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
Grant category: Research Grants in open competition
Year: 2017
Geography: Denmark
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
Amount: DKK 4,700,000
Grant category: Research Grants in open competition
Year: 2017
Geography: USA
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; Christine G. Lian, MD, Assistant Professor, and George F. Murphy, MD, Professor, both Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts
Amount: DKK 3,000,000
Grant category: Research Grants in open competition
Year: 2017
Geography: USA
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
Amount: DKK 3,820,000
Grant category: Research Grants in open competition
Year: 2017
Geography: Denmark
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
Amount: DKK 600,000
Grant category: Research Grants in open competition
Year: 2017
Geography: Denmark
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
Amount: DKK 3,252,204
Grant category: Research Grants in open competition
Year: 2017
Geography: USA
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
Amount: DKK 952,095
Grant category: Research Grants in open competition
Year: 2017
Geography: France
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
Amount: DKK 5,078,619
Grant category: Research Grants in open competition
Year: 2017
Geography: Denmark
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.
Determining the role of retinoic acid metabolism in acne treatment: Genetic and small molecule blockade of CYP26 in the Rhino mouse model of cystic acne
Grantee: Professor Martin Petkovich, PhD , Cancer Research Institute Queen’s University, Kingston, Ontario
Amount: DKK 2,180,000
Grant category: Research Grants in open competition
Year: 2017
Geography: Canada
Retinoids have been used in the treatment of skin disorders for many years, particularly for hyperkeratotic diseases such as ichthyoses, psoriasis, and severe acne. Retinoid agonists are potent modulators of epidermal proliferation and differentiation, but are also associated with several side effects including hypertriglyceridemia, fatty liver, and teratogenicity.
In this project, it is believed that selective modulation of the activity of the so-called CYP26 enzymes present in skin cells and involved in inactivation of retinoic acid (RA) could provide a route to safer, equally effective treatments.
More specifically, the project uses a two-pronged approach in which:
1) The role of CYP26 is evaluated by genetic knock-out, and
2) The effect of topical administration of CYP26 inhibitors is investigated, arguing potential advantages over existing therapies by limitation of systemic increase in RA since inactivation of the enzyme is limited to the target tissue
Moreover, the project aims at showing that topical CYP26 inhibitor application is superior to topical RA agonists as the latter may induce CYP26 expression that, on repeated dosing, can limit their effectiveness; this would not be the case for CYP26 inhibitors.
Development of elastin-based biomaterials for wound healing
Grantee: Assistant Professor Andrea Heinz, LEO Foundation Center for Cutaneous Drug Delivery, Department of Pharmacy, University of Copenhagen
Amount: DKK 1,472,000
Grant category: Research Grants in open competition
Year: 2017
Geography: Denmark
Wound healing is a complex biological process involving interaction of different types of cells, mediators, and components of the extracellular matrix.
In particular, re-epithelialization, closure of the wound by the epithelial cells, is a crucial step as it re-establishes skin continuity. The process, however, may be impaired in various pathological conditions such as diabetes, leading to the development of acute or chronic non-healing wounds.
This project, involving participants from Denmark, France, and Germany, aims to develop wound dressings based on novel polymer- and protein-based biomaterials capable of delivery of bioactive molecules. The basis will be elastin, an extracellular matrix protein with unique properties such as elasticity and biocompatibility.
In order to form the 3D scaffolds needed for wound dressings, state-of-the-art electrospinning will be utilized and hydrogels will be prepared by in vitro cross-linking of elastin-based peptides. The conditions of preparation will be tuned to produce a biomaterial of desired mechanical properties, which will then be characterized physio-chemically using a range of analytical techniques.
Addition of bioactive peptides and growth factors will allow for stimulation of wound healing. The materials will be tested in vitro using human fibroblast cell cultures and in vivo using animal wound models.