In vivo gene editing for genodermatoses

Grantee: Thomas Kocher, Postdoc, EB House Austria, Salzburg

Amount: DKK 1,389,845

Grant category: Research grants in open competition

Year: 2020

Geography: Austria

The goal of this project is to evaluate the translational and therapeutic potential of two in vivo CRISPR/Cas9 delivery methods. CRISPR/Cas9 is a gene-editing technology that enables researchers to edit parts of the genome by removing, adding or altering sections of a specific DNA sequence. Although CRISPR/Cas-based technologies hold great promise as genome editing tools in many genetic diseases, its clinical application, especially in genodermatoses, remains a big challenge.

To challenge this hurdle, CRISPR/Cas9 molecules will be delivered into the skin of a suitable animal model via two application methods: laser microporation and gene gun bombardment. The first method uses a laser to make micropores into the skin to allow the CRISPR/Cas9 constructs to enter the outer skin barrier and subsequently the target skin cells. The second method uses a “gene gun”, where gold particles covered with CRISPR/Cas9 constructs are shot directly into the skin/cells.

These constructs can then restore genetic defects in e.g. epidermolysis bullosa (EB) – a genetic condition that results in easy blistering of the skin and mucous membranes – which is used in this project as a model, and potentially cure the disease.

The project will investigate the potential of these two delivery methods in a mouse model using grafted human skin equivalents from expanded recessive dystrophic epidermolysis bullosa (RDEB) patient-derived fibroblasts and keratinocytes. If either delivery method proves efficient, it may hold the potential for development of future treatments, or even cure, of genetic skin diseases.

Identification and biological basis of immunomodulation of skin inflammation by S. epidermidis

Grantee: Peter Arkwright, Senior Lecturer, The University of Manchester

Amount: DKK 4,369,423

Grant category: Research grants in open competition

Year: 2020

Geography: United Kingdom

The ultimate goal of this project is to contribute to the development of new medicines to treat bacterially induced eczema.

The project is a continuation of previous work supported by the LEO Foundation on the impact of bacterial infection, specifically caused by Staphylococcus Aureus (S. Aureus), on eczema. Here, a single factor secreted by S. Aureus was identified as the primary causative agent for eczema development or flare-up. Furthermore, it was also found that the naturally occurring variant, S. Epidermidis, has an inhibitory effect on eczema-induction.

The objective of the present project is to further elaborate on the disease-preventing effect of S. Epidermidis. First, the team will identify any factor(s) secreted by S. Epidermidis that inhibits eczema and then confirm its role by knocking out any relevant gene(s). Finally, the effect of any identified factor(s) on S. Aureus-induced eczema will be studied.

Deciphering the Role of Non-Coding RNAs in Epidermal Carcinogenesis

Grantee: Andor Pivarcsi, Senior lecturer/Associate Professor, Department of Medical Biochemistry and Microbiology (IMBIM), Uppsala Universitet, Uppsala

Amount: DKK 4,164,300

Grant category: Research grants in open competition

Year: 2020

Geography: Sweden

The goal of this project is to investigate the potential role of long non-coding RNAs (lncRNAs, RNA molecules, which do not function through coding for protein, but by regulating other genes) in the development of the most common form of skin cancer with metastatic potential – Squamous Cell Carcinoma (SCC). Such RNAs are known to be key regulators of multiple cellular functions, tissue development and homeostasis, but their role in SCC is not clear. Andor Pivarcsi and his team have identified a group of long non-coding RNAs that have altered expression in this disease. As these lncRNAs may prove to be key players both in the development of cutaneous cancers and in the maintenance of normal skin homeostasis, they now want to investigate their function.

Andor Pivarcsi and his team will do so by defining the role and mechanism of action of selected lncRNAs by a combination of methods, including inhibiting them with anti-sense oligonucleotides, that will effectively prevent their association with natural binding partners. The results will improve our understanding of long non-coding RNAs in cutaneous malignancies and may pave the way towards improved antisense oligonucleotide-based skin cancer therapy.

Andor Pivarcsi is a former LEO Foundation Silver Award Winner (2010).

Rapid Clinical Assessment of Skin Barrier Function by Corneocytes Nanotexture

Grantee: Edwin En-Te Hwu, Associate Professor, Technical University of Denmark

Amount: DKK 2,824,593

Grant category: Research grants in open competition

Year: 2020

Geography: Denmark

The goal of this project is to develop a clinically applicable imaging method for evaluation of atopic dermatitis (AD) development, progression and impact of therapeutic intervention.

It is known that AD is closely linked to the status of the skin barrier and therefore Edwin En-Te Hwu and his team will utilize a newly developed biomarker for skin barrier function, the Dermal Texture Index. This index is based on the number of circular nano-objects found on corneocytes (skin cells in the outermost part of the epidermis) of the skin by atomic force microscopy (AFM). However, the current analytical setup is both costly and has a limited throughput which makes it less suitable in a clinical setting.

