Current funded research

Novel MRI Fingerprinting of Congenital Hepatic Fibrosis in ARPKD Patients

Autosomal Recessive Polycystic Kidney Disease (ARPKD) affects approximately 1/20,000 children and has two main features, polycystic kidneys and the liver disease, congenital hepatic fibrosis (CHF). CHF results in progressive deleterious changes in the bile ducts of the liver and can be associated with significant, life-threatening complications, including portal hypertension (leading to severe bleeding), bile duct infection or cancer. Although kidney disease is common in many ARPKD patients early in life, CHF may not be evident until later in childhood or adulthood. As more ARPKD patients survive after kidney transplantation, significant CHF is becoming more common. Unfortunately, there are currently no disease-specific therapies and treatment is focused on addressing CHF complications. Several novel therapies have shown efficacy in animal models, but have not been studied in ARPKD patients due to the absence of safe and reliable measures of CHF progression.

Newer ultrasound (US)-based elastography methods, that measure liver stiffness (scarring) can distinguish mild vs severe CHF but may lack sensitivity to detect and measure early CHF, when therapies are most likely to be effective. Our collaborative research team (Drs. Dell & Flask) has been studying novel MRI methods to assess ARPKD kidney and liver disease progression for over a decade. In previous studies in an ARPKD animal model, we showed that T1 mapping is a sensitive measure of progressive CHF. While encouraging, one major limitation to MRI is that it usually requires long scan times and is affected by movement, which necessitates sedation/anesthesia for many children. This increases risk and would likely prevent participation of younger ARPKD children in clinical trials that use MRI.

To address this important limitation, our group has applied and optimized a novel technique, MR-Fingerprinting (MRF), to study both ARPKD kidney and liver disease. MRF allow for rapid and simultaneous acquisition of multiple imaging parameters, including T1 and T2, and is resistant to motion artifact. In a current NIH R01 longitudinal kidney imaging study, we obtained kidney MRF results in ARPKD patients with excellent repeatability and no need for intravenous contrast or sedation. With supplemental funding, we obtained initial liver MRF images, showing that mean T1 values are significantly higher in ARPKD patients with advanced CHF vs. both healthy volunteers and ARPKD patients with milder disease. The overall goal of this project is to establish liver T1-MRF as a safe, sensitive and reproducible CHF imaging biomarker that would facilitate design and implementation of future clinical trials. The Specific Aims are to evaluate T1-MRF across a spectrum of ARPKD liver disease and compare T1-MRF with US measures of liver scarring. The proposed studies would provide a key element needed to conduct clinical trials of CHF treatments and ultimately improve outcomes for ARPKD patients.

Glycosylation as a regulator of liver disease in ARPKD

Autosomal recessive polycystic kidney disease (ARPKD) is a genetic disorder characterized by the growth of fluid-filled cysts in the kidney. The liver is also affected by the same genetic mutation in ARPKD, and as such, the majority of individuals with ARPKD will also have a liver disease called congenital hepatic fibrosis (CHF). CHF is where excessive scar tissue is deposited in the liver and can disrupt normal liver function. Currently, there are no treatments to cure the liver disease in CHF/ARPKD except for liver transplantation. Therefore, more research efforts to better understand how we can prevent or reverse liver scarring in ARPKD is essential.

This project focuses on the role of glycosylation in CHF/ARPKD. Glycosylation is the process where sugars are added to target molecules, such as proteins, to direct their function or location within or outside a cell. When glycosylation is disrupted, this can lead to a myriad of diseases, including kidney and liver diseases. Mannose is a sugar similar to glucose, and the processing of mannose is a key pathway in maintaining correct glycosylation of proteins. Our research data and clinical observations stimulated us to explore the role of glycosylation and mannose metabolism as important regulators of CHF in ARPKD. With the following aims, we will test our hypotheses that abnormal glycosylation drives liver scarring in ARPKD, and that mannose supplementation can be effective at treating ARPKD-associated liver disease.

