Targeted protein signatures to direct the repurposing of inflammatory kidney disease treatments (The PRESIDENT study).

Description

Background

Rare inflammatory diseases affecting the kidney, called glomerulonephritis, are a leading cause of kidney failure and current treatments are unable to achieve disease control in everyone. Management of these conditions relies on “untargeted” or broad-spectrum immunosuppressive agents, such as high dose corticosteroids. These have limited efficacy, they cause significant toxicity, and the drugs themselves can further contribute to co-morbidity.

Modern therapeutic agents can target individual biological molecules or signalling pathways to stop inflammation. Namely, biologic disease-modifying antirheumatic drugs (bDMARDs) and small molecule inhibitors have been successfully introduced into the treatment of autoimmune/inflammatory arthritis. Across disciplines, but especially between rheumatology and nephrology, there is no systematic way to select how to “repurpose” (use for a different disease indication) drugs to identify patients with inflammatory kidney diseases who may benefit from these improved targeted therapeutic agents. One barrier is the lack of scientific data regarding the precise role of these pathways.

Repurposing drugs would provide huge opportunity to bring new treatment options to the rare inflammatory disease field, even in children, and may prevent the journey to irreversible kidney failure. An evaluation of 9,249 prescribed episodes of biologic agents over a 4-year period (March 2018-2022, Alder Hey Children’s NHS Foundation Trust, Liverpool) involving 687 children and young people demonstrated that only 2.3% of current biologic agents are prescribed for inflammatory kidney diseases. However, the following agents were being safely administered to children with other inflammatory conditions; drugs that disrupt B cell pathways (rituximab, belimumab, ofatumumab), anti-tumour necrosis factor (TNF) alpha (infliximab, adalimumab, etanercept), inhibitors of interleukin (IL) 1 (anakinra, canakinumab), IL4/IL13 inhibition (dupilumab), IL6 inhibition (tocilizumab), anti-C5 (eculizumab), IFN targets JAKi, TYKi with IFN antibodies, and IL12/IL23 (ustekinumab). Protein screening for circulating inflammatory products is not yet in widespread clinical use, unlike NHS genetic screening which began with small, targeted panels and has since rapidly expanded to bring whole genome sequencing to the clinical arena. It is anticipated that it could be feasible to bring proteomics into more widespread use to guide better treatments.  

The aim of this project is to develop a targeted proteomics panel to screen for specific inflammatory proteins based on available biologic agents to improve the management of inflammatory kidney diseases.

This study will use state-of-the-art mass spectrometry at the largest Centre for Proteomics Research in the UK in collaboration with inflammatory disease experts across specialities. The student will be expected to commit to a course to learn how to use R software for statistical computing to gain confidence in statistical analysis of large data.  They will also be required to complete the NIHR Good Clinical Practice (GCP) training and Human Tissue Act training.  The post graduate development hub contains online resources that will be accessible for the student whilst completing their PhD studies.

This studentship will be part of an exciting new national project called the UK Kidney Ecosystem based in Liverpool in the Department of Women’s and Children’s Health in the Institute of Life course and Medical Sciences. They will work collaboratively across the Liverpool region with others interested in kidney and inflammatory research. They will also connect with the Experimental Arthritis Research Centre for children (EATC4C) and engage with others nationally as part of a science pipeline to bring better treatments to children with rare kidney diseases. The student will have access to proteomics, and other ‘omic facilities under full supervision of an experienced supervisor. The combined clinical and scientific supervision provides a unique opportunity to work on the forefront of translational research to truly appreciate the benefit of their research. As some of this work will be located at Alder Hey Children’s Hospital, the student will be asked to make a Disclosure & Barring Service check and ensure they have adequate hepatitis B immunity.

Qualifications: You will have at least a B.Sc. 2:1 in a Biological/Life Sciences or Analytical Chemistry. Previous experience in clinical research and/or mass spectrometry is an advantage.

How to apply

Informal enquiries can be made via a covering letter and CV to the named contact. If deemed suitable candidates would then be asked to complete a formal application and an interview will be required.