Developing a Cell-Based Therapy for Alopecia

Grantee: George Cotsarelis, Perelman School of Medicine, University of Pennsylvania, Philadelphia

Amount: DKK 3,793,808

Grant category: Research Grants in open competition

Year: 2018

Geography: USA

Androgenetic alopecia (AGA, Male or Female Pattern Baldness) is the most common type of hair loss, affecting approximately 50% of men and 30% of women by the age of 50.

Current therapies, including pharmaceutical and surgical interventions, are either marginally effective or expensive with significant limitations. Over the last decade, breakthroughs made in the field of adult stem cells have laid the foundation for a cell-based approach to tissue and organ regeneration. Cell-based therapies will comprise a new wave of medical breakthroughs.

In this study we propose to produce human hair follicles from induced pluripotent stem (iPS) cells by directing these cells to form the two types of cells that are needed for human hair formation, namely the human hair follicle epidermal cells and the hair inductive dermal fibroblasts.

We will combine our hair biology and tissue-engineering expertise to generate early stage human hair follicles in culture that can be implanted into an animal model to grow into a mature hair. The long-term goals are to develop an innovative cell-based treatment for hair loss and an in vitro platform for testing hair growth compounds.

Psoriasis: a microbiome-driven disease?

Grantee: Patrick Zeeuwen, Radboud University Medical Center, Nijmegen

Amount: DKK 2,545,944

Grant category: Research Grants in open competition

Year: 2018

Geography: Netherlands

Psoriasis is highly prevalent and has a significant medical and socio-economic impact.

The prevailing dogma has been that abnormalities of the adaptive immune system were primary, but genetic studies have highlighted the importance of local skin-specific factors. We and others have identified epidermis-specific innate immunity genes, like beta-defensins and Late Cornified Envelope (LCE) genes, to be associated with disease development.

We recently made two exciting observations. First, deletion of LCE3B and LCE3C does not merely imply the loss of two genes but has a genomic effect that leads to a strong induction of the flanking LCE3A gene. Secondly, we found that LCE proteins, and LCE3A in particular, have broad-spectrum antimicrobial activity. We hypothesize that the LCE3B/C-del status affects the cutaneous host defense repertoire thereby shaping the skin microbiome. We aim to investigate the biology of LCE genes and to translate these findings to our understanding of psoriasis pathogenesis.

Key objectives are to:

  1. assess the antimicrobial activity and specificity of all LCEs and their synergy with other antimicrobial proteins. This will be investigated by metagenomic approaches and classical in vitro microbiological assays, using recombinant and synthetic LCE proteins and peptides derived thereof
  2. investigate LCE3B/C-del in isogenic 3D-skin equivalents in vitro generated from the immortalized human keratinocyte N/TERT cell line. Deletions of other LCE genes or their regulatory sequences will be made using CRISPR/Cas9 technology. Effects on epidermal biology relevant to psoriasis will be studied and include antimicrobial host defense, innate immune response and skin barrier function

The 2019 Gordon Research Conference on Epithelial Differentiation and Keratinization (GRC-EDK)

Grantee: Valentina Greco, Yale University, New Haven, Connecticut

Amount: DKK 146,536

Grant category: Education and Awareness Grants

Year: 2018

Geography: USA

The 2019 Gordon Research Conference on Epithelial Differentiation and Keratinization (GRC-EDK) is the premier international meeting in epithelial biology since 1979. It showcases the latest conceptual and technological advances in epithelial biology bridging basic and translational research.

This 2019 meeting entitled “Innovations in basic and translational epithelial biology” aims to bring together preeminent speakers at the forefront of epithelia development, stem cell biology, cell biology, pathology and therapy.

The main objective is to discuss latest developments and generate synergistic approaches towards future discoveries and therapeutic prospects. To ensure this, over 30% of speakers are from outside the immediate field, 50% did not speak in the 2017 meeting, and over 30% will be selected from submitted abstracts. Finally, a power hour will open a debate on ways to recognize and tackle discriminations in science.

Trainee mentorship will be promoted through the 4th Gordon Research Seminar on Epithelial Differentiation and Keratinization (GRS-EDK), immediately preceding the GRC-EDK. GRS meetings are organized and featured by trainee scientists providing a unique opportunity to discuss their research and develop life-long collaborations.