This project is relevant to PKD as it examines an extra-renal manifestation of ARPKD from a novel viewpoint – changes in liver glycosylation associated with ARPKD and examines mannose as a potential therapy for ARPKD-associated liver disease. The Impact/Significance of this project, in addition to mannose being used therapeutically, is potentially identifying novel glycoproteins that impact severity of liver disease in ARPKD which could become therapeutic targets or diagnostic markers for severity of liver disease. This proposal provides conceptual, technical and translational innovation as it focuses on the novel idea that changes in mannose metabolism and protein glycosylation drive CHF in ARPKD patients, it uses cutting-edge glycoproteomic analyses to identify key changes in the pathobiology of CHF, and it integrates findings from divergent fields which, together, introduce the novel prospect that manipulating mannose levels in the liver can improve fibrosis in ARPKD.

Charles DeRossi, Ph.D., is an Assistant Professor in the Department of Pediatrics at the Icahn School of Medicine at Mount Sinai. He earned his Ph.D. in Biochemistry and Glycobiology from Ruprecht-Karls Universität Heidelberg in Germany, and postdoctoral training at the Icahn School of Medicine at Mount Sinai where he was awarded training grants in Investigative Gastroenterology and Transplant Immunology. Dr. DeRossi has a long history of studying how metabolic and glycosylation pathways contribute to development and disease. Most recently he has been examining the glycosylation and metabolic changes that take place during the progression of liver fibrosis and has identified the simple sugar mannose as an effective anti-fibrotic in multiple animal systems. He now aims to expand this research to study the diseased liver associated with autosomal recessive polycystic kidney disease (ARPKD), in particular identifying novel glycoproteins that play a role in driving fibrosis in the ARPKD liver, and the potential utility of mannose to lessen the progression of liver disease.

Effect of Whole Compared to Ultra-Processed Foods in PKD

Individuals with PKD are no different than the general population in that they are very interested in information that can help them improve their health via dietary choices. However, they are faced with a dizzying array of options of whole and processed foods and much conflicting dietary advice. The lay press is filled with dietary advice, but there are no official dietary recommendations for PKD, as indicated by the following statement on The PKD Foundation web site: “Currently no specific diet has been proven to make your polycystic kidneys better or keep them from getting worse. It is, however, ideal to eat a balanced and healthy diet to maintain optimal body conditions.” Despite recommendations by nutrition authorities to eat a balanced and healthy diet by consuming whole foods (WF), the consumption of ultra-processed foods (UPF) is still very high in human diets. These food products are highly processed, tasty, convenient, and often cheaper than buying WF. The average US diet contains 50-60% UPF. Unfortunately, these food products are generally lower in nutrients and higher in salts, sugars, fats and additives.

Evidence of the benefits of WF diets and the detrimental effects of UPF is mounting for many major chronic diseases, and recently this has been shown to be true for chronic kidney disease (CKD) as well. However, this has not been shown for PKD specifically. Therefore, the first impact of the current study is that it will address this gap in knowledge by testing the effects of well-defined WF and UPF diets on disease progression in 2 established mouse models of PKD. Animal studies allow dietary effects (and drug effects, as exemplified by Tolvaptan studies) to be tested without the confounding effects of the vast diversity in human populations, and offer a comparatively cost-efficient way to test the validity of these concepts.

The second impact of this proposal is that it will test the effects of diets based on entirely plant food sources compared to diets containing a 2/1 ratio of animal/plant protein sources, and will examine the effects of low protein compared to normal protein diets in PKD. There is interest in plant-based and lower protein diets, but the benefits of these dietary strategies remain unclear due to the often-conflicting scientific literature results. One of the sources of such inconsistencies may be due to the inclusion of UPF in studies to date, which may counteract any benefits of plant-based or protein-reduced diets. Therefore, the current study will test the effects of WF compared to UPF using diets containing animal products (e.g. common American diet) and diets composed exclusively of plant products (e.g. vegan, vegetarian diets). Further, diets will be formulated to have a low (but adequate) level of dietary protein or a normal level of protein (similar to the average American intake of protein). This will provide the first information in PKD on whether the beneficial effects of plant-based and low protein diets are influenced by food processing.

