NIHRDataInsights/HRCSData huggingface dataset:
Title: Development of a 'humanised' model for renal cancer
Funder: Medical Research Council

Abstract: Unfortunately, pre-clinical development of novel drugs for renal cancer (RCC) is significantly restricted by a lack of pre-clinical models with a functional human immune response. Therefore, the development of a preclinical model of RCC with a competent 'human' immune system is a critical unmet need for RCC, especially given the plethora of immune checkpoint inhibitors (ICPIs) targeting the immune system which may be of benefit to RCC patients. Recent advances have shown that knocking out HLA I and II from in an immunocompromised preclinical model (lacking T-, B-, NK-cells, and HLAI/II) allows the development of a functional 'humanised' immune system using peripheral blood mononuclear cells (PBMCs) from patients. This translational project aims to use this novel preclinical model to develop a novel 'humanised' preclinical model for RCC. The specific objectives (in order of priority) are: 1) To generate a novel 'humanised' preclinical model of RCC using with allogenic and autologous PBMCs, renal cancer and normal kidney tissue from RCC patients 2) To determine the extent to which this 'humanised' model reflects patient responses to immune checkpoint inhibitors (ICPIs) 3) To provide pilot data for a future Clinician Scientist application RCC and normal kidney tissue from RCC patients will be implanted under the kidney capsule and subcutaneously in the 'humanised' preclinical model above. Preliminary validation of the model will then be achieved by comparing blood, RCC, normal tissue, and toxicities in the 'humanised' model vs RCC patients receiving ICPIs (at baseline and 4 weeks) using mass cytometry (CyTOF), Luminex based multiplex cytokine assays, and immunohistochemistry. The model would be useful to identify the most efficacious (and least toxic) novel immune-directed therapies for RCC patients for clinical trials and will be useful to researchers for drug development and investigating the interactions of RCC with the human immune system.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL
Title: Using minimal Factor H therapy and normothermic conditions to prepare kidneys for transplantation
Funder: Medical Research Council

Abstract: Factor H (FH) is the key fluid phase regulator of Complement. We developed a homodimerised mini-FH (HDM-FH) drug that is significantly more active than full-length FH. We recently demonstrated that the HDM-FH drug will home to the mouse kidney (FH deficient mice) and reverses uncontrolled complement activation, establishing the functionality of HDM-FH in vivo (JASN, 2018). Therefore, we postulate that HDM-FH may offer an exciting potential to restrict complement activation and associated kidney damage during reperfusion of kidneys after organ transplantation. Indeed, we have developed some preliminary data in vitro that supports that hypothesis. In order to test this idea more fully, we will develop unique model systems in Newcastle, based on our extensive knowledge of ex vivo normothermic machine perfusion (EVNP). We will first confirm our pilot binding data of HDM-FH to human kidney, we will next introduce whole blood into the system to re-create the effects of reperfusion injury and establish a novel ex vivo model system. We will carry this out in both human and porcine kidney, paving the way to test the drug in vivo. In order to achieve this we will develop a porcine version of the HDM-FH construct and fully test its functionality in our standard tests (see JASN, 2018) in parallel to developing the complement activation model. This drug will then be tested in pig kidney EVNP. We will continue to evaluate the use of the original human HDM-FH to bind and protect discarded human kidneys from complement activation while on the EVNP rig, assessing efficacy and toxicity of the drug ex vivo. Once these have all been concluded successfully, we would carry out pig auto-transplant studies, where donor organs are coated with HDM-FH on the rig and then transplanted back into the donor pig. These animals would be monitored for 10 days to follow animal health and organs collected for in depth histology. These studies would provide proof of concept for human trials


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL
Title: Macrophage Therapy for Acute Liver Failure
Funder: Medical Research Council

