Scarless wound healing: exploiting the regenerative properties of the spiny mouse

Grantee: Sofia Ferreira Gonzalez, Fellow, University of Edinburgh

Amount: DKK 3,995,846

Grant category: Research Grants in open competition

Year: 2023

Geography: United Kingdom

Sofia Ferreira Gonzalez’s project aims to characterize the regenerative capacity of the spiny mouse – the only mammal known to fully regenerate skin with minimal scarring – to optimize future wound treatment in humans.

Skin fibrosis is often a sequela of suboptimal wound healing following significant epidermal and/or dermal injury (burns, trauma, major surgeries). Fibrotic material replaces native skin with dense, non-functional connective tissue, ultimately leading to loss of function. In its mildest form, fibrosis is a minor aesthetic problem, but in the most severe cases it can lead to debilitating skin pathologies that result in limited movement, high morbidity, and prevention of patient reintegration into society.

Current treatments for fibrosis include physical therapy and surgery, but there are no therapies that directly target the underlying cellular and molecular mechanisms of skin fibrosis.

The spiny mouse (Acomys) is, to date, the only mammal capable of skin autotomy (i.e., self-amputation of the skin to elude a predator’s grasp). Fascinatingly, the spiny mouse completely regenerates the lost skin and regrows cartilage and appendages (nails, hair) with minimal fibrotic response.

A multimodal approach addressing the mechanisms driving spiny’s scarless regeneration may provide novel therapeutic opportunities to treat and prevent skin fibrosis.

In this project, Sofia Ferreira Gonzalez and her team investigate three questions: 1) is the spiny mouse’s scarless regeneration depending on specific cell populations, circulatory factors or a combination thereof, 2) which specific pathways are responsible for the scarless regeneration, and 3) how can the research findings be translated into novel therapeutics to improve skin wound healing in humans?

Global Atopic Dermatitis Atlas (GADA)

Grantee: Carsten Flohr, King's College London

Amount: DKK 10,000,000

Grant category: Standalone grants

Year: 2023

Geography: United Kingdom

Atopic dermatitis, also called atopic eczema, or just eczema, is a non-contagious, chronic skin disease, causing dry, patchy, and itchy skin. It affects up to 20% of children and up to 10% of adults. Of all skin diseases worldwide, it is the most common type, with a burden that remains a significant challenge for the people affected, their families, and societies.

Despite progress made in treating severe forms of atopic dermatitis, there is a need for high-quality information showing how many people per country have atopic dermatitis and how severe it is. With strong data, atopic dermatitis can be better understood and treated.

With a grant from the LEO Foundation, the Global Atopic Dermatitis Atlas, or GADA, will help address gaps in current data by creating and maintaining a living online atlas, where the newest research-based knowledge and data on atopic dermatitis, its prevalence, severity, and treatment are available in one place – collected and analyzed in the same way for all countries.

About GADA

The Global Atopic Dermatitis Atlas (GADA) is a worldwide, long-term project. GADA is led by Professor Carsten Flohr (St John’s Institute of Dermatology, King’s College London, UK) and is an initiative established by the International League of Dermatological Societies (ILDS) in 2022 in collaboration with supporting stakeholders:

Visit GADA’s website

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Skin bacteria lipopeptides: key modulators of keratinocyte immune responses and atopic dermatitis

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

Amount: DKK 4,163,557

Grant category: Research Grants in open competition

Year: 2023

Geography: United Kingdom

Dr Peter Arkwright’s project aims to functionally characterize a group of recently discovered anti-inflammatory bacterial substances and investigate their potential therapeutic value in atopic dermatitis.

Staphylococcus aureus is unique in being the only bacterial species that consistently triggers flares in atopic dermatitis (AD). In previous work, also supported by the LEO Foundation, Dr Peter Arkwright, Dr Jo Pennock, and their team at the University of Manchester discovered “Sbi” as the unique factor produced by this bacterium that initiates AD in skin cells. Recently, they have identified factors produced by skin bacteria that completely block Staphylococcus aureus-induced AD, both in the lab and in an eczema mouse model. These factors are small, stable chemicals, made up of both fats and small proteins (lipopeptides).