Can a Fragment of Polycystin-1 Unlock the Door for Gene Therapy in ADPKD?

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent potentially lethal monogenic disorder. Approximately 78% of cases are caused by mutations in the PKD1 gene, which encodes polycystin-1 (PC1). PC1 is a large 462-kDa protein that undergoes cleavage in its N and C-terminal domains. C-terminal cleavage produces fragments that translocate to mitochondria. We have found that transgenic expression of a protein corresponding to the final 200 amino acid residues of PC1 in a Pkd1-knockout orthologous murine model of ADPKD dramatically suppresses the cystic phenotype and preserves renal function. This suppression depends upon an interaction between the C-terminal tail of PC1 and the mitochondrial enzyme Nicotinamide Nucleotide Transhydrogenase. Expression of the PC1-CTT stimulates NNT activity.
Recent data from Dr. S. Somlo’s laboratory demonstrate that re-expression of full length PC1 or PC2 can dramatically reverse advanced cystic disease attributable to inactivation of Pkd1 or Pkd2, respectively. These data suggest the intriguing possibility that development of an intervention that produces expression of functional PC proteins in the renal epithelial cells of patients could potentially not only prevent disease progression but could also diminish the severity of established cystic pathology. The development and testing of such an intervention are complicated by the fact that the cDNA encoding full length PC1 is far too large to be packaged in any currently available conventional viral gene delivery vector. Our data show that initiation of conditional PC1-CTT expression simultaneously with conditional disruption of Pkd1 substantially dampens the development of the ADPKD phenotype in a mouse model. In Aim 1 we will determine whether expression of the PC1-CTT recapitulates the capacity of the full length PC1 protein to induce the resolution of extant cysts. Were this to be the case it would constitute a strong proof of concept for the development of gene therapy strategies built around the delivery of the sequence encoding the PC1-CTT, since this sequence is only ~600 bp in length.
In Aim 2 we will take advantage of in vitro assays to define the minimal active piece of the PC1-CTT that is needed in order to mediate its effects on NNT activity and on cyst formation. The sequence that encodes the PC1-CTT and the sequence that encodes its minimal active piece will be employed in the creation of viral gene delivery vectors. We will test the capacity of these vectors to drive the expression of the encoded proteins in the epithelial cells of mouse kidneys in vivo. Will also assess whether administration of these vectors is able to slow or reverse cystic disease in orthologous mouse models of ADKPD. A demonstration that delivery of the PC1-CTT or its minimal active piece reduces ADPKD severity in vivo would provide strong support for further translational development of this approach.

Unraveling the earliest cellular behaviors at the inception of ADPKD

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disorder, and it is caused by mutations in the genes PKD1 and PKD2. ADPKD patients have one mutation in either of these genes in all their cells but, in their kidneys, some cells carry two mutations and are the ones that become cysts. There is no cure for the disease and current treatments aim at ameliorating the symptoms of cyst growth: pain, hypertension and impaired kidney function; in half of the patients, ADPKD will progress to kidney failure. In 2018, the FDA granted approval of Tolvaptan, a drug that slows down cyst growth in rapidly progressing ADPKD patients. However, not all patients are rapidly progressing, and the drug has significant liver toxicity. The disease is usually diagnosed between the ages of 30 and 50, when the increase in size of a multitude of cysts blocks the flow of blood and filtrate in nearby nephrons, therefore compromising kidney function. Despite being an “adult” disease, the mutant cells that will give rise to the cysts are believed to be already present in children.

Here we propose to study the behavior of these mutant cells at their inception, in the embryonic developing kidney, using a unique mouse model. Our rationale is that, by understanding the earliest events leading to cyst formation, we will be able to formulate better therapies addressed at the asymptomatic ADPKD pediatric population. This is a specially neglected population. Affected parents question the need to genetically or ultrasonographically identify the disease in their children given the absence of an active treatment. Their hesitance is understandable when the only possible treatments are diet and lifestyle changes that can be implemented without the label of a pre-existing condition.

