Developing 1600 nm OCT angiography to quantify severe inflammatory epidermal hyperplasia in atopic dermatitis

Grantee: Stephen Matcher, Professor, University of Sheffield

Amount: DKK 4,197,519

Grant category: Research grants in open competition

Year: 2021

Geography: United Kingdom

The aim of this project is to enable quantification of the effects of treating atopic dermatitis (AD) with new therapies. New therapies have similar effectiveness to steroids but are much more expensive. Thus, there is a need for demonstrated benefits and better long-term safety to persuade healthcare providers to fund them.

Optical coherence tomography (OCT) is an ideal tool to quantify the benefits of new drugs for treating AD, whilst checking that they do not cause skin thinning, which is a risk with long-term use of steroids. OCT is a non-invasive imaging technique that uses laser light to provide ultrasound-like images with higher resolution – and OCT avoids the need to perform painful biopsies.

One problem with the current OCT systems is that if the skin inflammation becomes too high, it becomes difficult to quantify because OCT can only image to depths of around 1 mm. This limited depth penetration can potentially be improved by using a longer wavelength of laser light. With the project, Stephen Matcher will quantify the improvement in OCT image quality when using 1600 nm light rather than the current 1300 nm light.

If successful, the project holds a strong potential for use in both clinical trials and clinical practice with a highly needed more patient-friendly tool for measuring drug efficacy in skin diseases such as atopic dermatitis.

Investigating the developmental basis for anatomical variations in wound repair and disease susceptibility

Grantee: Tanya Shaw, Senior Lecturer, King's College London

Amount: DKK 2,498,527

Grant category: Research grants in open competition

Year: 2021

Geography: United Kingdom

The aim of this project is to investigate why skin in the facial region heals faster and often with less scarring than the rest of the body but are still prone for other fibrotic diseases like keloid scars. 

Tanya Shaw hypothesizes that this is due to the dermal cells of the face being of a different origin than cells at other sites of the body. Dermal cells of the face stem from so-called neural crest cells and these cells are known for their fast migration and capacity to develop into a multitude of differentiated cells.   

The approach of the project will be to:  

  1. investigate the genetics and epigenetics of keloid scars to determine to what extent they originate from neural crest cells  
  2. compare neural crest cell-derived fibroblasts to fibroblasts from other origins in term of plasticity and cell migration  
  3. manipulate the neural crest cell features in a mouse wound model to investigate if they are critical for wound healing and scarring.   

If the hypothesis can be confirmed, the project holds a strong promise for improvement of wound healing and scarring.   

Identification and biological basis of immunomodulation of skin inflammation by S. epidermidis

Grantee: Peter Arkwright, Senior Lecturer, The University of Manchester

Amount: DKK 4,369,423

Grant category: Research grants in open competition

Year: 2020

Geography: United Kingdom

The ultimate goal of this project is to contribute to the development of new medicines to treat bacterially induced eczema.

The project is a continuation of previous work supported by the LEO Foundation on the impact of bacterial infection, specifically caused by Staphylococcus Aureus (S. Aureus), on eczema. Here, a single factor secreted by S. Aureus was identified as the primary causative agent for eczema development or flare-up. Furthermore, it was also found that the naturally occurring variant, S. Epidermidis, has an inhibitory effect on eczema-induction.

The objective of the present project is to further elaborate on the disease-preventing effect of S. Epidermidis. First, the team will identify any factor(s) secreted by S. Epidermidis that inhibits eczema and then confirm its role by knocking out any relevant gene(s). Finally, the effect of any identified factor(s) on S. Aureus-induced eczema will be studied.

Mechanisms involved in decreased cutaneous immunity during ageing: reversal by Vitamin D pre-treatment

Grantee: Arne Akbar, Professor of Immunology, University College London

Amount: DKK 4,478,517

Grant category: Research grants in open competition

Year: 2019

Geography: United Kingdom

There is a sterile inflammatory response to needle challenge driven by recruitment of inflammatory monocytes to the skin in old humans. This inflammatory response negatively correlates with cutaneous immunity after injection of varicella zoster virus antigens into the skin. Inhibition of the inflammation associated with the injury response, with a p38-MAPkinase inhibitor, reduced inflammatory monocyte recruitment and significantly enhanced antigen-specific immunity.

The aim of this project is to understand how inflammation and inflammatory monocytes inhibit antigen-specific T cells in the skin of old human volunteers.

The following experimental questions will be addressed: 1) Which cells are responsible for the inflammatory response to needle injury and how does the interaction between the infiltrating monocytes and other inflammatory populations amplify the response? 2) How are the inflammatory monocytes recruited to the site of challenge in the skin? 3) How do the recruited monocytes inhibit antigen-specific immunity in vivo in the old? 4) Using biobanked skin biopsy samples before and after the same older subjects have been treated with Vitamin D, we will determine gene expression signatures of how this treatment enhances cutaneous antigen-specific immunity.

These investigations will identify ways to enhance the immunity of older humans to vaccination and also infection and malignancy.

