Investigating the regulation of Interleukin-36 cytokine activity in the pathogenesis of generalised pustular psoriasis

Grantee: Mark Mellett, Group Leader, University Hospital Zürich

Amount: DKK 2,055,914

Grant category: Research grants in open competition

Year: 2022

Geography: Switzerland

The overall aim of Mark Mellett’s project is to shed light on the differences and the mechanisms governing regulation of IL-36 activity in both skin inflammation and viral infection.

IL-36 cytokines (a substance secreted by cells that affect the response of nearby cells) are well-known to contribute to inflammatory skin diseases in particular generalised pustular psoriasis. Yet the mechanisms regulating the activitiy of the cytokines remain poorly understood.

Mark and his team suggest that IL-36 is an important response mechanism protecting the skin against viral infection and this response is “switched on” in error in generalised pustular psoriasis. They propose to elucidate the reasons for this to better understand how pustular psoriasis is triggered.

Molecular genetics of recalcitrant warts

Grantee: Hassan Vahidnezhad, Assistant Professor, Thomas Jefferson University

Amount: DKK 2,131,526

Grant category: Research grants in open competition

Year: 2022

Geography: USA

This project led by Hassan Vahidnezhad aims to elucidate the mechanisms behind skin warts that do not resolve automatically.

Warts are very common, approximately present in 20-35% of the general population. While they typically disappear within a few months, some linger and may be hard to get rid of. These persistent warts are caused by infection with Human Papilloma Virus (HPV) in persons where the immune response is insufficient due to genetic defects. Particularly, defects in T cells are suspected as a causation, but exactly how the warts are formed and how they persist is to a large degree unknown.

Hassan and his team seek to identify the genetic and molecular causes of recalcitrant warts, which will not only better the understanding of the skin’s immunological response to HPV infection, but may also provide diagnostic, prognostic and therapeutic improvements for patients with recalcitrant warts.

Control of cutaneous immune responses by T follicular regulatory cells in systemic autoimmunity

Grantee: Søren Degn, Associate Professor, Aarhus University

Amount: DKK 2,795,064

Grant category: Research grants in open competition

Year: 2022

Geography: Denmark

This project, led by Søren Degn, aims to investigate the role of a newly discovered immune cell, the T follicular regulatory cell (Tfr), in controlling systemic autoimmunity.

Søren Degn and his team have discovered that Tfrs are able to maintain tolerance in the skin even in the face of systemic inflammation, which in that case appear to be reversible, but also that if Tfr control in the skin fails, the systemic inflammation becomes irreversible and chronic.

Using a mouse model where Tfrs are selectively deleted, Søren and his team will investigate immune responses and identify which specific self-antigens are targeted when the tolerance maintained by the Tfrs is lost.

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.

The role of eosinophils in atopic dermatitis skin inflammation and itch

Grantee: Nathan Archer Ph.D., Assistant Professor, Johns Hopkins School of Medicine

Amount: DKK 3,783,727

Grant category: Research grants in open competition

Year: 2022

Geography: USA

This project led by Dr. Nathan Archer investigates the interplay between bacterial colonization and a specific immune cell, the eosinophil, in development of atopic dermatitis (AD).

AD is a very common skin disease, particularly amongst young people, and the associated healthcare costs in the U.S. alone are estimated at USD 5.2 billion. Thus, there is a strong incentive to better understand the disease to improve its treatment.

The cause of AD is still unclear, but one interesting observation is that a specific type of immune cell, the eosinophil, infiltrates the affected areas and correlates with disease severity. The role of these eosinophils in AD remains unknown, but initial observations by Dr. Archer and his team point to a link between skin colonization of a specific bacteria, Staphylococcus aureus, and the observed infiltration – which may lead to both inflammation and itch. This bacteria-immune cell interaction is unusual, and Dr. Archer and his team will investigate the observed interaction in detail, with an aim to provide novel therapeutic targets for the treatment of AD.

Unveiling Novel Molecular Mechanisms Underpinning Chronic Pruritus and Developing Innovative Antipruritics

Grantee: Jianghui Meng, Assistant Professor, Dublin City University

Amount: DKK 2,200,000

Grant category: Research grants in open competition

Year: 2022

Geography: Ireland

Chronic itch (pruritus) is a major symptom of numerous dermatological and systemic diseases, which substantially impairs patients’ quality of life, resulting in considerable socioeconomic costs. Current treatment options have insufficient efficacy or side effects, and do not treat the underlying cause of itch. Thus, there is a significant unmet medical need for a better efficacy, longer lasting and safer therapy.

Specifically, Jianghui and her team will focus on understanding the role of b-type natriuretic peptide (BNP) signaling, which is known to be pivotal in the development and transmission of itch, yet no effective therapeutics targeting this molecule have so far been developed. To address this knowledge gap, the team will investigate the pathways in detail, validate the involved molecules as potential targets for anti-itch drugs and develop therapeutic candidates that can interrupt several key molecular events of BNP signaling, including release of BNP and its pruritogenic effect.

Adherens Junction Dysfunction in Hidradenitis Suppurativa

Grantee: Amanda Nelson, Assistant Professor, The Pennsylvania State University

Amount: DKK 3,996,947

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.

Towards a Cure of Genodermatoses: Intraepidermal Delivery of Gene Editing Tools Leveraging Smart Delivery Systems

Grantee: Sarah Hedtrich, Associate Professor, Charité Hospital Berlin

Amount: DKK 4,183,544

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.

Chemical compounds that impede the pathogenic effects of Staphylococcus aureus in atopic dermatitis

Grantee: Tim Tolker-Nielsen, Professor, University of Copenhagen

Amount: DKK 3,236,161

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.

Development of predictive psoriasis response endotypes using single cell transcriptomics in ustekinumab responders versus non-responders

Grantee: Kevin Cooper, Professor, University Hospitals Cleveland Medical Center

Amount: DKK 3,653,532

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.