The GRS-EDK will also feature a career mentoring panel discussion with emphases on transitioning to independence, careers in academia versus industry, and the importance of gender and racial diversity within science. Collectively, this GRC/GRS will move forward cutting-edge research in the area of skin biology, promote translation of key research findings to clinical practice, and further the careers of early stage investigators to maintain the highest level of innovation of this field in the future.

Skin Proteomic Atlas – a spatially and cell-type resolved landscape of protein expression in the human skin

Grantee: Matthias Mann and Beatrice Dyring-Andersen, University of Copenhagen

Amount: DKK 100,000

Grant category: Education and Awareness Grants

Year: 2018

Geography: Denmark

The skin is an amazing and complex organ that comprises multiple layers and cell types that are functionally distinct.

The aim of this study is to characterize the molecular composition of the healthy human skin by creating an atlas of all the proteins expressed in healthy skin as a function of their spatial location as well as its major cell types.

This atlas, comprising the identification of a global proteomic composition of human skin, will provide an important resource to the community studying the physiology and cell biology of the skin and serve as a basis for future studies comparing the proteomes of inflammatory and oncologic skin diseases.

Publication of the skin atlas will be accompanied by a freely accessible and well-advertised web page portal where information on proteins of interest and their protein profiles in the layers of the skin will be easily available.

LEO Foundation Skin Immunology Research Center

Grantee: University of Copenhagen

Amount: DKK 250,000,000

Grant category: Standalone grants

Year: 2018

Geography: Denmark

Diseases of the skin affect a quarter of the population, more than a billion people, at any given time. Despite impressive progress, especially in the area of immunology in skin diseases, the pace of innovation is not sufficiently high and new treatments are slow to reach patients.

Here, we propose to create a LEO Foundation Skin Immunology Research Center (Skin Immunology Center) that will become a beacon for skin research in Denmark and worldwide.

The Center will identify key questions relating to disease heterogeneity, new pathological mechanisms, and novel therapies of inflammatory skin diseases. With the ultimate aim of helping people with skin diseases in the best possible way, we will launch a focused effort employing cutting edge technologies to advance biological insights and translate basic discoveries to ‘proof of principle’ and then to ‘first in man’ applications (‘bench-to-bedside’). Importantly, observations and questions arising in the clinic will be taken back to the laboratory (‘bedside-tobench’). This team science concept and ecosystem with seamless translation and back-translation between basic biology and the clinic will animate the spirit of the Center from day one.

The Skin Immunology Center will be headquartered at the 12th floor of the Mærsk Tower, the new flagship building at the Faculty of Health and Medical Sciences, University of Copenhagen.

We will bring together the immunology of the skin, its diseases and comorbidities, ‘omics’ technologies, experimental models, and strong clinical integration to develop new stratification paradigms and therapies towards precision medicine. People will form the basis of the success of the Center and we will both empower existing scientists and strategically hire new talent. We will build a pipeline of future top researchers through excellent educational activities. In this way, the Center will incubate and form a new generation of multidisciplinary skin immunology researchers, ready to reshape the field for decades to come.

From the start, we will collaborate across specialties, institutions and geographies. The Skin Immunology Center will aim to have a total of 60 members in the core member research groups when fully operational, a critical mass allowing it to contribute significantly to raising the level and quality of research and education in inflammatory skin diseases.

The existing LEO Foundation Center for Cutaneous Drug Delivery will become an associated and collaborating partner. The Skin Immunology Center will integrate and advance basic and clinical science approaches to skin disease and develop future leaders in the field, while increasing knowledge and awareness of skin and skin diseases among medical professionals, patients and the public.

Bloom Festival 2019

Grantee: Svante Lindeburg, Golden Days

Amount: DKK 500,000

Grant category: Education and Awareness Grants

Year: 2018

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.

Prepared and communicated by some of the brightest scientists, thinkers, and artists of our time from here and abroad. 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.

Investigating the tumor suppressive functions of Notch signaling during skin cancer initiation and progression

Grantee: Sunny Y. Wong, Assistant Professor, University of Michigan, Ann Arbor

Amount: DKK 2,486,354

Grant category: Research Grants in open competition

Year: 2018

Geography: USA

Basal cell carcinoma (BCC) is the world’s most common cancer and is defined by uncontrolled activation of the Hedgehog (Hh) signaling pathway.

