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Professor Melissa Little – Murdoch Children’s Research Institute
University of Melbourne
In vitro modelling of autosomal recessive polycystic kidney disease
*co-funded with PKD Foundation US
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.
This grant will allow us to 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.
Professor Ian Smyth- Monash Biomedicine Discovery Institute, Monash University
Using functional genomics to diagnose PKD
Diagnosing the genetic cause of ADPKD can be challenging because of the sometimes-subtle nature of the changes found in the PKD proteins in patients. This grant will allow us to develop a new experimental model in which to assess whether such “variants of uncertain significance” cause disease, providing diagnostic certainty to individuals affected by PKD. In the future, these models may also be useful for better understanding how PKD develops and for trialling new therapies for the disease.
Dr Brooke Huuskes- Centre for Cardiovascular Biology and Disease Research, La Trobe University
The NLRP3 inflammasome in the pathogenesis of polycystic kidney disease
Patients with polycystic kidney disease (PKD) commonly have high blood pressure, which can increase their risk of cardiovascular disease. More and more research show that the immune system and inflammation contribute to the development of high blood pressure, with inflammation being a well-known to be key in driving the progression of PKD. Recently, we have shown that blocking a specific inflammatory pathway reduces blood pressure and kidney damage in animal models of high blood pressure. We suspect that this same inflammatory pathway is activated in PKD and this project will determine if blocking it with a new molecule to see if we can reduce blood pressure and stop cyst progression. Understanding this pathway may offer new therapeutic options to treat PKD.
Dr Amali Mallawaarachchi- Garvan Institute of Medical Research
Investigating Gene Conversion as a mechanism of disease in Autosomal Dominant Polycystic Kidney Disease
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic cause of kidney disease. In ADPKD, cysts overwhelm the kidney, leading to kidney failure. There are unfortunately limited treatments for ADPKD. Remarkably for such a common disease, it is not well understood what causes cysts to develop. A clear understanding of the mechanisms of disease is essential to developing effective treatments. ADPKD is most often associated with genetic changes in the PKD1 or PKD2 gene. A relatively unique feature of ADPKD is that PKD1 has 6 associated pseudogenes. These pseudogenes are ‘copies’ of part of the original PKD1 gene and are not currently thought to have a function. The pseudogenes have an almost identical genetic sequence to PKD1. There has been limited previous studies of the pseudogenes. We hypothesise that the pseudogenes contribute to a mutation in the PKD1 gene, through ‘gene-conversion’. Through a cell’s lifetime DNA can sometimes be damaged (called DNA ‘breaks’). When these breaks occur, the cell repairs them by using a copy of the gene sequence as a template. In regions with a pseudogene, because the pseudogenes look so similar to their original gene, the body can incorrectly use the wrong template to fix the break – this is called gene conversion and leads to a mutation in the DNA. We will investigate whether this is frequently occurring in PKD1. Understanding the causes of mutation in ADPKD are essential if we want to develop treatments that disrupt these mutational mechanisms.
Professor Melissa Little – Murdoch Children’s Research Institute, University of Melbourne
Deprivation of Induced Pluripotent Stem Cells from Patients with Autosomal Recessive Polycystic Kidney Disease
Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare (1 in 20,000 births), genetic disease that causes kidney failure in babies and children. About one quarter of babies born with ARPKD will not survive after birth. The remaining babies and older children with more mild disease will require dialysis or kidney transplantation. ARPKD also causes a progressive liver disease and some children require combined kidney and liver transplantation. The vast majority of ARPKD is caused by mutations in the gene PKHD1. The protein made by this gene is thought to interact with the proteins affected in the more common autosomal dominant polycystic kidney disease (ADPKD). However, very little is understood about why a defect in this protein causes disease or what can be used to treat this condition. To date, ARPKD has been studied using animal models, but these do not show the same severity of disease as humans.
We have developed a method to recreate human kidney tissue using stem cells made from babies with ARPKD. With support from PKD Australia, we will generate stem cells using blood samples taken from babies with ARPKD and use these to make a model of the patient’s disease in the laboratory. Ultimately, such patient models of ARPKD will be used to screen for new treatments to slow the progression of the disease.
Dr Denny Cottle – Monash Biomedicine Discovery Institute (BDI), Monash University
Screening candidate gene targets to reverse or prevent Autosomal Dominant Polycystic Kidney (ADPKD)
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common life threatening, inherited disease, affecting ~1 in 1000 individuals. It is characterised by development of fluid filled cysts that disrupt kidney function. Thus, patients eventually require dialysis and/or kidney transplantation. Recently, we have identified a critical factor which causes cysts and we have prevented PKD in two animal models by genetically removing it. In this application we wish to perform a screen inactivating related downstream factors to determine the best candidates for translating our findings into future therapeutics to treat ADPKD patients.
