The LEO Foundation Award 2017 – Silver Award

Grantee: Dr. Christoph Schlapbach

Amount: DKK 500,000

The Silver Award went to Dr. Christoph Schlapbach, dermatology resident at the University of Bern in Switzerland.

“It is a great honour for me to receive the LEO Foundation 2017 Silver Award on behalf of my emerging research team. Together with the generous financial support, this prize motivates and supports our journey towards a better understanding of how the human skin functions,” said Christoph Schlapbach.

The LEO Foundation Award 2017 – Gold Award

Grantee: Dr. Maria Kasper

Amount: DKK 1,000,000

The Gold Award went to Dr. Maria Kasper, presently leading a research group at the Karolinska Institute in Stockholm, Sweden.

“Receiving the phone call with the news of the LEO Foundation 2017 Gold award is one of these few unforgettable moments. My friends often call me “skin nerd” since I love everything about skin.  Thus, it’s such a happiness and great honour for me to receive this prestigious prize. I would like to express my deepest thank you to the LEO Foundation, the ESDR, and my lab members who make everyday’s work fun and colorful,” said Maria Kasper.

GLP-1R signaling in T cells in relation to psoriasis

Grantee: Carsten Geisler, Professor and Head of Department, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen

Amount: DKK 2,000,000

Recent studies of patients with psoriasis and type 2-diabetes have shown intriguing results: administration of glucagon-like peptide 1 (GLP-1) analogues was found to improve the severity of psoriasis. In another study, while not finding a significant beneficial effect of a GLP-1 analogue on disease score as compared to placebo, patients did report a significant decrease in their disease score as compared to baseline.

This has led a Denmark-based group to team up for further investigation of the effect of GLP-1 analogues on psoriasis, based on, among others, an assumption of a direct effect of GLP-1 analogues on the immune system – with the intention of clarifying if there may be a route to new treatment options for psoriatic patients.

More specifically, the team will investigate if the potential immunoregulatory effect of GLP-1R signalling on T cells in psoriatic plaques could be responsible for the patient-experienced alleviation of psoriasis. The team furthermore hypothesizes that vitamin D may play an important role in GLP-1R signaling and is important for alleviation of psoriasis as Vitamin D upregulates GLP-1R on T cells and low serum levels of vitamin D have been reported in psoriatic patients.

The majority of the experiments will be performed by Anna Kathrine Obelitz Rode under supervision of Martin Kongsbak-Wismann and Carsten Geisler, Department of Immunology and Microbiology, University of Copenhagen. Lone Skov, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen will be co-supervisor on the project. The project will be performed in close collaboration with Charlotte Menné Bonefeld, Department of Immunology and Microbiology, University of Copenhagen.

The clinical studies in humans will be performed at the Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen in collaboration with Lone Skov.

Towards a personalized medicine approach for atopic dermatitis

Grantee: Dr Emma Guttmann, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Amount: DKK 4,700,000

Atopic dermatitis (AD) is the most common inflammatory skin disease, with a prevalence in adults of 3% to 10% and a large unmet need for effective therapeutics.

Current clinical trials for AD patients assume a common disease mechanism. However, based on preliminary data, different therapeutics may be required to effectively treat different subsets of AD patients.

Biomarker-based studies show distinct clinical, and particularly molecular and cellular differences between different AD subpopulations such as African American, Chinese, and Indian AD patient populations.

However the characterization of the different and distinct clinical AD phenotypes is still at its very beginning. Indeed, there is high need of appropriate mechanistic studies to create a complete “molecular map” of AD across its different variants and hence to get a step closer for a personalized treatment approach.

Dr. Emma Guttman and her team at Icahn School of Medicine at the Mount Sinai Medical Centre, NY, USA, will seek a first time investigation to provide a systems biology approach for AD aiming to produce a molecular map of AD across its different subtypes.

The project integrates cellular and molecular biomarkers of lesional, but also non-lesional, skin and systemic inflammation to classify adult AD patients based on ethnic phenotypes, disease severity and age differences.

The proposal will set the stage for personalized therapy approach for AD based on skin and blood biomarkers and pathogenic variation of AD phenotypes related to severity, race/ethnicity and age.

Epidermal and Dermal Stem Cells in Psoriasis

Grantee: Markus Frank, MD, Associate Professor, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, USA; Christine G. Lian, MD, Assistant Professor, and George F. Murphy, MD, Professor, both Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, USA

Amount: DKK 3,000,000

Despite decades of research, the root cause of psoriasis remains unknown and targeted approaches to cure psoriasis have to date been elusive.