Our approach relies on 1) a unique mouse model in which we can visualize with fluorescent proteins a limited number of mutant cells in the embryonic kidney, and 2) our ability to culture and image those kidneys outside of the embryo, therefore enabling us to study the earliest behaviors of the mutant cells. In our preliminary studies using this mouse model we demonstrate that a single mutant cell is responsible for the development of each cyst. In order to do so, this cell must proliferate and prevent dispersion of its daughter cells.

In this proposal we aim at answering the following questions: How is proliferation of mutant cells driven and controlled? And how do mutant cells remain together to become a cyst?

Answering these questions will allow us to identify targetable pathways to prevent cyst initiation. In contrast with current treatments that prevent cyst growth in rapidly progressing patients, by preventing cyst initiation we aim at identifying a long-lasting early therapy for children at risk for ADPKD.

Targeting Tolvaptan-Resistant Mechanisms of Fibrosis in ADPKD

ADPKD is a systemic disorder in which kidneys become large due to tubular cyst expansion. This is accompanied by fibrosis (scarring) in the kidney. Tolvaptan is the only FDA-approved drug for treatment of ADPKD. It targets the V2 vasopressin receptor, causing the kidney to reabsorb less water from the urine. While tolvaptan reduces cyst size, modestly slowing the rate of declining renal function, the NIH sponsored “CRISP” study found that the decline in renal function in people with ADPKD correlated with the development of renal fibrosis, not renal size. There are no approved therapies – nor late-stage clinical candidates in development – to address fibrosis in ADPKD. PKD-associated pathology leads to alterations in blood flow and changes in the distribution of cell types within the kidney, including an invasion of inflammatory cells and proliferation of the interstitial cells. It has been proposed that rapid cyst expansion compresses blood flow, contributing to low oxygen in tissues and fibrosis. Our preliminary data our mcwPkd1(nl/nl) model of ADPKD shows that tolvaptan reduces cyst expansion, but not fibrosis. This suggests that fibrosis will be a persistent problem in people with ADPKD, even with tolvaptan treatment. Importantly, this indicates that specific therapies targeting this fibrotic mechanism, rather than cyst formation and growth alone, must be developed to affect progression of renal disease and loss of function in ADPKD. The mcwPkd1(nl/nl) provides an experimental model to dissociate and study causes of fibrosis that are independent of cyst expansion.

The “central dogma” of biology has been that that DNA is transcribed to RNA, which is translated into a functional protein. Some RNAs, called non-coding RNAs, have other functions. MicroRNAs (miRs) are very short, non-coding RNAs regulated like many protein coding genes. They are understood to bind and inhibit RNA translation. A single miR can targeting multiple RNAs causing broad regulatory effects. Our preliminary data indicate that therapeutic targeting of fibrotic signals, in addition to cyst expansion, is needed to slow progression of renal disease and loss of function in ADPKD. This proposal will focus on the role of transforming growth factor beta-1 (TGFB1) and miR-382, a miR increased in by TGFB1, on persistent fibrosis in conjunction with tolvaptan treatment in the mcwPkd1(nl/nl) model of ADPKD. Both are pro-fibrotic signaling factors, that are increased during periods of rapid fibrotic expansion in Pkd1(nl/nl) mouse models. We anticipate these studies will yield important information about the mechanisms regulating fibrosis. Further, this project has the potential to solidify the involvement of specific signaling pathways in the development of renal fibrosis. This knowledge could help develop new, focused therapeutic strategies to slow or preventing morbidity resulting from progressive fibrotic remodeling in people living with ADPKD.

