Grant category: Research Grants in open competition

Grant category: Research Grants in open competition

Year: 2022

Geography: USA

Amanda Nelson’s project investigates the role of two proteins, E-cadherin and p120, in the relatively common inflammatory skin disease Hidradenitis Suppurativa (HS), which is characterized by skin lesions that cause intense pain, odor, drainage and scarring.

The cause of HS remains unclear, and this limits the current treatment options. The current hypothesis is that there is a blockage in the hair follicle unit, which triggers the immune response. Amanda and her team have found that E-cadherin and p120, both important for skin integrity, are lost in HS-affected skin, and their project seeks to understand how this loss may contribute to the hair follicle breakdown and subsequent inflammation. If the link is proven it may provide novel approaches for treatment of HS.

Grant category: Research Grants in open competition

Year: 2022

Geography: Germany

Sarah Hedtrich, who is also Associate Professor at the Faculty of Pharmaceutical Sciences of the University of British Columbia, leads this project focusing on developing novel ways to treat genetic skin diseases through intra-skin delivery methods.

Skin diseases caused by specific genetic defects (genodermatoses) are often rare but can be severe and even life threatening – like epidermolysis bullosa. To cure such diseases, the genetic errors which cause the diseases would need to be corrected. In recent years there have been major advances in targeted gene editing – not least with the CRISPR/Cas system which allows for both tissue- and cell-specific correction.

However, while the skin is readily accessible it has two features which impede such treatment: Firstly, the skin’s barrier function makes efficient delivery difficult, and secondly, as the skin is an epithelium with rapid turnover of the cells, a persistent cure involving gene editing must reach the stem cells which lie at the base of the epidermis, the outer layer of the skin.

Sarah and her team, with expertise in both dermatology, gene editing and topical drug delivery, aim to develop such a delivery system for gene correction treatments using microneedles and nanocapsules, and will investigate its efficiency in both human skin samples and bioengineered skin (disease) models.

Grant category: Research Grants in open competition

Year: 2022

Geography: Denmark

The project by Tim Tolker-Nielsen aims to identify novel chemical compounds as potential drug leads for treating bacterial involvement in atopic dermatitis. The present project builds on findings from another LEO Foundation grant, which discovered a central factor, Sbi, responsible for the virulence (the ability to cause disease) of the bacteria Staphylococcus aureus in atopic dermatitis flares. As this factor appears to be unique to that bacterium it can be targeted with minimal impact expected on beneficial commensal (i.e. non-pathogenic) bacteria. Tim and his team will utilize existing libraries of chemical compounds to screen for lead candidates that can prevent the production of Sbi and which may be developed into a future treatment for atopic dermatitis flares.

Grant category: Research Grants in open competition

Year: 2021

Geography: USA

Among the biological treatments approved for the treatment of psoriasis, is ustekinumab, which is a monoclonal antibody targeting the shared p40 subunit of two cytokines, IL12 and IL23.

This project aims to improve psoriasis treatment by understanding why some psoriasis patients respond well to treatment with ustekinumab (responders) and others do not (non-responders). Interestingly, some non-responders to ustekinumab still respond well to inhibition of the IL23 pathway alone via the unique p19 subunit.

The pattern of differentially expressed genes among responders and non-responders may enable prediction of which intervention will be most beneficial for the individual patient. The plan is to compare single-cell transcriptomic analyses from both responders and non-responders to identify treatment response-linked gene expression patterns, so-called ‘endotypes’.

One size does not fit all for these biological therapeutics, and the goal is for the research to contribute to the development of a ‘companion diagnostic’, which is a diagnostic test used as a companion to a therapeutic drug to determine its applicability to a specific person, and thereby to personalized medicine in psoriasis.

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.

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.

Grant category: Research Grants in open competition

Year: 2021

Geography: Denmark

The research project by Professor Christian Olsen pursues a cutting-edge strategy for the treatment of skin infections.

Staphylococcal bacteria are the most common cause of skin and soft tissue infections, and with the rise of methicillin-resistant Staphylococcus aureus (MRSA), this new strategy could – if successful – help prevent minor infections from becoming severe medical conditions. Furthermore, the strategy could minimize the risk of emerging antibiotic resistance.