Abstract: Need: Acute liver failure (ALF) has no effective treatment other than liver transplantation, which has limited use because of its associated morbidity/mortality, expense to the health provider and the scarcity of donor livers. Paracetamol (acetaminophen) overdose is the commonest cause in the Western world. The only treatment for paracetamol overdose is acetylcysteine, which is preventative with regard to ALF only if treatment starts soon after overdose (within around 8h). Solution: The proposed product is an off-the-shelf, allogeneic, alternatively-activated, macrophage cell therapy derived from 'universal' blood group O donor monocytes requiring no further matching of donor to recipient. The product will be frozen, stored close to the point of treatment and thawed on demand prior to infusion. Rationale: Alternatively-activated macrophages reduce liver necrosis and inflammatory cytokines, and increase proliferating hepatic progenitors in mouse models of ALF. Our solution is anchored by these world-leading pre-clinical studies, success in delivering macrophage therapy to patients with chronic liver disease (MATCH Trial, supported by DPFS and published in Nature Medicine) and the recent completion of the first phase 1 trial in paracetamol toxicity (Lancet EBioMedicine https://www.ebiomedicine.com/article/S2352). Development plan: In the first 18 months we will complete the IMPD and obtain a clinical trial authorisation. This process will be guided by the Cell and Gene Therapy Catapult and builds on our previous success with CTA applications for macrophage cell therapy in liver disease. In the following 30 months will deliver a phase 1 clinical trial of allogeneic, alternatively activated, macrophages in patients with paracetamol-induced acute liver injury (using continual reassessment method). This builds on the local expertise in clinical trials of macrophage cell therapy in chronic liver disease and phase 1 clinical trials in acute paracetamol overdose.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: RENAL AND UROGENITAL
Title: Getting to the cause of Chronic Kidney Disease of unknown cause (CKDu)
Funder: Medical Research Council

Abstract: The underlying hypothesis is that CKDu is caused by currently unidentified factors to which the populations have become exposed due to changes in agricultural practice, or other environmental changes. The objectives are to: 1. Investigate the environmental causes of renal decline in high-risk populations (Nicaragua, India, Sri Lanka), using standardised instruments for four proposed causes of the disease: a. Metals and metaloids (using direct measurement in biological samples) b. Agrochemicals (using direct measurement in biological samples) c. Infection by nephrotropic organisms (using serological evidence and metagenomic analyses) d. Heat/dehydration (using standardised questionnaires on work history, lifestyle, and climate data, combined with environmental measurements to create a heat-exposure-matrix) 2. Identify early biomarkers of disease and genetic risk loci 3. Provide a bioresource of urine and blood samples from these three robustly characterized prospective studies to allow the exploration of other causal hypotheses going forward. To achieve these objectives we will: 1. Extend the follow-up to at least four years in each of the three prospective studies (Nicaragua, India, Sri Lanka). 2. Expand each prospective study to a total of 1000 participants to increase the power of the primary analyses. 3. Use standardized questionnaires to capture self-reported exposures 4. Using a nested case-control approach, directly measure urinary metal, agrochemicals and agrochemical metabolites in baseline samples in all three regions. 5. Using a nested case-control approach, to perform serial serology for several known nephrotopic pathogens. 6. Using a nested case-control approach, undertake proteomic studies to identify potential biomarkers of early disease. 7. Perform genome-wide association studies to identify genetic risk loci for decline in eGFR using the same array in the entire study sample from all three regions.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL
Title: Transplant for Life - Advancing HLA Matching in Paediatric Kidney Transplantation using Molecular Assessment of HLA Immunogenicity
Funder: Medical Research Council

Abstract: Kidney transplantation is the best treatment for children and young adults with end-stage kidney disease. Current methods of serological HLA mismatching (MM) cannot accurately assess individual risk of rejection and of HLA-specific sensitisation. We hypothesise that modern molecular HLA immunogenicity algorithms are superior to serological HLA MM in assessing the risk of adverse immunological outcomes and can be applied to determine long-term clinical outcomes. We will systemically assess donor HLA immunogenicity using computational algorithms that derive information from HLA protein sequence and structure, surface charge and T-cell epitope prediction. Work Package 1 (WP1): WP1 involves a deep phenotype and genotype analysis of paediatric kidney transplant recipients (<18 years) performed in the UK between 2010-2015 (n=760). Full HLA typing of donors and recipients will be performed using next generation sequencing. Longitudinal clinical data will be collected from local records and the UK registry, including immunosuppression levels and non-adherence. Screening for post-transplant HLA-specific antibodies and centralised biopsy reporting will be performed. We will construct an individual risk prediction score using Cox regression models. Primary outcome will be 50% reduction in estimated glomerular filtration rate. Results will be externally validated in a respective cohort of Australian patients (n=520). WP2: The individual risk prediction score will be applied at the population level using patients from 2000-2015 obtained from the UK Transplant Registry (n=2,030). The model will be extrapolated to test patient and graft survival. Additionally, the molecular HLA matching algorithm will be used in a multivariable regression analysis to predict HLA sensitisation in patients with failed transplants. Results of WP1 and WP2 may help improve the national kidney offering system and enable personalised medicine strategies in paediatric kidney transplantation


