University of California in Santa Barbara
KETO-ADPKD — A pilot trial of ketogenic dietary interventions in ADPKD
Our recent research suggests that simple diets which mimic fasting profoundly inhibit the growth of kidney cysts in animals with PKD. These diets induce the state of “ketosis” that allows fat reserves to be used for energy instead of blood sugar. We discovered that cysts in PKD are unable to adapt, and starve during ketosis. Based on these findings, we propose a clinical trial to test two well-established diets that induce ketosis: (1) fasting and (2) a high-fat/low carb ketogenic diet. ADPKD patients will be treated with either diet for 3 months to find out how well they tolerate these diets, how safe they are and which one is easier to adhere to. The results will be crucial for the design of a subsequent trial to test whether one of these diets slows disease progression in the long-term in a much larger number of ADPKD patients.
Dr. Roman-Ulrich Müller is Vice Director of the Department 2 for Internal Medicine (Renal Unit) at the University Hospital Cologne. He began his medical career at the universities of Freiburg and Heidelberg in Germany. After finishing medical school, Dr. Müller completed his scientific training at Rockefeller University (New York, USA) and Yale University (New Haven, USA). He then returned to Germany to obtain his board certification in Nephrology in the Department of Prof. Benzing at University Hospital Cologne where he now works.
Here, Dr. Müller is head of the ADPKD unit (website) and has established the „AD(H)PKD Registry“, which strives to collect information on the management of ADPKD and has become one of the largest cohorts worldwide. Furthermore, he leads a basic research group that tackles the molecular mechanisms underlying kidney disease, employing modern techniques in molecular biology and biochemistry (website). His special interest is dedicated to renal RNA biology — e.g. RNA-binding proteins and non-coding RNAs — including the discovery of small non-coding RNAs in polycystic disease. Research in Dr. Müller’s laboratory has been funded by grants from federal agencies, including the German Research Foundation and the Ministry of Science North-Rhine Westphalia, by private foundations, including the Marga and Walter Boll Foundation and the German Kidney Foundation, as well as several companies involved in biotechnology and medicine. Based on this work, Dr. Müller is the author of numerous publications on clinical and molecular nephrology in renowned journals.
Whenever this leaves time for other activities, Roman loves to discover the world, no matter whether by campervan, bicycle or — as required by the current pandemic — online.
Thomas Weimbs is a professor at the University of California in Santa Barbara (UCSB) where he directs a research laboratory focused on polycystic kidney disease (PKD). He received his doctoral degree from the University of Cologne, Germany, and then conducted postdoctoral research at the University of California in San Francisco. In 1999, he started his first independent research laboratory at the Lerner Research Institute of the Cleveland Clinic as an assistant professor. There, he started to research PKD after he was approached by a local family affected by PKD who financially supported PKD research in his newly-founded laboratory. Their family foundation still supports PKD research in Dr. Weimbs’ lab today. In 2005, Dr. Weimbs moved his laboratory back to California to join the Department of Molecular, Cellular, and Developmental Biology at UCSB. His laboratory studies molecular mechanisms underlying PKD with an emphasis towards developing new therapies. Research from Dr. Weimbs’ lab has led to a better understanding of PKD and led to novel methods to deliver therapeutics specifically to polycystic kidneys. Some of the most recent research has led to the discovery that commonly available, and safe, dietary supplements can prevent cyst growth in animal models on PKD. Research in Dr. Weimbs’ laboratory has been funded by grants from federal agencies, including the National Institutes of Health and the Department of Defense, by private foundations, including the Lillian Goldman Charitable Trust, the Amy P. Goldman Foundation and the Jarrett Family Fund, as well as several biotech companies. For more information on research in the Weimbs lab, see the website.
In his free time (what free time?), Thomas enjoys playing the saxophone in his jazz band (no, you wouldn’t have heard of them…).
Kristen Nowak, Ph.D.
University of Colorado Anschutz Medical Campus
Adiposity and Time Restricted Feeding in ADPKD
We showed previously that body mass index, determined by a person’s height and weight, is an important predictor of ADPKD progression, even when accounting for other factors. This may be explained by increased fat tissue, which can promote inflammation and other signaling leading to growth of cysts. We would now like determine whether fat tissue in the abdomen may explain this association, by looking at magnetic resonance images (MRIs) that were collected previously. We will also see if weight loss reduces abdominal fat and if this slows kidney growth in adults with ADPKD who are overweight or obese. We will use MRIs from our ongoing weight loss study to answer this question. Changes in metabolism also occur in ADPKD and affect progression. Periods of fasting (restricting the number of hours food is eaten each day, or time restricted feeding) was recently shown to slow ADPKD progression in rodents. We also propose a pilot study of time restricted feeding in adults with ADPKD (limiting intake to 8 hours a day), to ultimately see if this reduces abdominal fat and slows kidney growth. As an important first step, this pilot study will determine if this diet is feasible (whether people can adhere to the diet for one year). Together, these aims will provide a better understanding of the role of fat tissue in ADPKD and whether dietary approaches can slow kidney growth, in part by reducing abdominal fat. These results will provide the foundation for a larger scale trial on this topic.