Bacteria produce and release molecules known as ‘virulence factors’ which cause damage. The production of these harmful molecules is regulated through a form of cell-to-cell communication called ‘quorum sensing’, where the concentration of virulence factors increases as a function of cell density. The present project aims to weaken the severity of bacterial skin infections by inhibiting ‘quorum sensing’ with synthetic auto-inducing peptide (AIP) analogs, and as a result, decrease the excretion of virulence factors.

‘Quorum sensing’ inhibition will target the severity of the bacterial infection, rather than the viability of the individual bacterium and represents an alternative to antibiotics, as there is no evolutionary pressure on the individual bacterium to develop towards a state that is not affected by these compounds. Therefore, minimal risk of emerging antibiotic resistance is to be expected from this strategy.

Grant category: Research Grants in open competition

Year: 2021

Geography: USA

Melanocytes are pigment-producing skin cells. They serve as an excellent model for stem cell research because they are easily obtainable from the skin and have the potential to be modified into other types of cells. The aims of this project are to define molecular events that promote stem cell maintenance and to test if melanocyte stem cells can be transformed into other cell types (such as nerves).

Deborah Lang has created a unique transgenic mouse model that fluorescently marks melanocyte stem cells.  This model is an innovative and powerful tool to visualize and isolate pure stem cells without contaminating non-stem cells. The Lang lab, along with Andrey Sharov and other collaborators at Boston University, will investigate gene expression in the stem cells, and how these stem cells change into pigment-producing melanocytes. Further, the team will test the ability of the melanocyte stem cells to turn in to other cells, such as neurons and neuron-like cells.

This project will provide new insights into melanocyte stem cell function and flexibility to become other cell types. The potential long-term impact of this project is that it will provide insight on normal melanocyte function, melanocyte dysfunction and pathology, and stem cell therapy.

Grant category: Research Grants in open competition

Year: 2021

Geography: Denmark

This project aims to investigate the potential of using bacteria exchange or “microbiome transplant” as a viable treatment option for acne vulgaris.    

Acne vulgaris remains one of the most prevalent skin conditions worldwide affecting close to 10% of the population and impacting the quality of life of millions of people. Multiple factors contribute to acne, including genetics, excess sebum production, colonization of the skin by Cutibacterium acnes and an inflammatory cascade. Current treatments for acne such as retinoids and antibiotics have varied outcomes and side effects. As antibiotic resistance becomes an increasing concern in clinical practice, there is an unmet need for alternative treatment approaches.   

The team have previously identified a range of bacterial strains, isolated from healthy skin, that can selectively inhibit acne-associated Cutibacterium acnes strains. The current project takes a microbiome transplantation approach to acne treatment, utilizing a pre-existing in-house library of more than 1000 bacterial strains and testing their ability to modulate the skin microbiome and reduce acne symptoms in patients with mild-to-moderate acne.  

This project may pave the way for developing a personalized treatment to a very common skin disease while avoiding the issue of antibiotic resistance. 

Grant category: Research Grants in open competition

Year: 2021

Geography: Austria

The aim of this project is to investigate the crosstalk between T-cells (TC) and keratinocytes (KC) and its role in two less explored inflammatory skin diseases, namely cutaneous lupus erythematosus and lichen planus. Specifically, the role of co-receptor stimulation or inhibition of T-cells will be investigated. 

The researchers hypothesize that skin diseases with prominent infiltration of pathogenic CD8+ T cells (cells that attack and kill other cells – including keratinocytes in autoimmune diseases) are related to an imbalance of activating and inhibitory signals on T cells determining the extent of the T-cell–keratinocyte (TC–KC) crosstalk. 

The team will investigate this using skin biopsies from patients to map TC–KC receptor-ligand interactions by single-cell and spatial transcriptomics. They will then assess the properties of candidate receptors and decipher their mechanism of action by immunofluorescent imaging. 

While inhibitory T-cell co-receptors are already targeted for cancer immunotherapy, their therapeutic potential in T-cell-driven inflammatory disorders remains to be established. This study may provide the rationale to design T-cell-targeting therapies in inflammation and is particularly strong with its basis on patient material.