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;5.4 SURGERY
Health categories: RENAL AND UROGENITAL
Title: The discovery and validation of biomarkers of renal epithelial senescence in the human kidney.
Funder: Medical Research Council

Abstract: Senescent (dysfunctional, permanently growth arrested) cells are widely recognised to drive fibrosis and organ dysfunction. Their depletion improves the health of multiple organs including the kidney and prolongs lifespan in aged mice. This fellowship will test the hypothesis that biomarkers present in human urine will correlate to senescent cell number in the kidney and predict adverse renal outcomes in humans. Building on existing studies in our lab, I will address three aims: 1) Determine which candidate biomarkers of senescence in patient urine samples best correlate with senescent cell numbers in the kidney. 2) Determine if levels of the most promising urinary biomarkers predict 5-year patient outcomes. 3) Test the ability of urine biomarker measurement to identify successful pharmacological depletion of senescent cells. Aim 1 will measure 11 existing candidate biomarkers in urine from 100 patients from the seNSOR renal biorepository using ELISA, and correlate these with senescence quantified histologically using p16INK4a and p21CIP1 in matched renal biopsy samples. Additionally, urine LC-MS/MS analysis will be used to identify any novel factors unique to human CKD in a subset of patients with the highest and lowest levels of histological senescence. Aim 2 will correlate up to 5 of the best-performing biomarkers alone and in combination with existing markers of CKD progression risk in 600 patients (all of whom have 4+ years, and >450 having 5+ years follow-up) testing the ability of senescence quantification to predict patients at high risk of rapid progression. Aim 3 will analyse urine collected in an ongoing study (funded by Kidney Research UK and CSO) treating human kidneys undergoing normothermic perfusion ex vivo with vehicle control or the senolytic drug ABT-263. Pre- and post-treatment samples will be available and provide data supporting a non-invasive urine test that can be used to assess the efficacy of senolytic therapy in humans.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL
Title: Identifying New Molecular Pathways and Therapeutic Targets in Diabetic Kidney Disease
Funder: Medical Research Council

Abstract: DKD is the leading cause of kidney failure in the world. Its natural history is dominated by progressive albuminuria in the majority of patients suggesting that the glomerular podocyte may be an early target cell in diabetes. Our group has shown that podocyte insulin resistance could be an early initiator of DKD. We have therefore developed a medium-high-throughput human podocyte insulin signalling assay and screened 1280 compounds using it. The "top hit" from this assay was a drug called Yoda1 which activates a mechanosensitive cell membrane stretch channel called piezo1. We therefore intend studying this channel in much greater detail using an in vivo diabetic mouse and in vitro human podocyte cell approach. We hypothesize that piezo1 activity is an important link between podocyte stretching (as occurs with an increased glomerular filtration load after a meal) and podocyte insulin responses. We also think activating it could be beneficial in treating DKD. To address this hypothesis we have 3 aims to: 1. Assess if pharmacologically activating piezo1 with yoda1 in a mouse model of DKD is beneficial. 2. Genetically target and modify piezo1 activity specifically in the podocyte in diabetic and non-diabetic mice to assess the consequences of losing or hyper-stimulating its activity. 3. Define how piezo1 activity is controlled in the human podocyte and the molecular consequences for this cell of activating it. Ultimately we hope this project will advance our understanding of the physiology of the podocyte and also identify a new therapeutic target to treat DKD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL
Title: A Nanopathology Platform for Prediction and Early Detection of Disease in Kidney Transplant Rejection
Funder: Medical Research Council