Establishing the keratinocyte stem cell basis for skin field cancerisation and squamous cell carcinoma

Grantee: Girish Patel, Honorary Senior Lecturer, Cardiff University

Amount: DKK 3,935,737

Grant category: Research grants in open competition

Year: 2019

Geography: United Kingdom

Epithelial tissues, the environmental barriers of our bodies, are constantly exposed to cancer causing agents. As such carcinoma, the cancer of epithelial tissues, are the most common form of cancer accounting for 85% of all cancers and 78% of all cancer associated deaths.

Many carcinomas arise from a pre-cancerous transformation, known as intraepithelial neoplasia or field cancerisation (FC), within which multiple carcinoma can develop.

By studying skin FC in a mouse model of human papillomavirus 8 infection (K14-HPV8-CER), we have uncovered specific expansion of only the Lrig1 hair follicle junctional zone keratinocyte stem cells (HFJZKSC) driven by ΔNp63 expression, which is the basis for skin FC 1-3.

These findings raised two important fundamental questions:

  1. How does HPV8 induce Lrig1 KSC expansion? The background for this proposal and ongoing work (Leo Foundation grant 2017, LF17070).
  2. Are Lrig1 derived cells responsible for squamous cell carcinoma (SCC)? The basis for this Leo grant proposal.

The current Leo Foundation grant allowed us to identify E6 as the HPV8 protein responsible for Lrig1 KSC expansion through activation of the STAT3 intracellular signalling pathway.

Therefore, we are now positioned for a follow-on grant to determine whether Lrig1 derived cells are responsible for FC associated SCC. Herein we aim to:

1) confirm that Lrig1 HFJZKSC proliferation is responsible KSC expansion into the infundibulum and adjoining interfollicular epidermis

2) test the hypothesis that Lrig1 HFJZKSC progeny give rise to papilloma and SCC

3) determine whether STAT3 mediate HFJZKSC expansion occurs in human skin FC.

Implementation of novel 3-bounce 2-pass ATR FTIR spectroscopy into the Skin Testing for Atopic dermatitis (STAR) study

Grantee: Dr Simon G. Danby, Independent Research Fellow, The University of Sheffield Medical School

Amount: DKK 390,506

Grant category: Research grants in open competition

Year: 2018

Geography: United Kingdom

With this grant, the group led by Simon G. Danby seeks a potentially important technological addition to the ongoing A longitudinal investigation of skin barrier development from birth and the validation of early predictors of Atopic dermatitis (AD) risk: the skin testing for atopic dermatitis risk (STAR) trial (see Grants 2017).

This addition may prove valuable to the group’s envisioned paradigm shift – from management of established AD to primary prevention of the condition.

More specifically, the group will include enhanced ATR-FTIR spectroscopy to quantify biomarkers of skin barrier condition and AD severity in newborns. While existing spectroscopy works in adults and children, its sensitivity has been proven unsatisfactory when measuring newborns.

Working with the equipment manufacturer, the group has developed a solution that increases sensitivity 6-fold. This increase can help better prediction of the risk of AD in the newborn and thus enable targeted emollient intervention right from birth – potentially leading to a reduction of the incidence of the condition as increasing evidence suggests that topical emollient therapy can prevent the initial onset of AD by 50%.

AD is a very common chronic inflammatory skin condition affecting around 20% of children worldwide. The disease often heralds development of allergic diseases such as food allergy, asthma, and allergic rhinitis.

Project Group

Prof. Michael J. Cork and Mr J. Chittock, The University of Sheffield, United Kingdom

Dame Prof. Tina Lavender and Dr Alison Cooke, The University of Manchester, United Kingdom

Elucidating the stem cell basis for skin field cancerisation

Grantee: Dr Girish Patel, Senior Lecturer at the European Cancer Stem Cell Research Institute, Cardiff University, Wales

Amount: DKK 1,704,758

Grant category: Research grants in open competition

Year: 2017

Geography: United Kingdom

Gish Patel from Cardiff University in Wales leads an international collaboration of experts in a project that investigates the signalling pathways responsible for malignant transformation of skin epithelial cells. The hope is to identify novel therapeutic targets for future drug discovery and development.

Epithelia are continually exposed to environmental carcinogens and therefore, cancers of epithelial tissues called carcinoma, account for 85% of all cancers and 78% of all cancer-associated mortality.

Many carcinomas arise from pre-malignant transformation as intraepithelial neoplasia, also referred to as field cancerisation (FC). FC can give rise to multiple primary cancers and is a feature of malignancies involving many organs, including the skin.

The team hypothesises that the mechanism in skin FC arises from dysregulation of a particular signalling pathway. This is based on results from a murine model on Epidermodysplasia Verruciformis, where the team uncovered a novel keratinocyte stem cell (KSC) basis for the FC.

This is potentially relevant to FC in other tissues and the team targets utilisation of an innovative multiple-strategy approach to determine a drug-targetable signalling pathway involved in malignant transformation and expansion of this novel KSC population.

