Polycystic kidney disease (PKD) results in the formation of fluid filled cysts that gradually displace normal kidney cells and ultimately loss of kidney function. While PKD is studied by groups across the globe, a model that is derived from cells of human origin and closely replicates the disease is yet to be established.
In 2015, research led by a group of scientists in the Division of Nephrology at the University of Washington led to a paradigm shift in the way the community looked at PKD as a disease. They were able to recreate the disease in a controlled laboratory based setting using stem cell technology1, growing mini-kidneys – also termed “organoids”, from human stem cells. By deleting the two major genes causing PKD: PKD1 and PKD2, they created PKD in a petri dish. However, the fluid-filled cysts formed in the mini-kidneys did not exactly resemble the hallmarks of human PKD.
A new report from the same group has now shown that if the mini-kidneys are grown in a jelly like suspension, they develop large free-floating hollow cysts, more like what is observed in clinical PKD cases.2 By changing the cellular microenvironment they were able to better mimic the conditions that allowed for diseased kidney growth. This breakthrough has allowed the researchers to begin to unveil the processes that lead to the development of cysts. For example, one study hints that mutated PKD proteins loosed their ability to properly interact with the tissue surrounding the kidney cell, resulting in a loss of cellular shape and ultimately the integrity of overall kidney structure.
This exciting and innovative new model opens avenues for understanding the fundamental cues that determine the progression of PKD, and may even pave the way for the next phase of research involving the use of patient cell-derived mini-kidneys for rapid screening and personalised medicine testing.
1. Freedman, Benjamin S., et al. “Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids.” Nature communications 6 (2015).
2. Cruz, N.M., et al. “Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease.” Nature Materials (2017).
This event will be designed for patients and the general community.
• The Australian Genomics Research Program – bringing genomic medicine into patient clinics
• Kidney in a dish
• Modelling kidney disease in the laboratory
• Genome editing – Using CRISPR-Cas9
This is a free public event and everyone is welcome. Register interest at www.trybooking.com/304610.
Registration open until 6:00pm 21st September.
PKD Australia is pleased to announce it will be co-funding a two-year Research Grant with our American counterpart, US PKD Foundation, for a total of USD$160,000 (USD$80,000 per year). This will be awarded for research conducted in Australia, provided a suitable application is submitted by an Australian researcher.
The grant is to support the development of clinical interventions for the treatment of Polycystic Kidney Disease and proposals in the following areas will be accepted:
Please note: applications close 31-January-2018
It’s called the Paired Kidney Exchange Programme and the ABC 7:30 Report went inside an operating theatre to see to a carefully choreographed three-way kidney swap.
A novel genetic test for ADPKD
A new genetic sequencing technique which has shown promising results was previously trialed 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.
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.
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.
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.
The seminar is suitable for health and medical professionals, patients and, family and friends. You’ll hear the latest information on PKD and research, patient stories and be able to participate in a Q&A panel session.
Thursday May-18 6:00 – 8:00pm
|Harry Perkins Institute of Medical Research||Now open. Book here|
We are particularly interested in receiving applications in the following four areas, however are also open to receiving applications from other areas of research which will help towards finding a cure for PKD.
a. Fundamental in nature.
b. Aims to understand the genetic, biological and mechanistic processes leading to PKD and the overall disease presentation.
c. Not necessarily with an obvious clinical endpoint.
a. Research specific clinical problems in humans and/or animal models.
a. For translation into clinical practice.
b. For example, the development of treatments and interventions, testing the effectiveness of treatments; population studies; outcome studies.
a. Aims to improve patient care.
b. Transfer of research into policy and practice.
We are also interested in the emerging field of genetics and welcome submissions related to this area. Applications are due on 31-January 2017.
The two organisations will invest a total of US$50,000 per year in 2017 and 2018 to support an early-career scientist whose achievements and potential identify them as the next generation of scientific leaders in PKD research.
In 2010 there was anticipation surrounding the outcome of several clinical trials testing the effectiveness of a new class of drugs to treat PKD. These drugs, known as mTOR inhibitors because they switch-off a cellular pathway called mTOR, which is important for cyst growth, had previously shown great success in laboratory rodents. In humans, however, these drugs proved very toxic and consequently the results of these clinical trials were disappointing.
Having taken this research problem back to the drawing board, scientists from the University of California Santa Barbara, headed by Thomas Weimbs, may have now come up with an alternative strategy to target the same deleterious mTOR pathway without the need for potentially toxic drugs. The premise of their approach is to take advantage of an important property of the mTOR pathway: it switches-off when cell energy stores are running low. Consequently, they thought, it might be possible to turn-off the mTOR pathway and ultimately slow cyst growth by simply reducing daily food consumption.
To test their idea researchers placed mice with PKD (so called PKD1cond/cond:NesCre mice) on a 7 week diet consisting of 23% less kilojoules and assessed changes in kidney weight (which increases with cyst growth) and others signs of disease progression. What they found was striking. The kidney growth of PKD mice on the low-kilojoule diet was 3.7 times less than that of PKD mice without food restriction despite total bodyweight not being significantly affected by the diet. What’s more, food restricted PKD mice had less kidney scarring (or ‘fibrosis’) and also appeared less likely to develop renal failure.