In a collaboration with Professor Hiroshi Matsuda and Professor Akane Tanaka in Tokyo, Japan, they will apply lipopeptides derived from different bacteria to the skin of mice with AD to determine which are most effective at reducing the clinical dermatitis, itch, and skin damage. They will also explore how these factors work, using cell, protein, and lipid staining techniques. By purifying and characterizing these chemically stable immunosuppressive lipopeptides it is hoped that promising candidates identified here can be taken forward into clinical trials to develop novel therapies for AD.

The LEO Foundation Award 2023 – Region EMEA

Grantee: Dr. Lavinia Paternoster, Associate Professor, University of Bristol

Amount: USD 100,000

Grant category: LEO Foundation Awards

Year: 2023

Geography: United Kingdom

Dr. Lavinia Paternoster is Associate Professor at the University of Bristol in the UK.

She receives the award for her research pushing the boundaries of our knowledge on the genetic landscape of skin diseases. Lavinia Paternoster’s work has led to significant breakthroughs in the understanding of atopic dermatitis, psoriasis, and other complex human disorders.

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Global Psoriasis Atlas Phase III (2023-2026)

Grantee: Professor Chris Griffiths, University of Manchester

Amount: DKK 11,160,157

Grant category: Standalone grants

Year: 2023

Geography: United Kingdom

Psoriasis is a life-long and currently incurable immune-mediated skin disease affecting more than 60 million people worldwide. In addition to its cutaneous, stigmatizing manifestations, the disease is associated with other major medical conditions including depression, cardiovascular disease, diabetes, arthritis and cancer and can be construed as life-ruining. As such it represents a significant public health challenge. Despite remarkable advances in treatment options in some parts of the world, psoriasis continues to affect the quality of life of patients and impact health economics negatively.

GPA Phase III (2023-2026)

The GPA Phase III is focused on continued improvement of the understanding of the epidemiology of psoriasis and its incidence and prevalence at the global level. This third phase aims to build upon the previous achievements of the GPA Phase II. Here ambitions include:

  • An extensive update to the GPA’s large international dataset to create and launch edition 3 of the GPA.
  • To strengthen collaboration with the dermatology work stream of the Global Burden of Diseases (GBD).
  • To conduct new epidemiological studies to enhance the GPA.
  • To conduct new studies to improve knowledge about the comorbid disease burden of psoriasis.

Background

With a mission to ‘ensure that people with psoriasis, wherever they live in the world, have access to the best available care’, Professor Griffiths and the University of Manchester initiated the development of a Global Psoriasis Atlas in 2016. The GPA is a long-term iterative project, which was initiated in close collaboration with the WHO and international dermatology and psoriasis organisations. 

The LEO Foundation has been main funder of the development of the 1st edition of the GPA through a 3-year grant of DKK 6,370,000 from 2017 – 2020. The GPA project has in its first period (GPA Phase I) focused on research into the global prevalence and incidence of psoriasis – with the 1st edition of the GPA website launched on World Psoriasis Day 29 October 2019.

The LEO Foundation was also the main sponsor of GPA phase II, with a three-year grant of DKK 8,000,000 from 2020-2022. In this phase, the atlas-initiative has had a special focus on increasing its global outreach, including studies of psoriasis in Latin America, Malaysia, and Taiwan as well as on increasing and validating data on the association of psoriasis and cancer. Another important element of Phase II was to design and test a clinical diagnostic tool for health-care professionals globally, taking into account the different expressions of the disease, depending on skin colour. 

Visit the GPA website.

Genetic mechanisms of acne vulgaris

Grantee: Michael Simpson, Professor of Genetics, King's College London

Amount: DKK 2,870,799

Grant category: Research Grants in open competition

Year: 2022

Geography: United Kingdom

The aim of Michael Simpson’s project is to identify potential cellular or molecular targets for acne treatment, based on analysis of genetic variation found in a large pool of acne patients.

Acne vulgaris is a very common skin disease which is characterized by clogging and inflammation of the pilosebaceous unit, which consists of a sweat gland and a hair follicle including the hair itself. While various potential causes leading to the disease have been investigated over the years, the underlying disease mechanisms have not yet been sufficiently elucidated. One common approach to learning more about cellular and molecular causes for development of disease in some people is to investigate changes in the genes that influence the behavior and communication paths of cells – the signaling cascades known to be involved in the disease. Michael and his team have previously identified several areas (loci) in the human genome which are associated with acne.