A longitudinal investigation of skin barrier development from birth and the validation of early predictors of AD risk: the skin testing for atopic dermatitis risk (STAR) trial

Grantee: Dr Simon G. Danby, Independent Research Fellow, University of Sheffield Medical School, Professor Michael J. Cork and Mr J. Chittock, University of Sheffield, and Dame, Professor Tina Lavender and Dr Alison Cooke, The University of Manchester

Amount: DKK 2,115,500

Grant category: Research grants in open competition

Year: 2016

Geography: United Kingdom

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin conditions and prevalence of the disease seems to grow. Early onset of AD is often followed by development of other allergic conditions such as food allergies, asthma and allergic rhinitis – all together the most chronic diseases of childhood and a major financial burden to health services.

Evidence suggests that a skin barrier defect is the primary event in development of AD.

With this research project, a longitudinal neonate/infant cohort study, the team led by Dr Simon G. Danby seeks to investigate the development of the skin barrier from birth, before the development of AD, to 12 months of age, when the majority of AD cases have developed. The team has extensive experience in the characterisation of the skin barrier in AD patients and in conducting clinical trials in neonates.

In the study, the team will compare three technologies for the quantification of established biomarkers attributed to skin barrier function and AD severity, for their accuracy and feasibility at predicting onset of AD by 12 months of age.

In addition, the team’s multi-analytical approach may provide new insights into skin barrier development in neonates and the identification of tools that could help determine who do and do not go onto develop AD. The study thus has the potential to help drive forth a new generation of patient solutions specifically designed for neonates at risk of developing AD.

International Project on the Global Epidemiology of Psoriasis: Development of the Global Psoriasis Atlas

Grantee: Darren Ashcroft, Professor of Pharmacoepidemiology, The University of Manchester, UK, Chris Griffiths, Professor of Dermatology, Head of Dermatology Research Centre, University of Manchester, UK, & Matthias Augustin, MD, Professor and Director, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg, Germany

Amount: DKK 6,370,000

Grant category: Research grants in open competition

Year: 2016

Geography: Germany, United Kingdom

The LEO Foundation supports the project “International Project on the Global Epidemiology of Psoriasis: Development of the Global Psoriasis Atlas”.

The atlas (GPA) will be a seminal work with focus on epidemiological research that will allow researchers and medical practitioners to compare incidence and prevalence of psoriasis between populations in different countries and thus yield a global ‘picture’ of the disease burden of psoriasis

The work with the GPA is done in a project group with three of the world’s leading international dermatology organisations: International League of Dermatological Societies (ILDS), a global organisation representing 148 dermatological societies worldwide; International Psoriasis Council (IPC), a not-for-profit organisation comprising leading international psoriasis experts dedicated to advancing knowledge about psoriasis and enhancing care of the disease; and the International Federation of Psoriasis Associations (IFPA), a not-for-profit organisation representing psoriasis patients worldwide.

The mission of the GPA is to provide the common benchmark on the complete burden of psoriasis in all countries and regions throughout the world. The GPA will leverage existing data from publications and registries – and additional studies will be commissioned when gaps are identified.

The GPA is a long-term project that seeks to drive continuous improvement in the understanding of psoriasis and to uncover how it affects both the individual and society at large – and will as such play an important part of the overall quest to support research that will someday help researchers find a cause and a cure for psoriasis.

Full thickness skin models from human pluripotent stem cells for identification and testing effectiveness of personalised therapies in atopic dermatitis

Grantee: Dr Dusko Ilic, MD, PhD, Reader in Stem Cell Sciences, Kings College London, Dr Reiko Tanaka, Lecturer, Department of Bioengineering, Imperial College, London, Dr Patrick Harrison, Senior Lecturer, Department of Physiology, University College Cork, Ireland, and Professor Theodora Mauro, MD, Professor of Dermatology, San Francisco Veterans Affairs Medical Center, USA

Amount: DKK 9,980,000

Grant category: Research grants in open competition

Year: 2016

Geography: Ireland, United Kingdom, USA

This is an exciting project that, with the international group’s extensive research and know-how in mind, has the potential to create an intriguing base for novel personalised treatments for atopic dermatitis (AD). The project moreover holds an innovation potential that may make it stand out in the emerging global bio-economy.

The prevalence of AD, an inflammatory skin disease resulting in itchy, red, swollen and cracked skin, is constantly increasing. Today, it affects 15-30 percent children and 2-10 percent adults worldwide, presenting a significant economic burden to healthcare systems.

There is no cure for AD, only soothing of the symptoms. In the majority of AD patients, the disease is a consequence of a blend of genetic defects of the skin barrier defects and abnormal immune responses influenced by environmental factors.

Until now, the models used to assess the interplay are not particularly predictive. The group behind this project aims to change this by using the latest advances in stem cell science, gene editing and tissue engineering to develop and validate innovative 3D in vitro models of skin – making the models similar to skin in AD patients by emulating full thickness skin of varying barrier integrity; faulty, partially repaired or intact, and immune response composition.

As part of the project, the group will also develop mathematical computer models to accurately address the predictive, prognostic and therapeutic outcome of personalised AD therapy – in order to address co-dependence of the quantitative and qualitative changes in skin barrier and activation of immune cells.

The 3D models will also be made available to test various novel therapeutic approaches for AD treatment in a patient specific manner.