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NURTuRE and nephrotic syndrome: Utilising RaDaR to achieve a personalised medicine approach

NURTuRE and nephrotic syndrome: Utilising RaDaR to achieve a personalised medicine approach. Professor Moin Saleem Children’s Renal Unit University of Bristol. Nephrotic syndrome – response based classification. Nephrotic syndrome. Idiopathic.

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NURTuRE and nephrotic syndrome: Utilising RaDaR to achieve a personalised medicine approach

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  1. NURTuRE and nephrotic syndrome: UtilisingRaDaR to achieve a personalised medicineapproach Professor Moin Saleem Children’s Renal Unit University of Bristol

  2. Nephrotic syndrome – response based classification Nephrotic syndrome Idiopathic Secondary (e.g. diabetes, lupus, hypertension) Steroid sensitive Steroid resistant 10-15% Infrequent relapser Secondary steroid resistance Presumed steroid resistance (proven genetic, congenital or familial) Primary steroid resistance frequent relapser Steroid dependent Late non-responder

  3. Histological Classification • Minimal change nephrotic syndrome • Focal segmental glomerulosclerosis (FSGS) 3. Others – e.g. membranous nephropathy, MPGN, IgA nephropathy

  4. Towards a mechanism (and podocyte) based classification Single Gene Disorder Circulating Factor Disease INS population ?Other mechanism

  5. The UK Study of Nephrotic Syndrome in Childhood (NephroS) • A national web based registry (RaDaR) for all children with Idiopathic Nephrotic Syndrome (INS) • Currently collected >2000 patients • Used Whole Exome Sequencing on 200 patients with SRNS

  6. Benefits of the Nephros approach • A comprehensive collection of all UK patients - now including adult patients and SSNS • Detailed genetic analysis at a level never previously available (exome sequencing of the first 200 patients) • “To reassess the links between diseases and mutations, researchers must have access to a group of people whose detailed genetic and clinical information are known, and that’s rare “ – Nature, Editorial 12 Oct 2016 • Ability to discover podocyte specific biomarkers directly linked to patient disease activity • ‘circulating factor disease’

  7. Paediatric Steroid Resistant Nephrotic Syndrome 274 Genetic-testing negative 70.4% (193/274) Monogenic 29.6% (81/274) Complete response to first IIS 3.8% (1/26) Post-transplant recurrence 0% (0/21) Given IIS with response data available 154/194 Primary/Presumed Steroid Resistance 77.9% (120/154) Secondary Steroid Resistance 20.8% (32/154) No response to first IIS 56.7% (68/120) Complete response to first IIS 21.7% (26/120) No response to Rituximab 76.5% (13/17) Complete response to Rituximab 100% (1/1) Rituximab not tried 96.2% (25/26) Complete response to Rituximab 11.8% (2/17) Complete response to Rituximab 64.3% (9/14) No response to Rituximab 28.6% (4/14) Rituximab not tried or response unknown 56.3% (18/32) Rituximab not tried or response unknown 75.0% (51/68) ESRF 50% (2/4) ESRF 16.7% (3/18) ESRF 0% (0/9) ESRF 49% (25/51) ESRF 0% (0/2) ESRF 46.2% (6/13) ESRF 0% (0/25) ESRF 0% (0/1) Post-transplant recurrence 100% (3/3) Post-transplant recurrence 70% (14/20) Post-transplant recurrence 100% (2/2) Post-transplant recurrence 33% (1/3)

  8. Availability of NGS technology is Now changing clinical practice www.nbt.nhs.uk/genetics All known genes for SRNS tested (currently 60 genes) Rapid turnaround (4-6 weeks) £600 per patient

  9. Screening for Clinical Trials • Ability to rapidly screen the large RaDaR cohort (currently >3200 INS patients) against defined inclusion criteria • Ability to approach screened patients via their lead nephrologist • Currently being utilised for 2 cohorts (INS and IgAN) for an active industry led trial • Discussions currently under way with 2 other industry partners

  10. How can we continue to build on this momentum? • We need larger numbers of patients • We need distinct molecular signatures for each sub-type of NS – using the most current technologies on significant numbers of deeply phenotyped patients • Use these molecular biomarkers to stratify patients into biologically distinct groups, who will then receive the most appropriate targeted therapy • e.g. Abatacept • Rituximab • Anti-b3 integrin compounds • Anti-suPAR • Novel compounds

