Latest research news February 2020
New Research Summary for NeST February 2020, by Professor Moin Saleem.
‘The ground breaking progress we are making continues to build’ and the major projects NURTuRE and MRC Precision Medicine (formerly Stratified Medicine) encompass a large part of the exciting work going on in Bristol and across the UK (and the world!)
Rare Disease Registry www.renalradar.org
The renal Rare Disease Registry (RADAR) is a leading development for the UK, and has been developed by the Bristol team, as a national collaboration with all specialist renal units.
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) on a national web based database/registry which is continually updated.
This has led to a national study where additional blood samples and DNA are being collected from all patients, thus allowing for the first time detailed clinical and biological studies to be pursued on large numbers of patients in the UK. This will be the most powerful way to gather new information on the disease and also permit the design of the highest quality clinical trials for new treatments in the future. This study has been named NephroS.
The current total number of patients recruited to NephroS across the UK is over 1300, and we have commenced a major new initiative, called NURTuRE (see below)
The website also allows patient/parent access, clinical information, discussion groups and access to the latest literature, via patients signing up to RenalPatientView.
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.
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.
We obtained substantial funding from the Medical Research Council to set up an ‘International NephroS’ cohort of patients, utilising the expertise gained from the UK NephroS cohort. This is being 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 NS.
An exciting development is the analysis of DNA from patients on the RADAR registry, using Next Generation Sequencing (NGS). This is a new technological advance that allows sequencing of massive parts of the human genome for each patient, and thus discover important mutations or variations in the genetic code of each patient that will ultimately guide individual treatment options.
We are using NGS to test all patients in the NURTuRE cohort (see below) for detailed genetic analysis. This will allow identification of any known genetic mutation causing the disease, as well as be a powerful research tool to discover new genes and gene variants that 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 in patients with NS.
Benefits of genetic research to date
Using the new tools of genetic sequencing, and by developing the bioinformatics skills to analyse this complex data, 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 for mutations in the genes known to cause SRNS. A huge advance is that this test can test 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.
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 that we are developing for NS, by testing the UK cohort of patients we have discovered 5 new genes 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.
Future genetic research
We plan to continue to exploit the huge amounts of information this gene sequencing technology yields, by analysing UK NS patients for subtle genetic modifications that would predict for example their response to steroids, or other immunosuppression, or their risk of kidney damage.
We are also now funded by Kidney Research UK to undertake a gene therapy project, whereby we will attempt to rescue certain inherited genetic defects in the podocyte cell. This is progressing at great pace, and we are aiming to develop this into a therapy to be used in patients within the next 3 years.
We also have an exciting project that has discovered a new chemical drug that can reverse disease in a particular type of genetic NS. This is being taken forward towards commercial development.
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 ones that aren’t due to a genetic mutation). 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
NURTuRE – the national UK renal translational research enterprise.
A particularly ambitious and exciting development is the founding 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 2020. Follow up of the cohort with additional blood and urine samples is also funded. Additional funding has been obtained for genetic sequencing of the cohort, as well as a major MRC ‘Stratified Medicine’ grant (see below) 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.
Stratified Medicine for NS
The project is composed of six workstrands:
Work strand 1 – development of an IT platform to hold, share and analyse the large datasets generated from patients recruited to NURTuRE
Work Strand 2 – Analysis of DNA sequence data from NURTuRE patients, to find patterns relating to disease type and treatment responses
Work Strand 3 – Analysis of patient blood and biopsy samples to discover factors that cause relapses of NS, and markers of different types of disease
Work Strand 4 – Analysis of DNA and blood samples from all patients with Chronic Kidney Disease, to understand risk factors and mechanisms relating to more rapid progression of kidney failure
Work Strand 5 – Bioinformatics. Working with computing and Artificial Intelligence experts to develop new methods to analyse and interpret the huge amounts of data that NURTuRE will generate
Work Strand 6 – Patient and Public involvement. Ensuring that patients and parents are fully involved and engaged with the plans and outputs gained from the project.
The work of NeST
Fundraising and support from NeST underpins all of these activities, by allowing important projects to be kick started, and to gain that vital momentum that then attracts government and industrial research funding 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 enthusing and training the next generation of researchers.
We in the research team hugely enjoy the patient days in particular, where we can interact with the most important people involved in the research, you!
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.
Moin Saleem February 2020