The role of ferritin in polycystic kidney disease

Autosomal Dominant Polycystic Kidney disease (ADPKD) is a genetic disease which is caused by mutations in PKD1, PKD2 or rarely random genes. The disease manifests with the formation of huge cysts in the kidney. Initially, the disease progresses slowly and can go unnoticed until a person is 25 to 30 years old when symptoms such as elevated blood pressure, flank pain and increase in kidney volume can be noticed. The disease progression depends on the kind of mutation, each with varying level of severity. Regardless of the mutation, there are some common molecular pathways that are affected. The discovery of these pathways is important because manipulations in these pathways may serve as a strategy to treat the disease. We have recently discovered that ferritin, a protein which maintains iron homeostasis is abnormally expressed in the collecting duct cells (CD) (kidney segment where cysts are present) and inflammatory cells (macrophages) of ADPKD kidneys. To determine the role of ferritin, we cultured cyst lining cells from ADPKD patients in a 3D collagen gel where they formed cysts. Ferritin treatment on these cysts resulted in enlargement of cysts. Cell culture studies further revealed that cyst lining cells have increased capacity for ferritin uptake which induces inflammatory pathway (NF-kappa B) activation. These results suggest that ferritin aids in cyst growth. In the first aim of this proposal, we will find if NF-kappa B activation via ferritin induces cell proliferation and inflammation. We will study the effect of ferritin treatment on disease progression in a mouse model of ADPKD. In the second aim, we will delete ferritin from the CD of ADPKD mice and determine if disease progression slows down. We will also delete ferritin from macrophages of these mice to study if these cells contribute to disease progression. If our goals are successful, the study will provide a basis for treating the disease with ferritin inhibitors.

Properties of sensory neurons in ADPKD, and their contribution to ADPKD related chronic pain

A very common symptom and patient reported outcome in ADPKD is acute and chronic pain. A recent study with patients and clinicians in the United States, Europe and Japan found that ADPKD-related pain was the most important outcome impacting physical functioning, with complex and distinctive presentations ranging from feeling full/discomfort to acute sharp pain. However, the source of ADPKD-related pain is poorly understood, especially for chronic pain. Therefore, pain in ADPKD patients is often under-recognized and inadequately managed. Yet, chronic, long-term pain is known to affect at least two in three ADPKD patients and is associated with reduced quality of life, often intense distress, and considerable economic and healthcare costs from emergency hospital admissions, polypharmacy (antibiotics and pain relief including morphine) and impact on work/home life.

No gold-standard modality for pain relief exists in patients with ADPKD. Indeed, the current pharmacological analgesia management in ADPKD is prescribed according to the WHO three-step analgesic ladder. However, an important caveat in this ADPKD population is the nephrotoxicity of NSAIDs and the impaired clearance of opioids, limiting their use and safety. Patients with unsatisfactorily pain relief will undergo more invasive procedures ranging from cyst aspiration, renal denervation to radical nephrectomy.

Despite the scale and burden, there has been little research into ADPKD associated pain and its treatment. Why pain occurs is inadequately understood — it is not always related to kidney size and may occur in adolescence and early stages when no other symptoms are present.

One attractive strategy is to intercept pain at the source, by targeting the sensory neurons that generate nociceptive signals. Currently, there is virtually no knowledge on the properties of sensory neurons or molecular sensory receptors in the context of ADPKD. Considering that PKD1 and PKD2 (the two predominant genes in which mutations cause ADPKD) are expressed in sensory neurons, that mutations in PKD1 and PKD2 lead to abnormalities in cellular signaling in various cell types, and that secretion of a variety of factors (such as MCP1) which influence sensory neurons is altered in ADPKD, we hypothesize that the properties of nociceptive sensory neurons are distorted in the context of ADPKD, which might contribute to the precipitation of chronic pain in ADPKD patients and could even contribute to development of the disease.

Injury-induced tubular obstruction promotes cyst formation in ADPKD

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most commonly inherited genetic renal disorders affecting more than 500,000 people in the United States and 13 million people worldwide. ADPKD is due to a genetic mutation in one of two genes, PKD1 or PKD2, that encode the proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Despite its strong genetic basis, the presentation and progression of ADPKD varies widely in the population. The typical course is adult-onset disease with end-stage renal disease in the 6th decade of life. However, a small proportion of patients have adequate renal function into the 9th decade, whereas others present with enlarged kidneys as teenagers. This suggests that other factors, including environment and modifier genes, also play a role in disease severity.

