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  • Project No: 2023 iCase 2
  • Intake: iCase 2023

Overview 

Inflammatory dermatological conditions such as psoriasis and atopic dermatitis are an area of large unmet clinical need despite recent advances with immunomodulatory therapies. Equally, cutaneous manifestations of systemic autoimmune conditions (e.g. SLE, Sjogrens) represent a significant burden on patients. The development of new drugs to address these conditions is currently hindered by a lack of appropriate translational models.

Human immune challenge (HIC) paradigms, where a stimulant is employed to transiently induce disease-relevant pathways in healthy individuals, allow rapid exploration of candidate drug effects in the target tissue and species before entering a patient population to ascertain early proof-of-mechanism and pharmacology. Despite clear scientific and economic advantages over alternate approaches (e.g. animal models) this construct remains under utilised through insufficient characterization and heterogeneity in methodology. This project seeks to directly address this gap, uniquely seeking to compare alternate cutaneous HIC stimuli in healthy volunteers and hypothesizing that they will selectively elicit immunological pathways linked to different dermatological and systemic autoimmune diseases.

Specifically, the successful applicant will analyze the molecular, cellular and transcriptional profile of samples (blood and skin) arising from discrete human skin challenges including cantharidin, lipopolysaccharide, ultra-violet light and imiquimod (TLR7 agonist) down to single cell resolution, and compare these to samples from patients with inflammatory dermatological conditions. The utility and relevance of each approach to specific disease states will be determined and a tissue atlas formed to inform future development programs. In parallel, samples (humoral and cellular) from the different HIC stimuli will be employed in ex vivo assays and exposed to both DJS monoclonal antibodies in development and clinically-validated molecules. This work will provide an early read-out of comparative efficacy, informing their developmental path.

It is hoped that data obtained during the course of this project will standardize the in vivo assessment of both primary dermatological and systemic inflammatory diseases, facilitate exploration of their underlying biology and consequently catalyze the development of novel drugs to improve patient quality of life. 

Role of the commercial partner

DJS Antibodies are an Oxford-based biotech specializing in disease-modulating antibodies to GPCRs. As such DJS have vast experience in the generation of disease-relevant translational assays for drug discovery. As part of this project, DJS will provide expertise and support to a successful applicant in assay development, drug screening, therapeutic molecule production and in cellular/molecular techniques for characterization of ex vivo samples.  DJS Antibodies will also make available space in their Oxford research site for the student to carry out key project-related ex vivo and in vitro activities and access to various in-house expertise to ensure this project is successful. 

Training and support available

Throughout this project, a successful applicant will benefit from training by experienced laboratory and clinical scientists (Kennedy Institute, Botnar Research Centre) in a range of cutting-edge techniques (including single-cell RNA sequencing, flow cytometry). These will allow them to develop skills that are relevant and transferable to both basic, industrial and clinical scientific research environments. Unique exposure to HIC paradigms will be offered via working in the new NIHR Experimental Medicine Clinical Research Facility. 

More broadly, this project will hone the applicant’s communication skills and project management, affording significant responsibility as they run a clinical trial and participate in a live drug development program. They will be supported, trained and mentored in these activities by experienced clinicians and clinical/industrial science experts. Finally, via integration into DJS they will gain unparalleled exposed to the workings of the UK biotechnology sector.