Impact case study database

SRNS is a devastating disease disrupting the glomerular filtration barrier of the kidney, with multiple distinct pathological triggers, most of which are immune based and poorly understood. Hence traditionally it has been treated indiscriminately with heavy ‘toxic’ immunosuppression, with limited benefit and huge morbidity (e.g. infections, poor growth and nutrition (in children), low energy, loss of employment/schooling). 60% of these patients develop end stage kidney disease (ESKD) within 5-years of diagnosis. Our work has been based on insights into the target cell, the glomerular podocyte [1], and applied directly to clinical care via comprehensive national registries. This has distinguished genetic forms of SRNS from immune based SRNS, and further subclassified the latter in order to better target patients who will respond to specific therapies or transplantation [4-6].

Changed national and international clinical practice

The gene panel test developed by Saleem and Coward [3] was approved by UK Genetic Testing Network (UKGTN) in 2014 for clinical use. Bristol Genetics Laboratory were the first national provider of UKGTN panel testing for proteinuric renal disease and haematuria, and in 2019 were approved as one of two UK genetic testing hubs for all renal genetic disease, using gene panel technology [Aii (cites [3])]. In the UK over 1,000 patients from 81 UK and 44 international centres have been tested to date by utilising the UoB gene panel [A]. The cost saving to the NHS of implementing the results of the genetic test was estimated in the (successful) UKGTN application in 2014 to be GBP68,900 per patient, as a consequence of changing the patient clinical pathway [Ai].

Gene panel testing has been incorporated into the first International Pediatric Nephrology Association (IPNA) clinical practice recommendation for children with SRNS [B]. UoB research demonstrating clinical utility [3] and stratification [4] are cited among the evidence and rationale for genetic testing, and a ‘comprehensive gene panel analysis’ using the gene list identified in [4], is recommended [B (p.1539)]. This has resulted in standardisation of care across the world (IPNA members in 105 countries, bringing together eight regional paediatric nephrology societies). Assessment of risk of transplant recurrence using clinical biomarkers that predict recurrence with 90% sensitivity in non-genetic subgroups [6], has also been incorporated in the guideline for selection of transplant recipients [B]

Benefits to health and well-being of patients and families

Availability of comprehensive and rapid genetic test results for SRNS has eliminated previous indiscriminate and harmful diagnostic and treatment routes. A survey of UK paediatric nephrologists confirmed that the improved understanding of underpinning genetics and availability of genetic testing had changed clinical practice for all respondents [H]. Respondents noted the avoidance of immunosuppression and biopsy, as particular changes in practice [H]. Kidney biopsy looking for histological changes that caused discomfort, cost, and could require up to two weeks’ recovery for patients, is now no longer necessary. Harmful effects of inappropriate, trial and error immunosuppression protocols (e.g. mood changes, hypertension, poor growth, weight loss, infection, hair loss, GI disturbance), applied across the whole patient groups, have also been prevented. This management change translates to 30 new patients per year in the UK, and 150 per year in the US.

The gene panel test also predicts patients who will get recurrence of disease after kidney transplantation. 50-90% of patients with genetic or sporadic SRNS will suffer from renal failure and require transplantation. Up to 50% of patients with non-genetic SRNS will suffer recurrence of the primary disease in the newly transplanted kidney [4], with implications for counselling and disease management, whereas <2% of patients with genetic SRNS have been reported to get post-transplant recurrence. This will affect both patient counselling and the choice of live related kidney donors. For both the patient and family members, there is the additional benefit of being able to understand the nature of their condition, provide genetic and antenatal counselling, offer specific therapy for some mutations (mitochondrial diseases) and test other family members if necessary. Prof Saleem is a founding trustee of the Nephrotic Syndrome Trust (NeST) patient community which provides information and support to patients and their families, including through annual patient days and laboratory open days which offer the opportunity to meet scientific researchers and ‘help them understand the science directly’ [G]. The Director of NeST describes how UoB research is ‘embedded in our activities and patient interactions’ and the importance of the information for patients which is ‘impossible to find elsewhere for a rare but devasting disease’ [G].

