Harnessing molecular signatures to deliver personalised B-cell targeted therapies in Sjogren's syndrome

Lead Research Organisation: University College London
Department Name: Medicine

Abstract

Sjogren Syndrome (SS) is a persistent/long-lasting disease characterised by inflammation of the glands that produce moisture in the body. The signs and symptoms range from dryness, joint pain and fatigue affecting nearly all patients, to severe involvement of organs and systems, in a more limited group. The cause of SS remains unknown but is associated with defects in the immune system. Our preliminary research showed that specialised types of immune cells, called B and T cells behave more abnormally in adults with SS contributing to organ and tissue damage. We want to understand why immune cells and genes they transcribe are different in adults with SS and healthy controls (HC) of the same sex and age, and try to identify how we can influence the way these cells behave, which will hopefully lead to better treatments for patients with SS.

To be able to look into this, we established a collaboration with a pharmaceutical company, GSK, who run a study in patients with SS and treated them with two different therapies which target B cells, called Rituximab and Belimumab. They used these treatments alone as well as in combination and compared how effective they are versus normal treatment (which we call standard of care). In addition to assessing patient response, they collected blood samples and also salivary gland biopsies (small pieces of tissue removed to view under the microscope to help diagnosing SS).

What are our research aims?

Objective-1: Define the fingerprints associated with the genes that are transcribed by patients blood cells to look for differences between :(i) SS disease vs. healthy controls; (ii) SS disease which is active versus well controlled (iii) SS patients who responded to Belimumab and Rituximab versus non-responders (by looking at samples collected at baseline vs 24 weeks post B-cell targeting therapies/placebo).
Objective-2: Establish shared fingerprints between blood and salivary gland tissue that reflect disease activity (combining patients from the GSK trial and UCL cohorts) and potential response to B cell targeted therapies at the end of the the GSK trial

Technical Summary

Research question: Can a "molecular signature" or "endotype" (defined as a combination of whole blood - WB and salivary gland tissue transcriptomic signatures) be more relevant than the diagnostic label in defining unique disease characteristics?

Importance: If such a preliminary "molecular signature" can be identified, this is likely to help (after further validation in larger prospective studies) better patient stratification and ultimately guide treatment selection for better SS patient outcomes. Subsequently, this will address the challenge of SS patient heterogeneity as likely contributor to many negative interventional clinical trials in SS.

We propose an exploratory study to investigate this research question, focused on transcriptomic signatures, which will generate preliminary data for further validation in larger prospective studies, as well as support further investigation of other omic-signatures in the same SS cohort (such as targeted proteomics analysis based on the transcriptomic analysis generated by this proposal).

Rationale: B cell targeted therapeutic strategies (Belimumab and Rituximab, alone or in combination) have been used/trialled in SS with varied results.
This proposal will investigate both peripheral blood and salivary gland (SG) transcriptomic signatures associated with SS in a combined cohort of SS patients (GSK patients, n=65 matched samples at baseline and W24 and UCL patient samples n=46, total n=111).

These transcriptomic signatures could provide new insight into SS disease pathogenesis in different tissue compartments and generate preliminary data for further investigation of potential predictive biomarkers for patient stratification for selection of B cell therapies
 
Title Creation of female healthy control whole blood RNA sequencing dataset 
Description We are creating a female healthy control whole blood RNA sequencing dataset formed by more than 50 individuals whose age ranges from 40 to 65 years old. 
Type Of Material Database/Collection of data 
Year Produced 2023 
Provided To Others? Yes  
Impact Our aim is to share this dataset with the public using repositories such as Gene Expression Ommibus (GEO), thus, contributing to the research community as it could be used for many different researchers across the globe as a control population. 
 
Title Creation of high vs low disease activity SjogrenĀ“s syndrome whole blood RNA sequencing dataset 
Description We are creating a high vs low disease activity whole blood RNA sequencing dataset formed by more than 50 individuals in each group whose age ranges from 40 to 65 years old. 
Type Of Material Database/Collection of data 
Year Produced 2023 
Provided To Others? Yes  
Impact This will be one of the very few public dataset that compares patients with different disease activity scores and it will be shared using public repositories such as Gene Expression Omminbus (GEO) helping other researchers in the field. 
 
Description 'Treehouse School: Science Careers' 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 'Treehouse School: Science Careers' - hosting a short workshop for teenagers from a specialist school for neurodiverse pupils, to introduce them to different science-based career paths.
Year(s) Of Engagement Activity 2022
 
Description 'Women in Science Day' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 'Women in Science Day' - gave a series of talks about PhDs research, rheumatology/immunology to year 8 students at a local school. The idea of the day was to challenge gender stereotypes about STEM careers, and promote interest in young girls and respect/understanding in young boys.
Year(s) Of Engagement Activity 2022
 
Description Creation of a focused website 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact We are creating a focused website to showcase our research to the general public. The webiste will give visibility to the disease we are working on as well as to the funding bodies that are helping us to achieve our goals. Our aim is to make our research accessible for all and reachable. Therefore, we have condensed in one website all our latests findings, publications, conferences talks and posters presented and public and patient involvement events.
In the near future we will organize and event with patients and public to show them our website and ask for feedback. Afterwards, we will modify the website according to their suggestions.
Year(s) Of Engagement Activity 2023
 
Description In 2 Science scheme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact In2Science' - one placement (3 students) supervised and one placement (7 students) co-supervised. Sixth form students from underprivileged backgrounds with an interest in STEM were matched with us for a week-long placement in summer 2022. Students were given an introduction to adolescent rheumatology, and had the opportunity to run their own experiment on gender differences in antibody production. At the end of the week they each produced their own 'journal article' style report on their findings. They were also supported with their UCAS applications, and had the chance to meet a wide variety of staff and post-graduate students from different specialties.
Year(s) Of Engagement Activity 2022
 
Description Poster presentation at the ACR 2022 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Poster presentation at the ACR 2022
Year(s) Of Engagement Activity 2022
URL https://acrabstracts.org/abstract/childhood-onset-sjogrens-syndrome-is-characterised-by-dysregulated...
 
Description ULCH Patient and Public Involvement Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact A total of 15 patients and general public attended an event on the 24th of September at Friends House NW1 2BJ in London. On that day, we had the opportunity to discuss the importance of patient involvement in research and update the audience about this project we are working on at the moment after receiving funding from MRC-EMINENT. After the event attendees manifested an increased awareness of the research on Sjögren´s syndrome and the need of finding new therapies.
Year(s) Of Engagement Activity 2022