These results are truly exciting and give hope for a new treatment avenue for a disease for which there is currently no approved treatment in Australia. Nevertheless many important questions must be addressed in order to translate this research to clinical trials and following that clinical practice. The researchers themselves emphasise that it remains to be determined whether the remarkable effect that they observed in PKD mice is because of a lower energy intake as a whole or only that of certain nutrients (e.g. carbohydrates or fats).
Link: http://ajprenal.physiology.org/content/early/2016/01/07/ajprenal.00551.2015Published online Jan 13th 2016 American Journal of Physiology – Renal Physiology. A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease.
Kevin R Kipp, Mina Rezaei, Louis Lin, Elyse C Dewey, Thomas Weimbs.
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GRANT 1: Tissue Specific Targeting of an Epigenetic Therapy for Polycystic Kidney Disease Dr. Cherie Stayner University of Otago, New Zealand There are several projects being undertaken that investigate a group of genes and mechanisms associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD). One type of gene regulation can result from a process called epigenetic modification. Drugs that block epigenetic modifications have been approved for use in patients with cancer. These same epigenetic inhibiting drugs have been shown to slow cyst formation in animal models of polycystic kidney disease. To avoid potential drug side effects, this research will modify epigenetic inhibitors to target them to the kidneys. This will assist in the treatment of ADPKD with the overall goal of developing a new therapeutic option for PKD.
GRANT 2: PKD, Heart Disease and the Sympathetic Nervous System Professor Jackie Phillips Macquarie University, Sydney For patients with PKD, cardiovascular disease is often the primary cause of death however it is not fully understood what factors initiate the disease process and therefore treatments have limited success. The sympathetic nervous system is one potential factor that can act in an aggressive manner to increase the risk of heart disease. In PKD patients the sympathetic nervous system is overactive, however when and where this process begins is not known. This research will identify if the sympathetic nervous system is implicated in the development of heart disease in PKD. This finding could lead to early-intervention treatment strategies aimed at preventing the development of heart disease in patients with PKD.
GRANT 3: Pluripotent Stem Cells from Patients with ADPKD – Applications for Disease Modelling and Drug Screening Associate Professor Sharon Ricardo Monash University, Melbourne This research will study stem cell lines made from the skin cells of patients with PKD. Creating stem cells from PKD patients will allow comparison of cell behaviour leading to cyst formation due to the genetic differences in PKD cells compared to control cells. By doing this, it will pave the way for more patient-specific stem cell options and, in the long term allow for correction of the genetic defect identified in these cells. Ultimately, this ‘disease in a dish study’ of PKD may uncover important genetic information that will allow more specific and targeted therapies.
GRANT 4: Standardised Outcomes in Nephrology – Polycystic Kidney Disease (SONG-PKD) Associate Professor, Allison Tong University of Sydney The SONG-PKD project will establish core outcomes for PKD research based on the shared priorities of patients with PKD, their family and health professionals. The project will involve focus groups with patients and caregivers to identify, rank and describe reasons for outcomes as well as an international survey with all stakeholders to generate a prioritised list of outcomes. These activities will ensure meaningful and important outcomes are consistently measured and reported in research for patients living with PKD.
Using what are called human pluripotent stem cells (hPSCs), which are cells that under the right conditions can be made to turn into any type of cell, Joseph Bonventre and his team first showed that they could create mini 3D structures (called tubular organoids), which look and behave like kidney cells (3D mini-kidneys). They tested the 3D mini-kidneys with drugs that cause kidney damage and showed they responded in the same way as a kidney would, proving they could be used to test if a drug will harm the kidney (nephrotoxicity). They then took the cells and transplanted them into mice, to see if they would survive, and they did.
Finally, and most excitingly, using a gene-editing technique called CRISPR, they introduced a mutation into either PKD1 or PKD2, and much to their surprise, found that the 3D mini-kidneys now grew large-cysts from the tubular organoids – similar to how cysts grow from kidney cells in ADPKD. Using the same CRISPR techniques, the researchers introduced a gene mutation linked to glomerulonephritis in a protein called podocalyxin, and again were able to reproduce features of the disease condition.
The potential outcomes from this work are quite remarkable. Not only can researchers now reproduce PKD in a dish, but they can use the cells to rapidly test new drugs, both for their toxicity and potential to slow down or prevent cyst formation. Furthermore, it might be that the same CRISPR technique could be used to instead correct a gene mutation, rather than cause one, and in the future, healthy mini-kidneys derived from patients own cells could be used as functional transplant.
And: http://www.nature.com/ncomms/2015/151023/ncomms9715/full/ncomms9715.html Published Oct 23rd 2015 Nature Communications: 6:8715 DOI: 10.1038/ncomms9715 Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids Benjamin S. Freedman, Craig R. Brooks, Albert Q. Lam, Hongxia Fu, Ryuji Morizane, Vishesh Agrawal, Abdelaziz F. Saad, Michelle K. Li, Michael R. Hughes, Ryan Vander Werff, Derek T. Peters, Junjie Lu, Anna Baccei, Andrew M. Siedlecki, M. Todd Valerius, Kiran Musunuru, Kelly M. McNagny, Theodore I. Steinman, Jing Zhou, Paul H. Lerou & Joseph V. Bonventre