Towards the targeted phage-based nanodelivery of genome editing complexes to render pathogenic skin bacteria harmless

Grantee: Associate Professor Nicholas Taylor, Faculty of Health and Medical Sciences, University of Copenhagen

Amount: DKK 2,996,539

Grant category: Research grants in open competition

Year: 2019

Geography: Denmark

Bacterial skin infections are caused by bacteria that rely on several proteins to be infectious and resist antibiotic treatment. These proteins are encoded in the genome, or DNA, of the bacteria.

The specific knockout of these genes by genome editing has been shown to inhibit pathogenic bacteria, but delivery of the complexes that perform these modifications is still a major challenge.

To overcome this hurdle, we propose to use the large protein-injecting bacteriophage (a virus that can infect a bacterium) to inject a genome editing complex into bacteria. We will investigate the structure of the bacteriophage, to better understand which parts we can modify. We will exchange the recognition target of the bacteriophage, so that it can specifically bind to a bacterium of choice.

Additionally, we will modify the large protein of the bacteriophage that it normally injects, and replace it with a genome-editing complex: this will allow the targeted destruction of the DNA fragments in the bacterium that encode a protein that allows it to survive antibiotic treatment.

Life with Neurofibromatosis type 1

Grantee: Jeanette Falck Winther, Professor, Consultant, MD, DMSc; Danish Cancer Society Research Center (DCRC)

Amount: DKK 3,996,784

Grant category: Research grants in open competition

Year: 2019

Geography: Denmark

Neurofibromatosis type 1 (NF1) is a progressive genetic disorder characterized by changes in skin and growth of tumors along nerves in the skin and other parts of the body.

The clinical signs of NF1 are well‐described, but the impact of NF1 on the daily life and the burden of treatment is less studied.

By combining data from nationwide registries and questionnaires, we will assess drug use and surgery in individuals with NF1, socioeconomic consequences of living with NF1 as well as predictors of quality of life. Patients with NF1 are identified in the Danish National Hospital Register and from two National Centers of Rare Diseases at Copenhagen University Hospital, Rigshospitalet, and Aarhus University Hospital.

Outcomes in 2,517 individuals with NF1 (drug use, surgical procedures, employment status, income, social security benefits and ninth school grades) will be compared to those in a healthy comparison group. In a sub‐group of 244 adults with NF1, we will examine how these specific outcomes will impact quality of life. Individuals with NF1 are particularly vulnerable for a lower living standard and prosperity with extensive costs for the society.

We believe that the results of these studies will add a major contribution to the NF1 research field as well as improve our understanding of the implications this complicated disease may have on life. The clinical information provided by these large nationwide studies is highly requested by the patients and their families but also by the clinicians advising these patients.

Long-term improvement of psoriasis patients’ adherence to topical drugs: Testing a patient-supporting intervention delivered by healthcare professionals

Grantee: Mathias Tiedemann Svendsen, PhD, Specialist in dermato-venereology; Odense University Hospital

Amount: DKK 2,200,000

Grant category: Research grants in open competition

Year: 2019

Geography: Denmark

Psoriasis affects 2-4% of the Western adult population and is a socio-economic burden for patients and society.

Topical drugs are recommended as first-line treatment for mild to moderate psoriasis, but low adherence is a barrier for treatment success.

There is a need for improved patient support for psoriasis patients, which is suggested to improve long-term use of topical drugs.

The project aims to test whether a patient-supporting intervention delivered by healthcare professionals can improve the use of topical drugs.

The intervention design is based on experiences with previous adherence-improving studies consisting of digital support by conducting a systematic literature search and holding focus groups with patients as well as healthcare professionals. The intervention consists of shared decision-making with patients, nurses and doctors, frequent consultations, easy access to healthcare professionals through video or in-office consultations and holding patients accountable for taking the medication.

The intervention will be tested in a randomized controlled trial: during a 1-year period, a group of patients (18-75 years of age) diagnosed with mild-to-moderate psoriasis and treated with topical drugs will be randomized to an intervention (n=65) or non-intervention group (n=65).

The primary outcome will be primary adherence (i.e., rate of filled prescriptions) and secondary outcomes a reduction in the severity of psoriasis and cost-effectiveness. If the intervention can reduce the severity of psoriasis in a significant manner and is cost-effective, there is a potential for a national implementation of the intervention.

