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Gene therapy hope for children with kidney disease.

Researchers at the University of Bristol have made a remarkable step forward in finding a potential cure for a type of childhood kidney disease. 

The research project has shown that just one dose of gene therapy targeting cells in the kidney has the potential to cure a condition known as steroid-resistant nephrotic syndrome. 

The research project received early funding from the Wellcome Trust and charity Kidney Research UK, as a Ph.D. project for Dr Wen Ding, and has gone on to gain further support from Purespring Therapeutics.

The findings, which were published in Science Translational Medicine by the team in Bristol led by Professors Moin Saleem and Gavin Welsh, suggested that replacing one faulty gene that codes for a protein known as podocin could cure the condition. Podocin is a protein essential for the functioning of cells called podocytes which have a critical role within the kidney’s filtration system. 

Nephrotic syndrome is a condition where the kidney's filtering units are damaged, allowing large amounts of protein that should be kept in the bloodstream to leak into the urine. This can lead to swelling, particularly in the eyes and legs, and an increased risk of infections and blood clots, and the risk of kidney damage. It can occur at any age but is most commonly diagnosed in children under 5 years old. 

Often the symptoms can be managed with a type of medication known as steroids, however, around 10% of children with nephrotic syndrome do not respond to steroids and many will go on to develop kidney failure and will need dialysis or transplant within 2–5 years. This is the group where a faulty gene is frequently the cause of the disease.

Professor Moin Saleem at the University of Bristol said: “We are hoping that this treatment could be curative. You keep the same podocytes for life, so if you can change their gene expression right at the beginning of the disease, we should be able to prevent this disease from progressing. With most kidney diseases, there is a reasonable window of opportunity, often years, before you get irreversible damage to the kidneys, where we would hope to be able to intervene with gene therapy and avoid the need for dialysis or transplantation.”

The discovery could bring major benefits to many children who currently suffer from nephrotic syndrome. If the intervention works, patients will be saved from a life of kidney failure and subsequent dialysis and transplant treatments. 

For gene therapy to be successful, researchers must make sure the new genetic material reaches the right cells and is used by those cells for a long time to restore their normal function. The team used a virus – incapable of causing disease but excellent at carrying genetic information directly into cells - called adeno-associated virus (AAV) to deliver the podocin gene to the correct cell type . 

Using this technique, the team were able to replace the original faulty gene in the podocytes, successfully treating several different laboratory-based models of nephrotic syndrome.

Dr Aisling McMahon, executive director of research and policy at Kidney Research UK said: “If successful, this method could enable patients to live freely without the need for gruelling dialysis treatment or transplantation. This work offers real hope for patients impacted by steroid-resistant nephrotic syndrome and potentially other genetic kidney diseases too. We are delighted to see that our funding has helped progress a project that has real potential to be used in a clinical setting.   

Gene therapy using AAV is already being used in the clinic in the UK to treat other conditions but this is the first ever the application in kidneys and will need to be further assessed to ascertain the dosage and further safety. 

Despite this, researchers are confident that this technique is not too far away from making its way into clinical use. Further research in the next few years will determine whether this application of the therapy is viable to be used within the health service. 

To find out further information please read the following publication: -

Adeno-associated virus gene therapy prevents the progression of kidney disease in genetic models of nephrotic syndrome

https://www.science.org/doi/10.1126/scitranslmed.abc8226

Fabulous news from the Bristol team; much further progress has been achieved on how to protect the kidney from the circulating factor.

Idiopathic nephrotic syndrome (INS) is caused by an unknown substance that is released by the immune system and travels around the body in the blood. This is known as the circulating factor. It can damage a cell known as the podocyte in the kidney. The podocyte is an octopus-like cells that wraps its tentacles around the blood vessels of the glomerulus of the kidney.

Professors Moin Saleem and Gavin Welsh at Bristol Renal, University of Bristol, along with their postdoc Dr. Carl May have recently published a paper shedding light on how the circulating factor might be working.

Cells have receptors on their surface. This helps them get information about their environment and adapt their behaviour. Substances in the blood can act like a key and unlock receptors on the surface of cells. The team at Bristol thought that the unknown circulating factor might be working on a receptor called PAR-1. The circulating factor can unlock PAR-1, damage the podocyte and cause proteinuria and nephrotic syndrome.