They now want to study these areas in further detail to better understand the causal molecular and cellular events that lead to acne and hopefully identify targets for treatment. They will use a three-step approach. Firstly, by identifying the genetic variants linked to the disease by analyzing genetic data from more than 60,000 individuals with acne. Secondly, they will cross-link these variations to create a map of the signaling pathways and associated cells responsible. Finally, based on this mapping, they expect to be able to identify targets for future treatments of the disease. If successful, the results may provide the first steps towards a better and more targeted treatment for this very common and socially stigmatizing skin disease.

A single-cell dissection of the mechanisms underlying the ocular adverse effects of dupilumab in atopic dermatitis

Grantee: Francesca Capon, Associate Professor, King's College London

Amount: DKK 2,053,475

Grant category: Research Grants in open competition

Year: 2022

Geography: United Kingdom

This project, led by Francesca Capon, investigates the molecular and cellular mechanisms of dupilumab-associated conjunctivitis (inflammation of the eye), a comorbidity seen in one in three AD patients treated with the drug.

These mechanisms are poorly understood, and Francesca’s team wants to elucidate them by comparing immune profiles in blood samples from affected and non-affected patients. In addition, they will identify inflammatory molecules released by cultured immune cells treated with dupilumab to further understand the key signaling pathways.

The findings will enhance the understanding of dupilumab-induced conjunctivitis and eventually help improve treatment of patients with this condition.

Understanding the pathogenesis of steatocystoma multiplex

Grantee: Edel O'Toole, Professor, Queen Mary University of London

Amount: DKK 2,846,085

Grant category: Research Grants in open competition

Year: 2021

Geography: United Kingdom

This project, led by Edel O’Toole, aims to give new insights into the rare genetic skin disease, steatocystoma multiplex (SM) that may contribute to the development of a new treatment for affected individuals.

SM is a debilitating and embarrassing disorder, which presents as multiple smooth, yellow skin lumps or cysts distributed on the arms, trunk, neck, and underarm area. The lesions usually appear in the teenage years and for the severely affected patients with 100s to 1000s of cysts, these are a major burden causing disability and pain with frequent inflammation often mimicking infection.

The most common genetic defect is found in the gene coding for Keratin 17, a protein expressed in nails, hair follicles, skin on the palms and soles, and in sebaceous glands. The cysts in SM are believed to arise from the lining of these glands. The team will use single cell RNA sequencing and look at gene expression in individual cells lining the cyst and from the surrounding tissue, to understand the genetic differences.  In parallel, the O’Toole group will engineer cells from the sebaceous gland with and without the defect in the Keratin 17 gene. These cells will be used to form 3D skin models and cysts that mimic SM. Finally, drugs that target pathways of interest identified from the RNA sequencing will be used to ‘treat’ the 3D model, thereby adding to the many insights around SM expected from this project.

New diagnostic tool for scleroderma based on the detection of non-coding RNA biomarkers from skin interstitial fluid

Grantee: Claire Higgins, Senior Lecturer, Imperial College London

Amount: DKK 3,436,300

Grant category: Research Grants in open competition

Year: 2021

Geography: United Kingdom

Claire Higgins’ project aims to develop an early-stage diagnostic tool for scleroderma, a disease caused by an overproduction of collagen in both the skin and connective tissues, leading to a scarring of the skin and internal organs.

Among the early symptoms of scleroderma are poor blood circulation in fingers and toes, and an increased sensitivity to cold, which in many aspects is comparable to the much more common Raynaud’s phenomenon, and hence, scleroderma is often undiagnosed.

Utilizing the fact that certain molecules change expression level during disease (‘biomarker’ molecules), Claire Higgins aims to identify scleroderma-specific biomarkers in the liquid between individual skin cells, i.e., in the skin interstitial fluid. The identified biomarkers will be used to develop a non-invasive and painless test for general practitioners (GPs), enabling fast diagnosis – within minutes – and thereby differentiation between patients suffering from scleroderma and Raynaud’s phenomenon. Thus, patients will be able to get the most relevant intervention as early as possible. The actual diagnostic test will be developed along with the biomarker identification.

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.