Single Cell Sequencing Instruments – Add-on grant for LEO Foundation Skin Immunology Research Center

Grantee: University of Copenhagen

Amount: DKK 15,296,667

Grant category: Strategic grants

Year: 2019

Geography: Denmark

Researchers in immunology, cell biology and cancer were first movers in single-cell sequencing when they demonstrated a huge potential of this novel technology to unravel novel cell populations and disease heterogeneity.

This approach has gained further momentum fueled by new, exiting studies in neurobiology and rheumatology. So far, single-cell sequencing has not been used in relation to skin diseases – with few exceptions such as our new study on single-cell sequencing in cutaneous T cell lymphoma (CTCL) – the first paper of its kind – which was rapidly followed by three additional papers on single-cell sequencing in CTCL.

Moving from investigating an average of molecular changes in thousands or millions of cells to the study of changes in the transcriptome in single cells is critical to obtain a deeper and more precise understanding of disease heterogeneity and novel disease mechanisms. In other words, single-cell sequencing is expected to become the novel golden standard in all areas of research related to immunology and inflammation including the scientific focus area of the LEO Foundation Skin Immunology Research Center.

The “package” provides the sufficient capacity to conduct state-of-the-art single-cell analysis in the key areas of the LEO Foundation Skin Immunology Research Center. In order to get maximal advantage, value, and rapid implementation of the instruments, we will employ a novel protocol for this platform to run up to 5 different modalities (mRNA, TCRab, TCRgd, surface proteins, sample hashing and CRISPR lead sequences) in parallel to top-tune the technology.

Defining the mode of action of hydrocortisone on stem cell fate decisions in the epidermis

Grantee: Kim Jensen, Professor, BRIC, University of Copenhagen

Amount: DKK 2,754,990

Grant category: Research grants in open competition

Year: 2019

Geography: Denmark

Long-term topical application of steroids such as hydrocortisone have severe skin side effects. Here treatments lead to thinning of the outer layer of the skin, reduced production of natural moisturisers and an increased risk of skin ulceration.

We hypothesise that an increased understanding of how hydrocortisone exerts its effect on skin cells will help us understand why hydrocortisone treatment causes these adverse effects and also aid the development of treatments that can bypass these.

Here we propose to take advantage of exciting new methods we have developed, where we can measure how cells behave within the skin and thereby quantify exactly how hydrocortisone affects cell turnover. This analysis will be combined with detailed studies for how hydrocortisone function at the mechanistic level in order to identify potential new therapeutic targets. Such therapies could be used to help patients receiving long-term hydrocortisone treatment.

Engineering 3D bio-printed physiologically accurate human skin for basic and clinical research

Grantee: Jonathan Brewer, Associate professor, University of Southern Denmark

Amount: DKK 3,972,150

Grant category: Research grants in open competition

Year: 2019

Geography: Denmark

This project focuses on development of 3D bio-printed physiologically accurate human skin, which has important applications both clinically and for research.

3D printed human skin can be used in pharmacological and cosmetic testing, disease modelling, basic skin biology research, but also it can potentially save lives by providing skin grafts for burn or accident victims.

However, the current 3D printed skin is frail and prone to rupturing and does not recapitulate the native tissue. By combining quantitative imaging of intracellular junctions and cytoskeletal components at the sub-cellular, cellular and tissue levels in a rapid in vivo model and human 3D skin cell culture with direct measurements of tissue stiffness, we will deliver the most detailed description yet of the mechanical regulation and barrier properties of the skin.

Next, we will determine how the mechanical properties of skin change upon application of physical stimuli and if we could imitate the mechanical response by molecular perturbations.

Finally, we will identify and verify novel molecular players that set the mechanical properties of skin by unbiased single-cell sequencing of fragile and elastic tissues.

These results will be used to develop artificial 3D skin which more accurately represent human skin than current models. This interdisciplinary proposal is a crucial step forward in entering an era where animal experiments and transplants are replaced by synthetic organs printed for patients on demand.

Bloom Festival 2020-2021

Grantee: Svante Lindeburg, Golden Days

Amount: DKK 1,000,000

Grant category: Education and awareness grants

Year: 2019

Geography: Denmark

Bloom – at the core:

Bloom is an innovative festival about science and nature, which enlighten us on the Universe, the World and Ourselves. Framed in the lush Søndermarken at Frederiksberg in the heart of the capital city of Denmark, where some of the World’s greatest scientists, poets and philosophers have found inspiration through history, Bloom emerges each Spring as a sensual, experimental and thought-provoking festival version of natural sciences.

By uniting the best from the world of festivals with the best from the scientific world, Bloom arm wrestles with Life’s greatest questions and over two days invite the audience to debates, talks, laboratories, conversations and nature walks under open skies.