  11. CHRONIC KIDNEY DISEASEandIDIOPATHIC NEPHROTIC SYNDROME OCTOBER 2016

  12. A collaboration between two cohort studies – NS and CKD • Combined resources have allowed us to attract adequate funding and reduce costs so that both studies can be delivered • Unique collaboration with Industry partners • Kidney Research UK • Will establish the first UK national renal biosample repository as proposed in the UK Renal Research Strategy

  13. Principles • Prospective multi-centre CKD and INS Cohort • Address aspects not dealt with by other large cohorts • Build platform for future research • Biobank • Plasma and serum • Urine • DNA • Renal biopsies • Rapid recruitment • Utilise UK databases to obtain comprehensive outcome data • Renal Registry • HSCIC / NHS Digital

  14. Recruitment • Participants are being recruited from Nephrology Clinics at 14 sites in the United Kingdom. • INS – 800-1000 patients in 2 years (30-40/site/yr) • Biopsies where available • Follow up samples for RELAPSE/REMISSION

  15. Biosamples • 10ml plasma (30ml blood) • 10ml serum (30ml blood) • 2x3ml whole blood for DNA extraction • 100ml urine • Storage at National Biosample Centre, Milton Keynes • Partner allocations • Independent Access Committee

  16. Kidney Biopsies • Key distinctive of study proposal • Central analysis at Human Biomaterials Resource Centre, University of Birmingham • Surplus tissue available to partners for ongoing research

  17. Genetic Analysis • Aim for whole exome sequencing (WES) of whole cohort • Diagnosis of genetic disease • Discovery of new genes responsible for NS • Detailed understanding of ‘genetic architecture’ of NS

  18. Partners • NURTuRE-NS • Renal Fibrosis group • Kidney Research UK • UK Renal Registry • National Biosample Centre • Human Biomaterials Resource Centre, University of Birmingham • Industry Partners • University of Bristol • University of Nottingham • University of Geneva

  19. Funding • Industry: • UCB • Evotec • AbbVie • Retrophin • Astra Zeneca • MRC • Future research grants

  20. MRC Stratified Medicine award • NURTuRE – changing the landscape of renal medicine to foster a unified approach to stratified medicine • £3.2M awarded over 4 years, commencing July 2018 • Aims to utilise the valuable patient data and biosamples collected in NURTuRE to redefine NS according to the underlying molecular causes • Detailed analysis of genetics, plasma biomarkers and RNA transcriptomics to discover molecular signatures of disease that correspond to the correct treatment for each individual patient

  21. Stratified Medicine Champions • A team of designated patient/parent ‘Champions’ from around the country • Appointed to represent the patient voice and help link the research to the patient community • More specifically will help with • Encouraging patients to participate in NS studies • Informing patients about advances in the research, and access to the latest clinical trials • Design of clinical trials • Design and rollout of patient App • Patient days • Etc.

  22. Wellcome Trust Patient Engagement Award • Wendy Cook and Polly Moseley • £70k awarded to develop a patient App for NS, informed by patient roadshows and young patient ambassadors

  23. Nephrotic Syndrome – A Precision Medicine approach Treatment A Deep Phenotyping NURTuRE Clinical Trials Treatment B Genotyping World’s first NGS Gene panel Biomarkers Biological, and from deeper understanding of genetic architecture Treatment C A mechanistic reclassification of INS

  24. The NephroS team • Study team – Liz Colby, Tracey Chapman, Maryam Afzal • Academics – expertise in podocyte biology (Saleem, Welsh, Rachel Lennon) • Clinical leaders in NS (Martin Christian, AniaKoziell, Lorraine Harper) • NS clinical trials – (Nick Webb, Martin Christian) • Genetic epidemiology (Colin Campbell, Tom Gaunt) • Glomerular proteomics (Rachel Lennon) • Patient charities (Michael Nation, Elaine Davies KRUK, Wendy Cook NeST) • National Registries (Fiona Braddon, Retha Steenkamp) • Industry (Evotec, UCB, AZ etc)

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