Abstract: Chronic kidney failure affects about 11% of the world population, of which one third of cases involve immune-mediated disease. Those patients who reach end stage kidney failure require renal replacement therapy with dialysis or transplantation. Dialysis is associated with poor outcomes, and though transplantation considerably improves quality of life, the longevity of transplant organs is limited, mainly due to immune rejection. The current accepted pathophysiological model of antibody-mediated injury derives from low resolution imaging and gene expression studies on human biopsy material, and on live imaging of animal models. This model shows that antibodies and complement fragments are deposited in the kidney, which recruits innate and adaptive immune cells, which in turn cause injury to the kidney cells leading to cellular changes, matrix accumulation and loss of kidney function. Understanding which immune cells are important in the early response to antibodies, and the mechanisms by which they cause injury, underpins development of effective future therapies. However, to do this, we need to develop better microscopy methods that are capable of imaging all immune cells within human biopsies. The resolution required to image subcellular features of immune cell activation is in the order of 10 nm. For a biopsy of 10 mm length and 1 mm diameter, it would take around 55 years to image. We will develop a multimodal multiscale imaging and spatial analysis pipeline, which will allow us to visualise all blood vessels and immune cells within a biopsy, whilst incorporating ultrastructural features, surface markers and gene expression to unequivocally assign immune cell IDs and activation states. We will reduce the time taken to analyse a single human biopsy from 55 years to 5 days, so that we can start to look for patterns in the data using supervised and unsupervised machine learning, and create a pseudotime model of disease progression at the nanoscale.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: RENAL AND UROGENITAL
Title: Deep phenotyping and precision medicine approaches to understand and treat autosomal dominant tubulointerstitial kidney disease due to UMOD mutations
Funder: Medical Research Council

Abstract: Chronic kidney disease (CKD) has an estimated global prevalence of 12% and carries a high burden both at individual and societal levels with limited therapeutic options. Autosomal dominant tubulointerstitial kidney disease (ADTKD) is among the top three commonest aetiologies of monogenic CKD and is most often caused by mutations in UMOD, encoding uromodulin. Patients with ADTKD-UMOD present with a steady decline in renal function and progress invariably to end stage kidney disease (ESKD) requiring dialysis or kidney transplantation. A striking intrafamilial and interfamilial variability in disease progression has been observed with ESKD onset ranging from the third to seventh decade of life. The disease mechanisms driving kidney fibrosis and modifiers of disease progression are unknown. In this project proposal, I will build on existing UK data and biobanks to create a comprehensive registry of ADTKD patients with longitudinal deep phenotyping and genomic information. Using this registry, I aim to identify clinical as well as genetic disease modifiers through candidate gene association studies. Exosomes isolated from patient urine samples will allow deep phenotyping of patients with molecular characterization of renal transport systems. I will also establish patient urine-derived kidney cell systems in ADTKD-UMOD. Such personalised cell systems represent an unmet need for the investigation of molecular mechanisms of disease progression for the validation of identified target genes and pathways. A better understanding of the genetic architecture of ADTKD and of pathways underlying the variability in disease progression will pave the way towards new actionable targets and enable a precision medicine approach with individual patient counselling regarding prognosis and therapy. In addition, disease pathways operating in ADTKD-UMOD are relevant for more common diseases of the kidney and beyond in which fibrosis is the main driver of progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: Assess the feasibility of an AI-enhanced Urology Triage Platform ( AI-UTP) to augment clinical capabilities of front line Junior Medical and Allied Healthcare Professional staff
Funder: Department of Health and Social Care

Abstract: Urology referrals to secondary care have risen by nearly 20% over the last 20 years and now account for 5% of all outpatient appointments (2.2m appointments annually[1]) with patient demand expected to rapidly increase, largely linked to our ageing population. This is creating considerable NHS and patient burden. The NHS spends >&pound;650m in Urology secondary care referrals. Patients being referred for non-2WW (two week wait) urology services now face 18-week+ waits for a first outpatient appointment in most trusts, leading to negative patient impacts and operational pressures on primary and secondary care services[2]. At Guys and St Thomas (GSTT) our urology team face these challenges head-on, whilst acting as a centre of excellence. The Urology Guidance Outpatients Transformation has identified the importance of improved primary care referrals, greater support of specialists advice for primary care assessment and a greater emphasis on MDT clinical resources including specialist nurses to play a greater role in increasing the capacity of Urology assessment services. A study estimated that ~50% of urology referrals from primary care were unnecessary, and could have been improved with greater awareness of urology guidelines and specialist support in their clinical assessment[3]. DemDx, an innovative health technology company, has an existing AI enhanced Ophthalmology Triage Platform co-developed with Moorfield Eye Hospital NHS Trust focused on improving the quality of ophthalmology referrals into secondary from primary care, with data demonstrating 5% (3.2%-6.7%) reduction in urgent referrals[4]. GSTT Urology team will collaborate with DemDx to translate and refine the existing AI algorithms to the Urology speciality, adding a focus on junior medical and allied health professional triaging patterns, with the intention of demonstrating the clinical safety and technical suitability of the AI within the speciality. This will unlock the roadmap to creating a Urology Triage Platform (UTP) realising significant and urgently needed efficiencies.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: RENAL AND UROGENITAL