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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.

Grant category: Research Grants in open competition

Year: 2019

Geography: USA

This two-year proposal is based on the hypothesis that skin stem cells are critically involved in the pathogenesis of psoriasis and atopic dermatitis.

In previous work, the three principal investigators have identified a cytokeratin 15-expressing stem cell niche at the tips of epidermal rete ridges, discovered immunomodulatory dermal mesenchymal stem cells, and defined an epigenetic mark that regulates skin stem cell behavior.

During the past year that was funded by the LEO Foundation, we have provided data that supports epidermal stem cell participation in human and experimental psoriasis and begun to probe the genetic and epigenetic underpinnings of this phenomenon.

We now propose to advance these findings to determine mechanistic commonalities in stem cell behavior that may unify the pathogenesis of psoriasis and atopic dermatitis. Specifically, the proposal focuses on epidermal and dermal stem cells in the context of innovative experimental models, human biospecimens to test relevance, and epigenetic modifiers that may be transformative in normalizing stem cell aberrations responsible for the initiation and propagation of these two prevalent, pernicious, and potentially preventable skin diseases.

Grant category: Research Grants in open competition

Year: 2018

Geography: USA

Two major challenges when using mouse models to model human cancers such as melanoma are that the human tumor cells transplanted to mice 1) represent the end-stage of the disease and 2) that the host animals are usually immunocompromised.

Thus, these models fail to actually show development of the disease and they fail to display the ongoing interaction between melanoma cells and the immune system as the disease progresses.

To curb these two shortcomings, the team led by Rudolf Jaenisch of Massachusetts Institute of Technology, has set out to create an experimental model system that will make it possible to study initiation, progression, and manifestation of human melanoma in immune competent host animals.

Their basis is generation of human-mouse neural crest chimeras – where mice embryos are introduced with human neural crest cells carrying the genetic dispositions alleged to lead to development of the particular cancer – and their goal is a model that has the potential to show how melanoma cells evade the immune system.

Given a positive outcome, this innovative project can help devise strategies to improve the effectiveness of current immunotherapies, to test novel immunotherapies, and to identify novel targets in melanoma treatment.

Project group

Malkiel Cohen, Postdoctoral researcher

Kristin Andrykovich, Graduate Assistant

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.

Grant category: Research Grants in open competition

Year: 2016

Geography: Austria

The Austrian-American team behind the study, led by Dr. Igor Vujic, aims at identifying more specific and sensitive biomarkers in order to better detect and monitor progression of malignant melanoma – a common and deadly skin cancer that is difficult to treat, and that accounts for numerous deaths each year.

In the clinic, physicians face two main problems around malignant melanoma: detection of early disease, and monitoring of disease progression, recurrence and its response to therapies. The existing melanoma biomarkers are not very specific and only rarely help.

Melanoma cells, however, produce a specific set of RNA molecules of which some are excreted and found in the blood stream – ready for identification and use as biomarkers. Recent technical advances make it possible to extract and analyse serum RNA and identify the cell of origin.

The team will mainly concentrate on non-coding RNAs, a new class of molecules known to be very specific for certain diseases such as cancer. Preliminary studies have identified and confirmed 237 interesting candidates through RNA-Seq TCGA (The Cancer Genome Atlas) data.

In the course of the study, the team will perform RNA-Seq studies on serum samples from melanoma patients and healthy individuals to find differences in RNA quality and quantity to be used as melanoma serum-markers. The team will moreover test changes of the amount of these specific RNA molecules in melanoma patients over time to discover if they can be used as disease progression biomarkers.

Grant category: Research Grants in open competition

Year: 2022

Geography: Germany

Michael Bader’s project aims to develop novel angiotensin-converting enzyme 2 (ACE2) inhibitors to be applied to the skin for treating inflammatory skin diseases.

Alpha-melanocyte-stimulating hormone (α-MSH) acting through its receptor, melanocortin 1 receptor (MC1R), is the most important regulator of melanogenesis (i.e., the production of melanin, the pigment of the skin) and also exerts significant anti-inflammatory actions in the skin. Therefore, MC1R may be a significant treatment target for inflammatory skin diseases and for prevention of melanoma, and several agonists are already clinically approved or currently being developed.

Michael and his group have discovered that ACE2 limits melanogenesis in mouse and human skin by degrading α-MSH. Thus, ACE2 inhibition in the skin may be a novel strategy for dermatological diseases by stabilizing α-MSH and thereby activating MC1R.

However, ACE2 is also a protective enzyme in the circulation limiting the actions of the blood pressure regulatory system, the renin-angiotensin system. Therefore, systemic inhibition of ACE2 may cause severe side-effects, making topical application of ACE2-inhibitors preferable.