Although previous studies have suggested that elevated Hh may be sufficient for BCC formation, mutations in the Notch pathway are also commonly observed. Furthermore, Notch-deficient mice are susceptible to forming BCCs, and our recent studies have shown that Notch can modulate tumor-drug response.

These studies seek to understand whether Notch affects multiple aspects of BCC tumorigenesis. Using a combination of animal studies and human BCC specimens, we will investigate how Notch modulates tumor progression and stem cell origin.

We will also model in mice a recent clinical trial, where Alzheimer’s patients treated with a Notch inhibitor reported increased incidence of BCC. We hypothesize that Notch may suppress tumorigenesis at multiple levels by controlling cell differentiation, apoptosis and turnover, similar to its function in normal skin and hair follicles.

These studies will ultimately build on the novel premise that BCCs may originate from a precursor lesion. Given that Notch mutations are the most commonly observed genetic aberrations in human skin, a deeper understanding of the tumor suppressive properties of this pathway is urgently needed.

Characterizing the disease memory in atopic dermatitis

Grantee: Patrick M. Brunner, Medical University of Vienna

Amount: DKK 2,920,541

Grant category: Research Grants in open competition

Year: 2018

Geography: Austria

Atopic dermatitis (AD), the most common chronic inflammatory skin disease, typically starts very early in life.

While many patients outgrow their disease, some develop chronic disease for the rest of their lives. Mechanisms responsible, however, are completely unknown, and no biomarker exists that can predict the course of the disease.

Thus, we want to compare skin from young adults that have outgrown their AD, with skin from patients with active disease (namely normal appearing AD under topical glucocorticoid treatment, which can be expected to flare up again after cessation of treatment, thus harbouring a “disease memory”).

Skin from healthy control subjects will serve as baseline comparators. Due to low immune cell numbers in this type of tissue, we want to use in vivo suction blistering of AD patients to obtain (i) skin resident immune cells and (ii) skin proteins. Suction blister fluid will be analysed with low cytometry and single cell RNAseq (for cells) as well as a proteomic multiplex assays (OLINK) for soluble proteins. The blister roof (i.e. the epidermis) will also be harvested, and keratinocytes will be stored in liquid nitrogen for functional experiments.

Results obtained from flow cytometry, single cell RNAseq and proteomic approaches will then be used for such functional in vitro experiments (e.g. co-culturing, skin equivalents, stimulation experiments) in future research projects.

Overall, we hope that the identification of cellular and/or molecular factors influencing the natural course of AD could possibly identify targets for novel therapeutic approaches in AD, that could induce long term remission – or even lead to a cure – of AD.

Compartmentalized and Systemic Interactions of the Skin Microbiome in Cancer Immunotherapy Response

Grantee: Julia Oh, Jackson Laboratory, Farmington, Connecticut

Amount: DKK 2,107,529

Grant category: Research Grants in open competition

Year: 2018

Geography: USA

My vision is to use metagenomics to better predict patient responses to immunotherapy and rationally design microbial adjuvant cocktails and engineered microbes to improve therapeutic outcomes.

However, a central question is the role of the local microbiota vs. systemic effects in potentiating these immunotherapeutics. In skin cancer, we have been studying how the skin microbiome affects predisposition and progression. Specific gut microbes have been implicated in the outcomes for immunotherapy response in melanoma skin cancer, supporting a role of systemic immune interactions via the gut in potentiating immunotherapy response.

However, because many aspects of cutaneous immunity are compartmentalized from systemic immune effects, we hypothesize that the skin microbiome could uniquely impact skin cancer outcomes during immunotherapy by modulating the cutaneous immune milieu.

The LEO Foundation Award 2017 – Silver Award

Grantee: Dr. Christoph Schlapbach

Amount: DKK 500,000

Grant category: LEO Foundation Awards

Year: 2017

Geography: Switzerland

The Silver Award went to Dr. Christoph Schlapbach, dermatology resident at the University of Bern in Switzerland.

“It is a great honour for me to receive the LEO Foundation 2017 Silver Award on behalf of my emerging research team. Together with the generous financial support, this prize motivates and supports our journey towards a better understanding of how the human skin functions,” said Christoph Schlapbach.