Psoriasis is a physically and psychologically devastating skin disorder affecting more than 7.5 million Americans, with global prevalence ranging up to 4.6%. The disease causes profound physical, emotional, and social burdens translating into massive healthcare costs.

Theories of the biological mechanisms behind the disease range from genetic and epigenetic deviations to acquired defects involving a plethora of cellular and mechanistic culprits, including epidermal cell kinetics, endothelial-leukocyte interactions and perturbations in dermal nerve fibres, mast cells, lymphocytes and dendritic cells.

However, even if it is clear that a multiplicity of cellular pathways is involved, the primary events that initiate and drive disease remain unknown.

The team behind this study proposes a novel hypothesis that psoriasis is driven by immune-mediated dysregulation of stem cells within the epidermal and dermal compartments.

In the course of the study, the team will, for the first time, test the skin stem cell hypothesis of psoriasis causation with a highly-focused goal of defining the primary event(s) in lesion formation, thus providing a foundation for future pre-clinical targeted therapeutic approaches designed to actually cure psoriasis.

The pro-autophagic tumor suppressor AMBRA1 as a novel therapeutic target for melanoma

Grantee: Professor Francesco Cecconi, Head of the Cell Stress and Survival Unit (CSS), Danish Cancer Society Research Center (DCRC), Copenhagen, Denmark

Amount: DKK 3,820,000

The LEO Foundation has supported this project in appreciation of the fact that malignant melanoma has the highest death toll among skin cancer.

If and when melanoma is not diagnosed and treated early, the cancer may develop and spread to other parts of the body, where it becomes harder to treat and potentially fatal. Therefore, work to find new therapeutic targets for this particular aggressive cancer type is of extreme importance.

Professor Cecconi and his team have extensive and comprehensive expertise on the molecular ‘switch’ AMBRA1, believed to play a significant role in the body’s own defense against diseases such as cancer.

As an example, professor Cecconi was the first to identify the AMBRA1 gene and has been unraveling its multiple functions over the last 10 years. In particular, he has already demonstrated AMBRA1 playing a role as tumor suppressor in vivo, and preliminary data indicates the gene’s supposed role as a therapeutic target in cancer. Very intriguingly, most AMBRA1 mutations were found in melanoma patients.

The LEO Foundation finds this project to be innovative and commends its multidisciplinary approach, putting together different fields of research ranging from cell biology, mouse genetics, biophysics, computational biology and CRISPR/Cas9 technology.

Prof. Cecconi is member of the European Consortium Mel-Plex (Horizon 2020 Marie Curie Action), which includes several international researchers with the common aim of tackling melanoma – and these existing collaborations with melanoma experts will be of great importance in order to accomplish the project.

Instantaneous monitoring of allergic reactions in the skin

Grantee: Stephan Sylvest Keller, Associate Professor, DTU Nanotech, Denmark

Amount: DKK 600,000

Allergy is one of the world’s most common chronic conditions. It is caused by immunoreaction of the human body towards in principle otherwise harmless allergens, and the current method for allergy screening and monitoring is the skin prick test (SPT) where different allergens are introduced into the tested person’s skin.

This widely used method, however, is non-quantitative, relatively lengthy and patients might experience unpleasant reactions. Furthermore, clinical evaluation of the SPT requires physical assessment of visible changes of the skin due to local inflammation by an experienced health care professional.

In the supported PhD project, which involves collaboration between DTU Nanotech, the Allergy Clinic at Gentofte Hospital in Denmark, Malmö University in Sweden and the University of British Columbia in Canada, an allergy test based on a micropatch will be developed which may be both more efficient and accurate as well as less cumbersome.

The micropatch will introduce allergens to the skin with carbon micro needles and allow for instantaneous and quantitative monitoring of allergic reactions in the skin through in vivo electrochemical sensing of the histamine released from activated mast cells in the interstitial fluid.

If successful, the new micropatch-based test will provide for less unpleasant allergy tests, in particular relevant with children suffering from atopic dermatitis. Further, a successful micropatch test will be a valuable and effective mean to identify potential immunoreactions towards newly developed topical dermatological drugs.

The project is supported by the LEO Foundation, the Copenhagen Center for Health Technology – CACHET (www.cachet.dk) and DTU Nanotech.

Regulation of immunity by Calcitonin Gene-related Peptide through effects on endothelial cells

Grantee: Richard D. Granstein, MD, George W. Hambrick, Jr. Professor and Chairman, Department of Dermatology, Weill Cornell Medical College, NYC, USA

Amount: DKK 3,252,204

Many observations suggest interactions between the skin immune system and the nervous system. Psoriasis and atopic dermatitis (AD), as examples, are believed to worsen with stress.