Michael and his team have already tested a number of available ACE2-inhibiting compounds, but none were suitable for topical application “as-is”. In this project, they will chemically design variants of known ACE2 inhibitors to optimize for skin permeation and test them in a mouse model of vitiligo. If they are successful, these compounds can also be tested in other inflammatory skin diseases, such as acne and psoriasis, for melanoma prevention, and perhaps even for cosmetic applications, such as skin tanning and prevention of hair greying.

Grant category: Research Grants in open competition

Year: 2022

Geography: Spain

This project led by Xavier Gasull, also Professor at the Neuroscience Institute of the University of Barcelona, seeks to investigate and validate the potential of a newly identified target molecule on sensory nerves of the skin for treatment of chronic itch.

Chronic itch is a very important problem for patients suffering from several dermatologic diseases such as psoriasis, atopic dermatitis, or dry skin. Constant skin scratching in response to itching may further worsen the skin lesion.

In all these dermatological conditions, pruritic (itching) stimuli activate specific sensory neurons in the skin that send the message to the brain, where the sensation of itch is perceived and trigger the scratching response. The recent description of the specific sensory neuron subpopulations involved in this process has started the elucidation of some of the neural mechanisms involved in itch signalling.

From recent RNA sequencing databases and the functional characterization of itch sensing neurons, Xavier and his team have identified a new pharmacological target that can be used to decrease neuronal activation and relieve itch sensation. They have also identified a candidate drug activating this pharmacological target, which shows positive results decreasing acute and chronic itch not mediated through histamine, for which no effective drugs exist to date.

The focus of this project is to validate this new target in different skin disease models that produce chronic itch. They will use computational methods to design new drugs against this target, synthesize and then test them for therapeutical purposes. The hope is to benefit patients suffering from chronic itch in different skin diseases and, if successful, will add new pharmacological regimes for treating chronic itch.

Grant category: Research Grants in open competition

Year: 2022

Geography: USA

This project initiative by Richard Granstein extends research previously funded by the LEO Foundation into the role of calcitonin gene-related peptide (CGRP) in regulating skin immunity by acting on endothelial cells (ECs – the cell type which lines the interior wall of blood vessels) and aims to elaborate on this regulation by studying the potential involvement of non-skin located ECs.

Recent studies have defined a novel pathway by which CGRP can skew the outcome of an immune response away from one type of T-cell mediated immunity (Th1-type) and toward another type (Th17-type) through actions on ECs. This work was originally done in cell cultures but subsequent studies using mice specifically lacking functional CGRP receptors on ECs found that this pathway indeed operates in vivo. Immunization of these mice led to decreased generation of Th17-type T cells in regional lymph nodes, but increased generation of Th1-type helper T cells. In addition, these mice were found to have severely depressed contact hypersensitivity responses. It is not known if the reduction in contact hypersensitivity responses relates to the observed changes in T helper cell differentiation. These results suggest that it may be possible to therapeutically manipulate diseases involving Th17 mechanisms, such as psoriasis, and, perhaps, other hypersensitivity disorders affecting the skin.

Given these results, it will be important to know more about the physiology of this novel pathway. Preliminary data suggest that ECs not in the skin may be sufficient targets for CGRP to exert the effects seen on T helper cell responses. Richard’s project proposes experiments to 1) test the hypothesis that ECs within regional lymph nodes are sufficient for the T helper cell effect observed in vivo and 2) to further define the mechanisms by which contact hypersensitivity is reduced in mice lacking functional CGRP receptors on ECs. Ultimately, these studies may suggest novel new routes for therapies.

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.

Grant category: Research Grants in open competition

Year: 2023

Geography: Austria

Johannes Griss’ project aims to elucidate the immunological memory of biologics-resistant psoriasis patients using advanced screening methodology. This, coupled with identifying immune composition in lesions, may reveal new treatment options.

Efficient treatment of cutaneous psoriasis is an example of the great success of modern biologicals. Nevertheless, a subset of patients remain that do not respond to most biologic treatments. This group remains in high need of efficient treatment options. It has been speculated that therapy-resistant psoriasis is caused by either specific compositions of the microbiome or unique previous viral infections.

Viral infections can trigger autoimmune diseases and dysregulated immune responses against the microbiome may trigger inflammatory and autoimmune diseases. However, to date it has not been possible to cover the vast space of antigens represented by the microbiome. Johannes Griss and his team recently showed that phage display libraries (PhIP-Seq, a high-troughput screening method utilizing bacteria-infecting viruses) can be used to identify and characterize antibodies against several 100,000s of antigens simultaneously instead of several 100s with conventional methods. This method can reveal both previous viral infections as well as the composition of the microbiome at large scale and low cost.

In this project, the team will use their novel PhIP-seq approach to characterize the immunologic state of a large in-house cohort of psoriasis patients. They will pair this with an in-depth characterization of the lesional immune composition. In this way, they aim to be able to test whether a patient’s immune memory alters psoriatic inflammation and influences therapy response.

If successful, their findings may reveal novel treatment approaches and biomarkers to allow optimal matching of biologic treatments.