The team has recently developed a new AFM technique and now aims to develop ‘Dermal AFM’, which will allow a ten times higher throughput in a clinically applicable unit. The unit may also help facilitate the understanding of the biology behind the observed corneocyte nanostructures.

The project is a collaboration between Denmark, Netherlands and Taiwan headed by DTU Health Technology.

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Targeting Aberrant STAT3 Signaling in CTCL

Grantee: Sergei Koralov, Associate Professor, NYU Langone, NY

Amount: DKK 2,676,248

Grant category: Research grants in open competition

Year: 2020

Geography: USA

The goal of this project is to elucidate the mechanism behind the beneficial effects of atovaquone, a well-tolerated anti-microbial drug, on the rare type of skin cancer – the T-cell lymphoma (CTCL). It is known that atovaquone inhibits malignant cells from growing and may induce cell death, but the precise mechanism(s) is not known.

Sergei Koralov and his team have previously developed an animal model of the CTCL disease and will use this along with cells from patients to investigate the effects of atovaquone. Specifically, they will look at how the drug affects the gene regulating protein STAT3 as hyperactivation of this has shown to be critically important in the development of cancerous T-cells.

Given the outstanding tolerability of atovaquone, it is believed that if its mode of action can be deciphered it may prove a powerful tool in the future for treatment of malignant and inflammatory diseases.

Global Psoriasis Atlas Phase II (GPA 2020-2023)

Grantee: Professor Chris Griffiths, University of Manchester

Amount: DKK 8,000,000

Grant category: Strategic grants

Year: 2020

Geography: United Kingdom

Psoriasis is a significant, life-long and currently incurable skin disease, which, according to the first edition of the Global Psoriasis Atlas (GPA), affects at least 60 million people worldwide.

The need to understand and uncover how psoriasis impacts both the individual and society at large is in demand. The Global Psoriasis Atlas is a long-term project that seeks to become the ‘go-to’ evidence-based resource within the understanding of psoriasis and its effects on people and society all over the World.

GPA Phase II (2020-2023)

The GPA Phase II  is focused on continued research to establish robust data that address existing knowledge gaps within psoriasis on epidemiology, improving diagnosis, comorbid disease and economic impact.

Furthermore, if sufficient and robust data are available, the plan is to perform a pilot implementation study as part of GPA Phase II.

Addressing these key areas and how they differ between countries and regions will support the aim to provide better access to care for people with psoriasis worldwide.

Background

With a mission to ‘ensure that people with psoriasis, wherever they live in the world, have access to the best available care. The grant for the first version of the GPA was granted to Professor Griffiths and the University of Manchester in 2016.

The LEO Foundation has been main funder of the development of the first edition of the GPA through a 3-year grant of DKK 6,370,000 from 2017 – 2020. The GPA project has in its first three years focused on research into the global prevalence and incidence of psoriasis – resulting in the first edition of the GPA website which can be accessed free of charge here: Global Psoriasis Atlas online

The LEO Foundation Award 2020 – Region EMEA

Grantee: Dr. Ning Xu Landén

Amount: USD 100,000

Grant category: LEO Foundation Awards

Year: 2020

Geography: Sweden

Ning Xu Landén is an Associate Professor in experimental dermatology and venereology at the Department of Medicine, Solna at the Karolinska Institute in Sweden where she leads a successful research group. She is the author of around 50 scientific articles with more than 3000 citations.

Ning Xu Landén receives the award in recognition of her high impact research in wound healing.

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The LEO Foundation Award 2020 – Region Americas

Grantee: Dr. Ya-Chieh Hsu

Amount: USD 100,000

Grant category: LEO Foundation Awards

Year: 2020

Geography: USA

Ya-Chieh Hsu is the Alvin and Esta Star Associate Professor at the Department of Stem Cell and Regenerative Biology at Harvard University, Cambridge, USA.

Ya-Chieh Hsu receives the award in recognition of her research achievements in studying cell-cell interactions and how systemic changes in the body influence these interactions in the skin.

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The LEO Foundation Award 2019 – Region Asia Pacific

Grantee: Dr. Tetsuro Kobayashi

Amount: USD 100,000

Grant category: LEO Foundation Awards

Year: 2019

Geography: Japan

Dr. Tetsuro Kobayashi is a Research Scientist at the Laboratory for Innate Immune Systems, RIKEN, Center for Integrative Medical Sciences (IMS), Yokohama, Japan.

Dr. Tetsuro Kobayashi receives the award for his research in understanding the interaction between microbes and the immune system in skin.

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The LEO Foundation Award 2019 – Region EMEA

Grantee: Dr. Shoba Amarnath

Amount: USD 100,000

Grant category: LEO Foundation Awards

Year: 2019

Geography: United Kingdom

Shoba Amarnath is a Research Fellow at the Institute of Cellular Medicine at Newcastle University, UK

She receives 100,000 USD for her research in the field of immune tolerance in cutaneous inflammation.

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