It has furthermore been shown that denervation of areas of human skin bearing psoriasis leads to improvement or resolution of the disease – and studies on mice have shown that an intact nerve supply is necessary for development of murine psoriasiform dermatitis.

The underlying mechanisms addressed in this project revolve around the Calcitonin Gene-related Peptide (CGRP) and the use of a novel, specifically targeted murine model.

Psychological stress increases the CGRP content of cutaneous nerves and dorsal root ganglia, and the team behind the project suggests that CGRP effects on the dermal microvascular endothelial cells may, at least in part, explain stress-exacerbation of Th17-mediated skin diseases such as psoriasis.

The LEO Foundation believes that the project can provide relevant insights into the role of the nervous system in regulating skin immune responses and thus provide a rational basis for developing novel drugs for modulation of skin immune responses.

Functional analysis of the genomic abnormalities of non UV-induced skin squamous cell carcinomas

Grantee: Dany Nassar, MD, PhD, Associate Professor, Department of Dermatology, Université Paris, France

Amount: DKK 952,095

Squamous cell carcinoma (SCC) of the skin is the second most frequent skin cancer. Generally, SCC occurs on sun-exposed areas of fair skinned in elderly individuals.

However, skin carcinogenesis is also observed in non-UV induced settings, particularly in chronic wounds and scars like chronic leg ulcers, inherited blistering diseases and deep burn scars. These wound-associated SCCs are highly invasive and prone to metastasis, making them a life threatening complication.

The mechanisms of chronic wound carcinogenesis are unknown. The absence of UV exposure and different clinical behaviour suggest different mechanisms of carcinogenesis, including different initiating driver genomic abnormalities.

The team behind this study aims to uncover genomic alterations through Whole Exome Sequencing on a cohort of 35 wound/scar-associated SCCs with matching germline DNA. They will compare achieved data to data on UV-induced SCCs and to murine models of skin SCCs.

Furthermore, they will perform micro-dissection of successive stages of carcinogenesis in a cohort of specimen and subject these to targeted genotyping. This will allow for determination of the successive genetic alterations that drive the multistep carcinogenesis in the absence of carcinogenic UV exposure.

The team expects to find a distinct and hopefully new mutational signature in skin carcinogenesis, to identify new oncogenes and tumour suppressor genes and to model the multistep genomic evolution of wound/scarring associated skin SCC.

Basis for the project lies in a multicentre collaboration gathering six University Hospitals in two countries, including Paris-based Hôpital Cochin and Hôpital Tenon as well as American University of Beirut Medical Centre in Lebanon.

Investigation of atopic dermatitis in Greenland; distinct genotypes, phenotypes, and immunotypes

Grantee: Jacob Pontoppidan Thyssen, Consultant, PhD, DMSc, Assistant Professor, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, Denmark

Amount: DKK 5,078,619

The LEO Foundation supports this study aimed at improving diagnostic accuracy and treatment of Atopic dermatitis (AD) in Greenland, and to add to the general knowledge of AD.

The project’s hypothesis is that Inuit children with AD residing in Greenland display a population-specific prevalence, set of risk factors, phenotype, genotype, immunotype, and bacterial load. As part of showing this, it is intended to clarify potential Inuit-specific loss-of-function mutations in filaggrin gene (FLG) addressing the latitude dependent gradient in FLG mutation prevalence and its potential role in providing an evolutionary advantage.

In general, the settings in Greenland differ on many parameters from a conventional western society: The AD study population is expected to be different due to variation in living conditions, diet, climate, and genetic admixture. This is of particular importance to better examine and understand AD etiology and related risk factors and may hopefully provide a break-through in AD research.

In the project, the team will establish a large children cohort in Greenland to estimate prevalence, genotype, phenotype, immunotype, and risk factors for AD. By examining Inuit children with and without AD, compared with Danish children with AD, along with a cohort comparison from collaborating partners, the team will be able to examine whether phenotypic traits correlate with genotype, immunotype, ethnicity, or environmental factors, including gut and skin microbiomes.

The study offers an exclusive opportunity to examine AD in a homogenous small population in a secluded environment, and is foreseen to contribute to increased understanding of AD as an overall term, hereby its phenotype, genotype, immunotype, and specific risk factors. Both to understand better the pathogenesis of AD, and to improve and implement diagnostic tools for Greenlandic patients with AD.