They made changes to the PAR-1 receptor in podocytes. These changes made it so that the PAR-1 receptor was always unlocked. This causes damage to the podocyte in the same way the circulating factor does. This caused damage that looked very similar to the damage seen in human FSGS. The podocyte communicates this damage via special signalling pathways. The team saw the same communication in podocytes in a dish in the lab and in tissue biopsies from INS patients.

This work identifies the PAR-1 receptor as being important in the damage the podocyte suffers in response to the circulating factor. Work will now focus on finding out how to jam the PAR-1 lock on the podocytes to stop the damage.

“It’s been great to work for Gav and Moin on this project. This is a brilliant result that could help us protect the kidney against the damage that is wrought by the circulating factor. I am at the point of branching out and becoming an independent scientist and want to make blocking this receptor in the podocyte my research focus” Dr. Carl May  

To find out more read the publication in the Kidney International Journal the full article, "Podocyte protease-activated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signaling events", can be found at https://www.kidney- international.org/article/ S0085-2538(23)00170-9/fulltext

Scientists at the University of Bristol have identified links between a brain chemical and kidney disease.

Scientists at the University of Bristol have identified links between a brain chemical and kidney disease. Researchers at the University of Bristol have found that a molecule called Neuropeptide Y (or ‘NPY’), which is usually found in the brain and nervous system, is also found in the kidney and can play an important role in kidney damage. The group have been studying kidney cells called podocytes, which are critical in keeping the kidney functioning and filtering. When podocytes are damaged, important proteins such as albumin leak into the urine; so-called albuminuria. This occurs in many forms of kidney disease, including nephrotic syndrome. The group found that changes in the levels of NPY occurred in experimental models of kidney disease and that NPY could directly signal to kidney podocytes. In addition to this, when NPY signalling was blocked using specific drugs, the levels of albuminuria and kidney damage were reduced, suggesting that NPY could play an important role in the development of kidney disease. Although there is much work still to be done, this exciting research has identified a new pathway which could potentially be targeted to treat albuminuria and kidney damage in the future. As we know, new, more effective treatments are desperately needed. It also adds important information to our understanding of how kidney disease can develop. In future, the group would like to investigate further ways of blocking this pathway and whether this could also prevent albuminuria in patients.

Find out more  

This research was led by Dr Abigail Lay and Dr Richard Coward at the University of Bristol and was published in the Proceedings of the National Academy of Sciences of the United States of America, earlier this year. The full article, “A role for NPY-NPY2R signaling in albuminuric kidney disease”, can be found at: https://www.pnas.org/content/117/27/15862

Bristol secures £45M to advance gene therapy treatment of chronic kidney diseases

Purespring Therapeutics will become one of the first kidney gene therapy companies

The University of Bristol has secured a £45million deal to advance its groundbreaking gene therapy technology for chronic kidney diseases. The commitment, made by healthcare company Syncona Ltd to Bristol spin-out Purespring Therapeutics, aims to address a global unmet need for renal conditions in one of the largest single investments made to a new UK university biotech company.

Over two million people worldwide currently receive treatment with dialysis or a kidney transplant to stay alive, yet this number may only represent ten per cent of people who need treatment to live. Until now, advances in the treatment of kidney diseases have lagged significantly behind other diseases such as cancer and heart disease. 

This investment marks a significant step forward in the innovation of long overdue new therapies for kidney diseases, which have historically been disproportionately expensive to treat.

Gene therapy — a technique which replaces or alters a faulty gene or adds a new gene to treat or prevent disease instead of using drugs or surgery, offers a potential new type of treatment for renal conditions.

Syncona’s £45 million investment to Purespring will be used to progress to the clinic gene therapy research pioneered by Professor Moin Saleem, Professor of Paediatric Renal Medicine at Bristol Medical School and Bristol Children’s Hospital, and Dr Gavin Welsh, Associate Professor of Renal Medicine. Professor Saleem’s work is the only study to date (as yet to be published) to have successfully demonstrated disease rescue in animal models using this technique for a kidney disorder called nephrotic syndrome. 

Purespring will develop gene therapies directly targeting the glomerulus in the kidney, which could see treatment progress from lab to patients in three or four years. The company will also have access to an in-vivo functional screening platform, FunSel, to screen for cell-specific protective factors delivered via gene therapy, that could have applications across several kidney diseases. FunSel has been developed by Professor Mauro Giacca at Kings College London.