Big Bang 2020-2021 – support for Denmark’s largest science conference

Grantee: Mikkel Bohm, Astra*, the national Centre for Learning in Science, Technology and Health in Denmark

Amount: DKK 2,000,000

Grant category: Education and awareness grants

Year: 2019

Geography: Denmark

Denmark’s largest science conference, the Big Bang Conference, has received DKK 2,000,000 for the period 2020-2021 from the LEO Foundation.

Big Bang is the largest Danish science conference and exhibition targeted all who teaches, facilitates or researches in the science and science fields – in primary and secondary schools and higher education.

The conference, held once a year, gathers more than 1,000 people for two involving and inspiring days with relevant keynote speakers, a humming exhibition atmosphere, involving workshops and novel ideas for the continued renewal of science education.

www.bigbangkonferencen.dk

GWA studies on common dermatological diseases

Grantee: Professor Gregor B. Jemec, Department of Dermatology, Zealand University Hospital, Roskilde, and Assoc. Professor Ole B. V. Pedersen, Department of Clinical Immunology, Næstved Hospital

Amount: DKK 5,770,000

Grant category: Research grants in open competition

Year: 2018

Geography: Denmark

In this study, the group led by Professor Gregor Jemec of Roskilde Hospital has set out to identify new genes for the development of a long line of common dermatological conditions, including deep skin infections, warts, fungal infections, and eczema.

Many of these common skin diseases are still poorly understood and the treatments often insufficient. A study of the genetics of these disorders will help increase the understanding of the pathogenic mechanisms. The study will have its origin in Denmark and be based on unique national biobanks, national registries, and with extensive genetic analyses done in collaboration with deCODE Genetics, Iceland.

This is possible due to the growing number of Danish large-scale biobanks as well as biobank based scientific studies suited for further genetic studies. The largest genetic study in Denmark is the Danish Blood Donor Study (DBDS) in which the genome wide association (GWA) arrays have been analysed on 110,000 research participants.

In addition to this cohort, Jemec’s group is currently pursuing genetic testing on the Copenhagen Hospital Biobank (CHB) that includes samples from around 350,000 patients. Both of these biobanks have established a collaboration with deCODE Genetics, Iceland – one of the leading genetic research centers in the world.

 

Project Group

Henrik Ullum, Professor, Department of Clinical Immunology, Rigshospitalet

Søren Brunak, Professor, Center for Protein Research (CPR), Copenhagen University

Simon Francis Thomsen, Professor, Department of Dermatology, Bispebjerg Hospital

Claus Zachariae, Professor, Department of Dermatology, Gentofte Hospital

 

International affiliations

Ingileif Jonsdottir, Professor, deCODE Genetics, Iceland

Errol Prens, Professor, Department of Dermatology, Erasmus University, Rotterdam, Netherlands

Christos Zouboulis, Professor, Department of Dermatology, Brandenburg Medical School Theodor Fontane, Dessau, Germany

Development of biomarkers and models for wound infection

Grantee: Mariena van der Plas, University of Copenhagen, Faculty of Health and Medical Sciences, Department of Pharmacy

Amount: DKK 2,745,375

Grant category: Research grants in open competition

Year: 2018

Geography: Denmark

Proper wound healing is a fundamental survival mechanism and dysfunctions cause significant disease, such as seen in infections after burns, trauma and surgery, as well as in non-healing ulcers.

Currently, the prevalence of non-healing wounds is estimated to be over 40 million worldwide, a number projected to rise with 6-9% annually, due to aging of the population and the increasing incidence of diseases that contribute to nonhealing ulcer development, such as obesity and diabetes.

There is a great and unmet need for novel treatments for improved healing, and thus better predictors for wound healing outcomes are essential. Given the importance of innate immunity and microbial interactions for development of impaired wound healing, the aim of this project is to define novel prognostic and diagnostic biomarkers for assessment of wound healing and infection risk.

For this purpose, we will use state-of-the-art techniques for peptidomics mass spectrometry. This unique approach, without the classical trypsin digestion of the samples, will give actual insight in processes occurring in the wound bed, e.g. enzymatic activity, infection, inflammation, and angiogenesis, instead of just reporting the presence of a protein, independent of the state it is in.

Furthermore, we will set up biological models for validation of biomarkers, as well as novel treatments. Together, the outcomes of these studies have the potential to improve diagnostic evaluations of wounds, and will enable us to develop novel treatment concepts for early prevention of infection, leading to improved healing results for large and significant patient groups.