Recent discoveries from animal studies have found that injury to the kidney can play an important role in cyst progression. In mice the absence of functional PC1/PC2 in the kidney results in slow cyst growth in focal locations. Subsequent injury to the kidneys, however, promotes rapid and widespread cyst growth. How injury drives the rapid disease progression is a mystery.

Based on my preliminary studies, I hypothesize that tubule obstruction caused by renal injury triggers rapid cyst formation. The kidney contains millions of renal tubules that function as filtration units for the blood to eliminate waste through the urine. If this filtration is blocked, it can cause the tubules to dilate causing injury to the surrounding tubules and promoting additional tubule dilation and accelerated cyst formation.

I predict that PC1 and PC2 have an important role in the kidney to respond to injury. Under normal conditions, cells in the kidney tubules respond and repair the injury to restore full function. However, in kidneys with PKD1 or PKD2 mutations, the kidney loses the ability to fully repair. The cells that fail to correctly repair die and slough off into the tubule. The accumulation of these dead cells in the tubule lumen leads to tubule obstruction and subsequent dilation, resulting in rapid cyst progression and further injury to surrounding nephrons. This hypothesis is supported by the nature of disease progression among patients with evidence showing individual cysts form early in life but progressively increase during adulthood and that the rate of new cysts accelerates with age.

To test this hypothesis, I will use the chemotherapy agent cisplatin to induce injury in the kidneys of ADPKD mouse model. This cisplatin treatment could mimic the low dose toxic injury that occurs in patients due to frequent medicine administration. This often happens among PKD patients who are suffering from other complications. The data obtained from this work will provide a better understanding of how injury accelerates disease progression and provide new potential mechanisms to decrease the rate of cyst formation in patients with PKD.

Investigating therapies to increase Polycycstin-1 protein expression to treat polycystic kidney and liver disease

Function of polycystins in ciliary extracellular vesicles

Autosomal dominant polycystic kidney disease (ADPKD) is a common, life threatening disease that affects 1/400-1/1000 individuals. ADPKD is caused by mutations in PKD1 and PKD2, which encode the proteins polycystin-1 and polycystin-2 (PC1 and PC2). Remarkably, the function of the polycystins remains controversial decades after their discovery on the primary cilia of the kidney. In the model organism C. elegans and in humans, the polycystins have similar protein structure, act in the same genetic pathway, function in a sensory capacity, localize to primary/sensory cilia, and are shed from cells in tiny extracellular vesicles (EVs), suggesting ancient conservation. Moreover, the biogenesis and shedding of ciliary EVs are evolutionarily conserved from algae to worms to humans. EVs have emerged as information carriers of central importance for signaling and with profound effects on physiology and pathology. EVs from PKD mice induce cyst growth, suggesting that EVs may contribute to ADPKD pathogenesis. The nematode C. elegans or “the worm” has consistently driven discovery in biomedical research. For example, Dr. Maureen Barr’s work in C. elegans provided one of the first links between cilia, polycystic kidney disease, and ciliopathies. This proposal will bring to bear the power of the C. elegans system to study aspects of polycystins and EV biology that are difficult to study in humans and other mammalian model systems. This proposal exploits C. elegans genetic amenability to rapidly generate mutations using CRISPR genome editing and to determine physiological consequences. We will also take advantage of the unparalleled in vivo readouts of polycystin function and ciliary EV bioactivity in this model system. For the first time, we will be able to tackle major challenges regarding the natural role of the polycystins on extracellular vesicles as extracellular signals in the context of a whole, live organism. We will use multicolor super resolution microscopy to study how and where the polycystins act within the worm when released from the base of cilia internally into the space of neighboring cells. We will determine the consequences of genetically removing the polycystins in the context of EV function. We will examine the function of polycystin-containing externally-released EVs in animal-animal communication. “The worm” presents a unique opportunity to determine the fundamental properties and signaling function of the polycystins and PC-containing EVs. A basic understanding of polycystin-containing EVs is of paramount importance and may provide insight to the physiological roles of human polycystin-containing EVs found in urine and other body fluids in health and disease.

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.

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.

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”.

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.

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.

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.

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).

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.

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.

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.

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.

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