Associate Professor Andrew Mallet, Institute for Molecular Bioscience, The University of Queensland
Rab GTPase regulation in Ciliogenesis and Polycystic Kidney Disease
Rabs are a family of molecular switches that control the growth of the cilia or cell antennae that are essential for normal kidney development. Polycystic kidney disease is the result of gene mutations that cause cilia defects and malformations in the kidney that lead to renal failure. This project will investigate whether and how a subset of Rab proteins, particularly Rab13, contribute to cilia formation and kidney function under normal and disease conditions. Our findings stand to reveal these Rabs as important new cilia regulators that may open up new interventions for improving kidney formation and renal function.
Associate Professor Gopi Rangan, Westmead Institute for Medical Research, The University of Sydney
Effect of inorganic nitrate supplementation on systolic blood pressure in normo- and hyertensive adults with ADPKD
The aim of this project is to determine the feasibility, safety and efficacy of dietary nitrate supplementation on decreasing blood pressure in ADPKD. This project will determine if a daily dietary nitrate supplement lowers blood pressure either as monotherapy or together with conventional drug therapy, and persuade people suffering with ADPKD to make appropriate life-style changes. The study will provide data on tolerability and safety and determine if long-term nitrate supplementation clinical studies in ADPKD are required.
Dr Andrea Wise- Kidney Regeneration and Stem Cell Laboratory, Monash University
Kidney organoids from patients with Polycystic Kidney Disease
The reprogramming of adult cells to generate stem cells – namely, induced pluripotent stem cells – has advanced the study of disease modelling. Recently, there has been great excitement in the ability of iPSCs to self-assemble into three-dimensional structures that resemble mini-kidneys. These kidney organoids express markers of different kidney cell types and show great potential in many applications including disease modelling and regenerative medicine. This project will develop these “kidneys in a dish” targeted to PKD. This research will facilitate the use of kidney organoids from PKD patients, and genetically altered PKD organoids, for disease modelling, drug screening, and in the future, potential development of novel stem cell replacement therapies for this debilitating kidney disease for which there is no cure.
Dr Sayan Saravanabavan- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney
Role of mitochondrial genomic analysis as a prognostic biomarker in autosomal dominant polycystic kidney disease (ADPKD)
Genetic testing in ADPKD is in the early stages of development, and more sophistication is needed to help predict who is at higher risk of developing kidney failure. Energy metabolism in cells is altered in ADPKD and changes (mutations) in genes that regulate the mitochondria (the main energy producing organelle in our body which has its own genes) may worsen the severity of ADPKD. The aim of this study is to determine if mutations in mitochondrial genes affect the severity of ADPKD. The results of this study could help better identify patients who are at higher risk of developing kidney failure, and also lead to new approaches for treating ADPKD.
Dr Cara Hildreth- Department of Biomedical Sciences, Macquarie University
Is a hormone controlled by the brain driving high blood pressure in PKD?
It is well known that high blood pressure is common in people with polycystic kidney disease. Why blood pressure increases in people with polycystic kidney disease, however, is less well known. This project seeks to determine how the brain is contributing to the development of high blood pressure in polycystic kidney disease by uncovering what hormonal changes the brain is initiating that result in high blood pressure. This work has the potential to identify new treatment targets that could be used in individuals with polycystic kidney disease to lower blood pressure and reduce their risk of developing diseases associated with high blood pressure.
Assoc. Professor Andrew Mallett- Centre for Health Services Research, The University of Queensland, Australasian Kidney Trials Network
The IMPEDE-PKD Trial (Implementation of Metformin theraPy to Ease DEcline of kidney function in PKD).
There is an urgent need for treatments to slow the loss of kidney function and prevent complications in affected patients and families with ADPKD. Repurposing of existing medications is a promising way to potentially expedite this. Laboratory studies suggest Metformin, a common diabetes medication, might be one such medication.
The aim of this study is to establish a randomised clinical trial of Metformin amongst patients with ADPKD to investigate its potential to slow kidney function decline. Pre-clinical studies suggest that there are ADPKD disease pathways that can be advantageously modified by administration of Metformin. The common use of this medication, including in non-diabetic conditions such as polycystic ovarian syndrome, its relative inexpensive nature as well as its defined side effect and dosing profiles in kidney disease lend it to the conduct of a clinical trial to address this aim. If successful, this would dramatically change the prognosis for many Australians living with this condition and hoping for a future in which dialysis can be avoided.