Finally, there is a small but significant cohort of usually early onset mitochondrial disease individuals whose genetic disease is treatable by co-enzyme Q10 administration if recognised, preventing both renal disease and neurological deterioration. This impacts 5-10 patients per year across the US and Europe and is a life-transforming intervention.

Increased UK registry infrastructure

In parallel with the gene technology development and testing, in 2010 Saleem and Coward initiated the UK Renal Rare Disease Registry (RaDaR), housed in the UK Renal Registry in Bristol, and now nationally embedded within UK Renal medical practice. As of 31^st December 2020, there were 26,913 UK patients in RaDaR from 104 hospitals, and 29 rare diseases covered [C]. Genomic and molecular stratification into rare disease groups is facilitating personalised medicine and evidence-based care pathways.

The RaDaR registry now forms the core repository of NURTuRE (National Unified Renal Translational research Enterprise), formed in in 2017 collaboration with industry partners and under the strategic management of Kidney Research UK. This original initiative, delivered by UoB (Saleem) and the University of Nottingham (Prof Maarten Taal), has created a national Kidney Bio Bank for collection and storage of biological samples from 3,000 Chronic Kidney Disease (CKD) patients and up to 1,000 Nephrotic Syndrome (NS) patients. The enterprise has established renal research nurses in 14 large renal centres across England, Scotland and Wales, and also integrates patient support groups including the NeST, and Renal Patient Support Group [D, G]. Patient representatives from NeST attend biannual consortium meetings and patients receive updates via ‘Precision Medicine Champions’ [G].

Increased industrial capacity for R&D in renal care

Since 2018, NURTuRE has established a sustainable infrastructure with collaborative industry partners AbbVie Inc, Evotec AV, UCB Celltech Biopharma, Retrophin and AstraZeneca, with a total of GBP7.7M investment [Ei]. For the industry partners this forms the basis of significant R&D strategic impact in renal disease. Each industry partner within the NURTuRE enterprise is using a different approach to identify new drug targets. All data gathered are returned to a central database and made available to all. The fibrosis leads at UCB Biopharma noted that “This pre-competitive cooperation and combining of resources is a great model of how we should be working together to help bring benefit for patients” [Eii].

Evotec’s investment in NURTuRE, which will transfer significant clinical know-how to industry integrated with biological features, aims to form an integrated drug discovery model and high throughput patient sample analyses. The Chief Scientific Officer of Evotec noted that “This is a very important step for Evotec to expand its leadership in kidney disease drug discovery” [Fii]. To deliver this they have created NephTec, a virtual company within Evotec. This unique platform and business model enable unrestricted access to their leading drug discovery infrastructures and proprietary pre-clinical databases, accelerating the search for novel targets and pathways [Fiii]. Since 2012, their use of Bristol cell lines [1] and the work above has created more than 100 new jobs [Fi].

NURTuRE was further used as a partnership with NephCure Kidney International, a large US kidney charity, to participate in the Gateway Initiative – this is a multi-stakeholder partnership, including industry and the Food and Drug Administration (FDA), to optimise recruitment to industry led clinical trials in renal disease (e.g. Focal Segmental Glomerulosclerosis (FSGS)).

Human podocyte and glomerular endothelial cell lines [1] have been licensed to 15 of the world’s top 20 Pharma companies for internal R+D and drug screening generating [text removed for publication] income to date [I].

Gene Therapy Spinout Company

The underpinning work on renal genetic disease [2-4] has led to a significant new investment from Syncona, a major Life Sciences investment firm, to form the world’s leading renal gene therapy spinout company, aiming to directly target podocyte diseases. The recently completed deal led to the creation of Purespring Therapeutics, with a Series A commitment of GBP45 million [J]. The deal involved 5 patent families. The initial pipeline of therapeutic candidates to progress to clinic has been agreed, with certain options to other programmes developed at UoB. Premises and laboratories are being built in London, with initial recruitment of 20 new staff in 2021 (researchers, management team and CEO) [J].