Granzyme B: A novel therapeutic target in cutaneous leishmaniasis

Grantee: David Granville, Professor, University of British Columbia

Amount: DKK 2,023,506

Grant category: Research grants in open competition

Year: 2020

Geography: Canada

Cutaneous leishmaniasis (CL) is a designated ‘WHO top-neglected tropical disease’, with up to 1 million new cases worldwide annually. CL is an inflammatory skin disease caused by infection with Leishmania parasites that leads to tissue damage, ulcers, and severe scarring, despite current treatment options.

The goal of this project is to provide a key rationale for pursuing Granzyme B (GzmB) as a novel therapeutic target for the treatment of cutaneous leishmaniasis. 

GzmB is a protein that is aberrantly elevated in CL lesions and other inflammatory skin conditions. GzmB activity has been demonstrated to cleave important proteins in the skin, thereby worsening tissue damage, delaying wound healing, and causing scarring in inflammatory patient skin specimens and in experimental models. Importantly, inhibition of GzmB has shown efficacy in delaying these disease phenotypes.  

Using lesional specimens from CL patients, a well-established experimental model, and a GzmB inhibitor, the contributions of GzmB to inflammation, impaired wound healing, and scarring in CL will be delineated in this study. 

Investigation of genetic variation and development of genetically defined cell models for Acne vulgaris therapeutic and cosmetic products evaluation

Grantee: George Church, Professor at Harvard Medical School, Harvard University and MIT, Cambridge, MA

Amount: DKK 3,926,475

Grant category: Research grants in open competition

Year: 2020

Geography: USA

Summary available soon.

Deciphering the functional role of circular RNAs in psoriasis

Grantee: Lasse Sommer Kristensen, Associate Professor, Department of Biomedicine, Aarhus University

Amount: DKK 2,467,477

Grant category: Research grants in open competition

Year: 2020

Geography: Denmark

This project aims to answer key questions related to a recently discovered new class of biomolecules, called circular RNAs. These RNA molecules appear to have an important role in early immune responses and the project aims to functionally characterize them in psoriasis patients and compare the results with data from healthy controls.

To study the RNA molecules, the project uses a combination of traditional molecular biology approaches and high-throughput technologies such as RNA-sequencing and NanoString technology.

In summary, this project aims to shed light on the distribution and functional relevance of circular RNAs within psoriatic plagues as well as in normal skin and potentially open new avenues for better treatment and management of psoriasis.

Atopic dermatitis in Sub-Saharan Africa: exploring immune phenotypes and mycobiome

Grantee: Marie-Charlotte Brüggen, Assistant Professor, University Hospital Zürich

Amount: DKK 1,886,076

Grant category: Research grants in open competition

Year: 2020

Geography: Switzerland

The goal of this project is to improve the understanding of atopic dermatitis (AD) in Sub-Saharan Africa by characterizing the immune responses and potential changes in the associated skin and gut mycobiome (the composition of fungi found in a defined area) in AD patients from a dermatological clinic in Moshi, Tanzania. Subsequently, the results will be compared with equivalent data from Central European AD patients to identify similarities and differences.

As previous studies in this area is practically non-existing, this study will be a first step towards understanding the immune phenotype of Sub-Saharan Africa AD and how environmental factors like the fungi of the skin and gut could influence it. This will be important with regard to future treatment options of AD in the region.

Molecular investigation of CCL5-hi chronic adult rashes (CCARs)

Grantee: Raymond Cho, Associate Professor, Dermatology, School of Medicine, University of California San Francisco, CA

Amount: DKK 3,330,056

Grant category: Research grants in open competition

Year: 2020

Geography: USA

This project aims to characterize a newly identified type of persistent rashes which resemble both eczema and psoriasis, but which differ at the molecular level.

Initial single-cell genetic screening of relevant immune cells from the rashes has identified a strong overlap in their genetic profile – especially in the expression of two specific cytokines, CCL5 and IL32 – cytokines are substances that are secreted by certain cells of the immune system and have an effect on other cells. At the same time, the classical markers of both atopic dermatitis and psoriasis are absent, suggesting that these rashes indeed may represent a novel condition.

The project aims to further identify and substantiate the genetic profiling by studying a larger patient population and link this to dupilumab treatment outcomes in order to stratify and optimize the treatment options available for this patient population.

Protein aggregation in host defense and skin inflammation

Grantee: Artur Schmidtchen, Professor, Dermatology and Venereology, Department of Clinical Sciences, Lund University

Amount: DKK 2,100,000

Grant category: Research grants in open competition

Year: 2020

Geography: Sweden

The primary goal of this project is to identify and characterize the ‘aggregatome’, which describes the complete and complex network of proteins that are involved in the specific mechanism where the body – via its immune system – protects itself e.g. from bacteria. Subsequently, the project will explore and define the roles of the ‘aggregatome’ in inflammatory skin diseases.

The ultimate goal is to obtain new and deeper understanding of diseases affected by protein aggregation and potentially identify biomarkers of diagnostic significance.

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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