Professor John Iredale, Pro Vice-Chancellor for Health and Life Sciences at the University of Bristol, said: "Syncona’s expertise in gene therapy and landmark investment in Bristol spin-out Purespring marks an exciting new venture to progress Bristol’s breakthrough discoveries in the treatment of kidney diseases. Purespring’s gene therapy platform has enormous potential to improve outcomes in patients with kidney diseases and is a major leap forward for renal therapeutics globally.”

Professor Moin Saleem said: “This is an incredible opportunity to develop transformational treatments for kidney disease. Gene therapy has come of age in certain areas, but a major challenge in complex solid organs is to precisely target the genetic material to the correct cell type. Using accumulated expertise in the Bristol Renal research group we have solved this crucial hurdle, putting us in a position to deliver curative gene therapy to patients with chronic and intractable kidney diseases. Syncona have had the foresight to see this potential, and partnering with their world-leading gene therapy experience is the best possible springboard to successfully bring this technology to patients.”

Chris Hollowood, CIO, Syncona Investment Management Limited, said: “Purespring is the sixth gene therapy company to be founded by Syncona and clearly demonstrates our proprietary company creation approach. In Moin and his team, we are collaborating with clinical and scientific leaders and working in target tissue amenable to gene therapy, whilst the collaboration with Mauro provides a path for gene therapy to fulfil its promise in highly prevalent chronic degenerative conditions. We look forward to building a world class company around this innovative science, in order to develop therapies with the potential to deliver dramatic impact for patients. Purespring is an exciting addition to our gene therapy platform, where we are strategically positioned with significant expertise in building fully integrated platform companies.”

…Ends 

About Syncona

Syncona (LON: SYNC) is a healthcare company focused on founding, building and funding a portfolio of global leaders in life science. Our purpose is to invest to extend and enhance human life. We do this by founding and building companies to deliver transformational treatments to patients in areas of high unmet need. 

Our strategy is to found, build and fund companies around exceptional science to create a dynamic portfolio of 15-20 globally leading healthcare businesses for the benefit of all our stakeholders. We focus on developing treatments for patients by working in close partnership with world-class academic founders and management teams. Our strategic balance sheet underpins our strategy enabling us to take a long-term view as we look to improve the lives of patients with no or few treatment options, build sustainable life science companies and deliver strong risk-adjusted returns to shareholders.

About ICGEB and FunSel

Established in 1983 as a special project of UNIDO, the International Centre for Genetic Engineering and Biotechnology - ICGEB is an independent intergovernmental organisation since 1994 with HQ in Trieste (Italy) and with additional laboratories in New Delhi (India) and Cape Town (South Africa). As of today, it counts 65 Member States and 20 signatory countries. The ICGEB is a not for profit IGO – any revenues generated are re-invested in research and in the funding programmes for capacity building in its Member States. The Vision of the ICGEB is to be the world’s leading intergovernmental Organisation for research, training and technology transfer in the field of Life Sciences and Biotechnology. Its Mission is to combine scientific research with capacity enhancement, thereby promoting sustainable global development (www.icgeb.org). 

FunSel is an in-vivo functional screening platform. It was developed at ICGEB by Professor Giacca and his team while he served as the Director-General of the organisation until 2019. He continues to head the Molecular Medicine laboratory at ICGEB Trieste, Italy.

Prof. Moin Saleem
Professor of Paediatric Renal Medicine and Consultant Paediatric Nephrologist. Leading the team researching FSGS and nephrotic syndrome.

Dr Gavin Welsh
Professor of Renal Cell Biology, who is our senior scientist in the laboratory, and the key investigator for all the kidney disease projects ongoing in the Unit.

Prof. Richard Coward
Professor of Renal Medicine and Consultant Paediatric Nephrologist. He is doing important work in the field of the nephrotic syndrome associated with diabetes – a huge and increasing problem, and the major cause of kidney failure worldwide.

Dr Simon Satchell
Professor of Renal & Vascular Medicine and consultant nephrologist, and a key part of the team in Bristol working out the intricate details of how the filtration barrier of the kidney works.

Dr Becky Foster
Associate Professor in Microvascular Medicine who has developed world leading physiological ways of modelling kidney function, which are becoming a central part of the testing of patient samples.

Dr Emma Vincent
Senior Lecturer in Molecular Metabolism who is interested in the metabolic environment of kidney cells in both health and disease. Dr Matthew Butler is Consultant Senior Lecturer & MRC Clinician Scientist with a key interest in vascular biology.