I am trained as a physiologist with an interest in lifestyle interventions to reduce risk of cardiovascular disease and kidney disease progression. I conduct research on the mechanisms of vascular dysfunction in patients with kidney diseases, including ADPKD, as well as on novel therapeutics to alleviate such dysfunction. I have unique expertise in identifying integrative physiological mechanisms mediating vascular dysfunction, as well as in epidemiology, having recently completed a Master of Public Health. I direct the clinical vascular physiology laboratory for the Division of Renal Diseases and Hypertension. My K01 Career Development Award, sponsored by the National Institutes of Health, is testing the efficacy of curcumin, a naturally occurring polyphenol, in order to improve vascular function and slow kidney growth in children and young adults with ADPKD. I also became recently interested in the role of diet and metabolic dysfunction in ADPKD progression. I have an active NIH R03 grant evaluating the feasibility of two weight loss interventions, daily caloric restriction and intermittent fasting, in adults with ADPKD and overweight or obesity.
Stephen Parnell, Ph.D.
University of Kansas Medical Center
Rescuing Polycystin-1 G-protein Function
The only approved therapy for autosomal dominant polycystic kidney disease (ADPKD) is JYNARQUE, which must be taken long-term and has undesirable side-effects. Most ADPKD cases are caused by mutations in the PKD1 gene, which encodes polycystin-1 (PC1). However, JYNARQUE and other therapies target downstream pathways rather than the primary cause of disease, which is loss of PC1 function.
Prior experiments have shown that restoring PC1 via genetic engineering slows disease in juvenile mouse models. However, it is not known whether this approach will work in adult cystic mice, which are more representative of the human disease condition.
If restoration of PC1 works in both juvenile and adult models of disease, then restoration of PC1 is a potential therapy for PKD. However, genetic restoration of the PKD1 gene is currently not a feasible therapy in humans.
As an alternative to genetic engineering, small portions of the PC1 protein that retain biological activity and can be synthesized in vitro could be developed into a viable therapeutic option. A small peptide from the tail of PC1 contains a biological activity that could potentially copy an essential function of PC1. The hypothesis to be tested is that restoration of PC1 will slow cystic disease progression in adult mice, and that this effect can be copied by therapeutic administration of a synthetically produced, bio-active peptide derived from PC1.
Successful completion of the proposed work would provide a pathway to a deliverable therapy intended to overcome the loss of PC1 function in ADPKD patients.
Dr. Stephen Parnell received his PhD in biochemistry and molecular biology from the University of Kansas Medical Center for his work on the structure and function of the polycystin-1 protein. Following postdoctoral studies on signal transduction at the University of North Carolina – Chapel Hill, Stephen returned to Kansas to apply his new knowledge and skills to the PKD field. As a faculty member within the Jared Grantham Kidney Institute, Stephen’s laboratory utilizes molecular approaches and mouse models of PKD to continue his focus on polycystin-1 function and its role in regulating cellular signaling pathways. Stephen’s passion for PKD research extends beyond the laboratory, as he has numerous family members affected by PKD. The broad, long-term goals of his laboratory are to elucidate the mechanisms of polcystin-1 function in order to develop improved therapies for the benefit of PKD patients.
Christopher Ward, M.D., Ph.D.
University of Kansas Medical Center
Use of exosomal polycystin-1 (PC1) level to diagnose and monitor autosomal dominant polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited cause of renal failure affecting 1:800 individuals. At present, there is no biochemical test to diagnose or monitor the disease. Using the finding that small membrane vesicles found in urine (exosomes) contain the protein products of the polycystic kidney disease genes, we have developed a urine based test for ADPKD. The test measures the amount of polycystin-1 in urinary exosomes and can be used to diagnose the disease. The object of this study is to ensure that this test can be used to determine the severity of ADPKD and thus its prognosis. Such a test may be used to make an early diagnosis (as the earlier a treatment is started the better) and to monitor the disease, perhaps as it is being treated. One interesting feature of the PKD1 gene is a large stretch of DNA composed of only two bases as opposed to the usual four. This results in a human gene that does not function as well as the same gene in other animals. When the gene is being copied to RNA, the copying process tends to stop early making a shorter defective form of polycystin-1. There appears to be considerable variation in how much of the full length protein is made by different people. This might be responsible for the variation in the amount of polycystin-1 seen in the urine and in the severity of polycystic kidney disease. We wish to investigate both phenomena in this application.