* This Project is funded in partnership with The BEAT-CKD Program
Professor Sharon Ricardo- Kidney Regeneration and Stem Cell Laboratory, Monash University
Clinical development of a monoclonal antibody-based therapeutic targeting polycystic kidney disease.
There are various supportive treatments that can be used to control the symptoms of PKD, to help prevent or slow down the loss of kidney function. However, there are currently no treatment options to prevent cysts developing or reverse the process once formed. As such, there is currently no cure for PKD, where the only options to treat kidney failure are dialysis or organ transplantation.
Our recent discovery has identified a novel protein, called WISP1, that may play an important role in the formation of kidney cysts and the detrimental scarring of the kidneys that leads to reduced kidney function over time. The successful completion of these studies will unravel the role that WISP1 plays in both cyst growth and kidney scarring. Moreover, we will develop a protein that inhibits WISP1 protein production that will be used therapeutically to retard cyst growth and slow or alleviate disease progression.
Dr Gopi Rangan- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney
Role of DNA damage signalling in Autosomal Dominant Polycystic Kidney Disease.
This project will determine if stopping damage to the genetic coding material (called DNA) reduces the formation of kidney cysts in polycystic kidney disease.
Professor John Shine- Molecular Genetics of Inherited Kidney Disorders, Garvan Institute of Medical Research, Sydney
Identifying novel mutational mechanisms in the genetic pathogenesis of PKD.
ADPKD is the most common genetic kidney disorder – it causes cysts to develop within the kidney, which eventually destroy the normal kidney tissue and lead to renal failure in many patients. Despite how common the disease is there are still many gaps in our understanding. In many families we still cannot identify the genetic cause of their disease and there remain questions about the reason kidney cysts develop and destroy the kidney. Our project will use the latest in genetic sequencing technologies, called Whole Genome Sequencing, to identify new genetic causes of ADPKD. Understanding new mechanisms will help in better understanding this complex disease and to develop ways to slow and treat ADPKD.
* This Project is funded in partnership with the PKD Foundation USA
Dr Amali Mallawaarachchi, Garvan Institute of Medical Research, Sydney
A novel genetic test for ADPKD – A new genetic sequencing technique which has shown promising results was previously trialled and now requires testing a larger study.
Partnering with the Mayo Clinic, this grant will work to test this with patients who have been sequenced by more established methods. It is anticipated that comparing the two methods will show the new test to be more detailed and accurate and to establish it as the lead genetic test for PKD in Australia. This will result in improvements for patients and assist with understanding underlying causes and to find a cure.
To read the final report please click here.
Professor Jacqueline Phillips, Macquarie University, Sydney
Genes and cellular stress in PKD- This grant will investigate how PKD genes can cause an increase in stress signals in kidney cells that drives cell damage and progression of kidney disease.
These same processes can also be driven by the build-up of toxins in the blood that arises when kidney function declines and this project will further test if the combination of PKD mutation and toxins worsens the stress response in the cell. Determining how PKD leads to cell damage has the potential to change the way we treat patients from symptomatic to strategically targeted.
To read the final report please click here.
Dr Bo Wang, Monash University, Melbourne
The therapeutic potential of miRNA-based MAPK inhibition to slow the progression of PKD
Several therapeutic interventions have been designed specifically to inhibit cell proliferation in a variety of animal models of PKD. A cell signal–regulated kinase (MAPK) inhibitor is shown to effectively block cyst growth and kidney enlargement, and to preserve kidney function.
Recently, a unique microRNA was discovered that is important in regulation of gene expression and can slow down the over proliferation of kidney cells that lead to cyst formation. The project will investigate the mechanisms of microRNA in maintaining normal kidney cell function that will result in reduced cyst growth. The study will provide a novel target for PKD treatment with a high potential for clinical translation.
Dr Annette Wong, Westmead Institute for Medical Research, Sydney
Validation of copeptin as a prognostic molecular biomarker in patients with CKD stages 1 – 3 due to ADPKD- Predicting patients at high risk of kidney failure who therefore require medical follow-up is important however, currently there are no blood tests to provide this information.
Vasopressin is a natural hormone in the body that may cause kidney cysts to grow bigger. In the past it has been difficult to measure vasopressin but it can now can be measured easily using a test for copeptin. This project will determine if a simple blood and/or urine test for copeptin can help predict this risk in patients with early-stage ADPKD.
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