Dr Wen Ding

is a NIHR Clinical Lecturer in Paediatric Nephrology, at the University of Bristol and Bristol Children’s Hospital who is developing new kidney gene therapy tools in the laboratory.

The team continues to grow, and we have a group of dedicated researchers working on Nephrotic Syndrome. In addition, we continue to work with and train researchers from abroad, with recent visitors from Japan, Nigeria, India, South Africa and Egypt spending time in Bristol learning techniques and forging aluable international collaborations for the research.

9-8-23

Adeno-associated virus gene therapy prevents the progression of kidney disease in genetic models of nephrotic syndrome

https://www.science.org/doi/10.1126/scitranslmed.abc8226

18-03-23

View the publication here Or Read our easy-to-understand Summary

Podocyte protease-activated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signalling events

09-06-20

View the publication here

A role for NPY-NPY2R signaling in albuminuric kidney disease

14-08-19
View the Journal publication here
Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways.

26-01-19
Effects of heparin and derivatives on podocytes: An in vitro functional and morphological evaluation.

00-01-19
Aldosterone induces albuminuria via matrix metalloproteinase–dependent damage of the endothelial glycocalyx

21-01-19
Renal Consequences of Therapeutic Interventions in Premature Neonates.

00-01-19
VEGFC reduces glomerular albumin permeability and protects against alterations in VEGF receptor expression in diabetic nephropathy.

00-01-19
Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function.

A particularly ambitious and exciting development is the birth of NURTuRE. This is a vision to create a national network of dedicated renal research nurses or study coordinators, based in (initially) the 14 busiest kidney units in the country. These   personnel are able to recruit patients (adults and children) to the RaDaR and NephroS studies in a systematic manner, which will catapult the size and depth of the cohort much beyond what has currently been possible. The network will be able to   benefit other renal disease cohorts as well as NS, therefore being able to collaboratively grow as the project progresses.

The project has considerable backing from pharmaceutical companies, in a way that clinicians/academics can contribute and benefit from industrial research and development, and vice versa.

Recruitment is well underway, and on target for completion of recruitment of the NS cohort by end of 2019. Additional dunding has been obtained for genetic sequencing of the cohort, as well as a major MRC ‘Stratified Medicine’ grant awarded to the NURTuRE team, led by Bristol. This grant is worth over £3M over 4 years, and has the ambitious aim of redefining NS through the detailed study of patient samples from NURTuRE, and therefore leading to the ability to target the correct new treatments to the correct patient, on an individual basis.

NURTuRE is overseen by a dedicated committee from the Renal Association and Kidney Research UK, who will govern how the information is kept safe, and used appropriately for research and patient benefit.

NephroS is a national study where additional blood samples and DNA are collected from patients who are registered with RADAR, thus allowing for the first time highly detailed clinical and biological studies to be pursued on large numbers of patients in the UK. This nationwide data analysis is the most powerful way to gather new information on the disease and also permits the design of the highest quality clinical trials for new treatments in the future.

The study was initially open to sites (Hospitals) within the United Kingdom. There are approximately 38 sites in active recruitment in the UK; 20 of which are paediatric and 18 of which are adult sites. More and More sites are joining our efforts on a regular basis. 

We have now obtained substantial funding from the Medical Research Council to set up an ‘International NephroS’ cohort of patients. Data will be gathered in two large sites in India (Delhi and Bangalore), Sri Lanka and South Africa. This allows us both to boost numbers of patients substantially, for research and trials, and also to compare disease in different environments, which will give us important clues about the causes of nephrotic syndrome.

The renal Rare Disease Registry (RADAR) has been developed by the Bristol team, as a national collaboration with all specialist renal units in the UK.

For the first time in the UK, we are recruiting all patients with Steroid Resistant Nephrotic Syndrome (SRNS - otherwise known as FSGS), and Steroid Sensitive Nephrotic Syndrome (SSNS), using RADAR as a centralised web-based database to compile nationwide data.

The website also allows patient/parent access, clinical information, discussion groups and access to the latest literature, via patients signing up to Renal Patient View. If you are a patient with FSGS/SRNS or SSNS, and are not yet registered on this database by your clinician, we encourage you to ask your renal physician to get you registered, via the website. Through RADAR, patients may either be recruited to NephroS, a well-established study with more than 1300 patient participants across the UK, or NURTuRE, our exciting new initiative. More information about these studies is available on the following page.