Dr. Christopher J. Ward was born and raised in Scotland and received his medical training at Edinburgh University qualifying in 1986. He then did a PhD in immunology at the University of Birmingham, England before joining the laboratory of Prof Peter Harris in Oxford. Dr. Ward was closely involved in the positional cloning of the tuberous sclerosis type 2 (TSC2) gene and the polycystic kidney disease type 1 (PKD1) gene and developed a range of antibody reagents designed to detect the product of the PKD1 gene, polycystin-1. In 2000, Drs. Ward and Harris moved to the Mayo Clinic and identified the gene for autosomal recessive polycystic kidney disease (PKHD1) using the pck rat model which is orthologous to PKHD1. Again, Dr. Ward developed antibody reagents to the product of PKHD1, fibrocystin, as well as generating two mouse models of the disease. In collaboration with Dr. Marie Hogan, Dr. Ward showed that extracellular vesicles contain the products of the three major human PKD genes and did an extensive proteomic analysis on these. This survey then lead to the development of a test for ADPKD and to the formulation of the exosome cilium interaction theory (ECIT). This idea suggests that extracellular vesicles, released into the urine flow, can transmit a `urocrine’ signal by interacting with primary cilia and that polycystic kidney disease is due to a failure of this novel signaling pathway.
Laura Onuchic, M.D.
Yale School of Medicine
Polycystic Kidney Disease Proteins and aGPCRs: Elucidating a Novel Signaling Pathway
ADPKD is one of the most common potentially lethal genetic disorders, affecting ~1:1000 individuals. It is characterized by the formation of kidney cysts, whose expansion over time compromises kidney structure and function.
Most ADPKD cases are caused by a genetic mutation in the PKD1 gene, which consequently encodes a defective polycystin-1 protein. The exact mechanisms through which this defective protein leads to disease remain unclear.
The polycystin-1 protein spans the cell membrane and has an intracellular and extracellular portion. We hypothesize that the extracellular portion of the polycystin-1 protein functions as a receptor that regulates intracellular signaling processes. We will study the structural basis for this receptor function and characterize the downstream elements of the cellular signaling machinery that respond to polycystin-1. These studies may illuminate a new biological role for the polycystin-1 protein and shed light on the processes that lead to cyst formation and on potential therapeutic targets.
Dr. Onuchic earned her medical degree from the University of São Paulo, Brazil, where she also completed her residency training as a clinical nephrologist. She moved to the Yale School of Medicine in 2019 to pursue postdoctoral research training under the mentorship of Dr. Michael Caplan, Chair of Cellular and Molecular Physiology.
2019 research grant awardees
Most grants from 2019 are complete, but the Young Investigator Award is a three-year grant.
2019 Young Investigator Award
Sorin Fedeles, Ph.D.
Yale School of Medicine
Controlling the viability of PKD mutant cells via inactivation of XBP1 as a novel strategy to treat ADPKD
Polycystic kidney and liver diseases belong to a family of genetic fibrocystic disorders that primarily affect the kidney and liver. The current proposal focuses on a pathway i.e. Ire1α-XBP1 that we have recently implicated in the pathogenesis of ADPKD and that we have found, to our surprise, to play an important role in controlling the viability of Pkd1 deficient cells. Genetic inhibition of this pathway in relevant mouse models of ADPKD led to a slowing down of disease progression and significantly improved kidney function. Avenues that can inhibit Ire1α-XBP1 may thus hold clear therapeutic potential for the treatment of ADPKD and potentially, ARPKD.
Sorin Fedeles has an extensive background in academic basic research with a focus on genetic kidney diseases. Through his research he has contributed to the understanding of the genetic and molecular mechanisms of Autosomal Dominant Polycystic Kidney and Liver Disease (ADPKD/ADPLD). He obtained his PhD in Genetics at Yale and after his postdoc continued at Yale as a research faculty. During the last few years, he spearheaded a collaboration with a bio-engineering group at MIT to develop a novel class of drugs for the treatment of ADPKD which has recently secured patent protection through the combined efforts of Yale’s and MIT’s technology licensing teams. Sorin is passionate about scientific innovation and the process required to advance discoveries along the science-business continuum. In order to develop his business knowledge, he pursued an MBA at Yale SOM (class of 2016) and complemented it with a Blavatnik Fellowship in Life Science Entrepreneurship where emerging science and business leaders identify breakthrough innovations emerging from Yale in order to foster their commercialization.
Core Lab Grant Award
The PKD Foundation’s Core Lab grant program is designed to support research facilities, databases, and services to benefit the entire PKD research community.
Mayo ADPKD Mutation Database
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
Last updated May 2021