Genetic Research
An exciting development is the analysis of DNA from patients on the RADAR registry (see next page). As present we use Next Generation Sequencing (NGS), to analyse massive parts of the human genome for each patient, and identify important mutations or variations in the genetic code that will ultimately help to guide individual treatment options.

We now have funding under a government initiative to introduce this technology into the NHS, and also to enable whole genome sequencing of NS patients on RADAR. This will allow identification of any known genetic mutation causing the disease, as well as being a powerful research tool to discover new genes and variants that may cause the disease, or predict response to particular treatments. By building our expertise in ‘bioinformatics’ within the research team, we will have the ability to analyse these huge amounts of data for patients with NS.

Using genetic sequencing and bioinformatics skills, we have developed a 'Gene Panel' test for clinical use, which is approved for NHS use. This means that any patient with steroid resistant NS (SRNS) can now be tested by their clinician in a rapid manner not previously possible, by the Bristol Genetics Laboratories. A huge advance is that this test can check for all known genes in one simple blood test, something that would never have been possible using previous technology. We are also able to respond to new gene discoveries by adding those genes to the panel on a regular basis.

This work has been recognised by NHS England, and Bristol has just been announced as one of 2 specialist renal genetic testing centres for the whole of the UK.

Future Genetic Research Aims:

1. Continue to explore the huge amounts of information this gene sequencing technology yields, by analysing UK NS patients for subtle genetic modifications that may help to predict their response to steroids, or other immunosuppression, or their risk of kidney damage.

2. Undertake a new gene therapy project, whereby we will attempt to rescue certain inherited genetic kidney defects. Funded by Kidney Research UK.

3. Commence an exciting project that will explore the viability of a new chemical drug that can reverse disease in a particular type of genetic NS. This is being taken forward towards commercial development.

Plasma Research
This continues to be a large part of the research effort, in order to discover the 'factors' in circulating blood plasma that are responsible for causing a large proportion of Nephrotic Syndrome cases. The main aspects of the work are:

1. Establish the components in circulating blood plasma that cause damage to the podocyte cell. We have identified a group of proteins that cause specific effects on the podocyte, and are actively seeking and collecting plasma samples from patients with active disease in order to extend and validate these findings.

2. We are simultaneously looking at the effect of these plasma proteins on specific 'pathways' within the podocyte that become active in disease states. This would allow targeted therapies to be tried that can block the activity of these pathways, and thereby reverse the damage to the podocyte.

3. We have developed an active academic collaboration with an Industrial partner company, which allows us to test candidate compounds in a high throughput fashion, which can reverse the pathological effects we discover in podocytes.

Hundreds of patients have now been tested, not just from the UK but also worldwide, and the test continues to be improved in terms of speed and scope. Using the rare disease registry and the genetic analysis tools, we have discovered 5 new genes in the UK cohort of patients that cause steroid resistant NS, called CRB2, FAT1, ADCK4, MAGI2 and TBC1D8B. These new genes have been added to the clinical panel of genes that are tested for whenever a patient is diagnosed with SRNS.

Nephrotic Syndrome may be considered as a collection of symptoms that indicate kidney damage.

Symptoms include:
• Albuminuria – Protein in the urine
• Hyperlipidaemia – High fat and cholesterol levels in the blood
• Oedema – Swelling, usually in the legs, feet or ankles
•Hypoalbuminemia – Low albumin levels in the blood

Within a kidney there are functional structures called nephrons, which consists of a glomerulus and an associated tubule. The glomerulus is essentially a ball of capillaries (fine blood vessels), and these are wrapped in cells known as podocytes.

Podocytes have foot projections that fit together with only narrow slits between them, and it is through these gaps that blood is filtered. These podocytes together with endothelial cells that line the inside of the capillaries are what makes up the glomerular filtration barrier. Podocytes are the cells targeted by diseases that lead to nephrotic syndrome, and therefore these symptoms occur because of a breakdown in the glomerular filtration barrier.

We receive fundraising and support from NeST, which underpins all of our activities. NeST helps us to kick-start important projects, and to gain that vital momentum that can then attract further funding from government and industrial bodies for the more ambitious projects. On a smaller scale this support is also used to fund projects undertaken by medical and science students, an important step in inspiring and training the next generation of researchers.

Patient involvement in research is vital to us, guiding our priorities, and inspiring us to do the best work possible to ultimately find a cure for this disease. We in the research team hugely enjoy our patient days in particular,
where we can interact with the most important people involved in the research, you!