Developing deep understanding of atopic dermatitis

Grantee: Joel Dudley, PhD, Director of Biomedical informatics, Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, USA, and Jeanne Duus Johansen, MD, DMSc, Director National Allergy Research Centre, Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Denmark

Amount: DKK 11,100,000

Grant category: Research grants in open competition

Year: 2016

Geography: Denmark, USA

Atopic dermatitis (AD) and hand dermatitis are heterogeneous disease entities and there has yet to be developed a good understanding of their many different clinical aspects. Thus it remains extremely challenging to provide patients with better treatment outcomes and prognosis.

A newly formed team of scientists at Gentofte Hospital in Copenhagen and Mount Sinai in New York has set out to change this.

“Next generation sequencing and advanced bioinformatics technologies give us powerful new opportunities to explore and understand the molecular pathophysiology of atopic dermatitis and hand dermatitis,” said Dr. Joel Dudley, Director of Biomedical informatics at Icahn School of Medicine, Mount Sinai in New York.

“It is a study that has not previously been performed, and we expect to make a breakthrough in the understanding, classification and treatment of these skin diseases. We hope to improve our knowledge and understanding of the molecular basis of atopic dermatitis and hand dermatitis and their relation to clinical features. Consequently, we also hope to pave the way for improved opportunities for managing and preventing disease,” said Dr. Jeanne Duus Johansen from the Department of Dermato-Allergology at Gentofte Hospital.

She and Joel Dudley will lead a trans-Atlantic team of researchers working with high-throughput, genome-wide profiling of multiple of the ‘–omics’ modalities, including genome, transcriptome, epigenome, and microbiome.

The goal is to develop a deeper understanding of how the molecular manifestation of the heterogeneous diseases correlates with clinical variables such as onset of disease and treatment outcomes. The technologies employed by the team can provide comprehensive molecular profiles that can enhance the understanding of the system-wide mechanics and properties of complex biological systems.

Dudley’s team will integrate the ‘-omics’ data sets to clarify the complex biological mechanisms underlying disease. They will do so by connecting molecular profiles with clinical data to identify molecular surrogates of drivers of important clinical features of disease.

The study will build on previous efforts to assemble and characterise a Danish cohort of individuals affected by AD in adulthood and/or hand dermatitis. The proposed study will add important new dimensions of molecular information that will enable new insights into molecular mechanisms and features of disease. Furthermore, the team sees that an incorporation of molecular measures, namely microbiome and epigenome, may offer insight into environmental correlates or determinants of disease.

Finally, the team foresees that the data and results generated may serve as an important new asset to the AD and dermatology research communities.

“We believe that the data and results generated by our study will enable new research directions and insights into AD and dermatological disease. Furthermore, we believe that such future insights would be enabled by the unique availability of the proposed comprehensive multi-omics data set integrated with comprehensive clinical data and assessment of a large patient cohort,” said Dr. Jeanne Duus Johansen.

Cardiovascular risk in psoriasis – meeting a profound clinical need

Grantee: Joel Dudley, PhD, Director of Biomedical informatics, Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, USA, and Peter Riis Hansen, MD, DMSc, PhD, Consultant (invasive cardiology), Associate Professor, Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark

Amount: DKK 13,100,000

Grant category: Research grants in open competition

Year: 2016

Geography: Denmark, USA

Cardiovascular diseases (CVD), such as myocardial infarction and stroke, are leading causes of death globally. Independent of traditional risk factors, however, psoriasis patients run an increased risk of CVD, adding considerably to morbidity and mortality for this large patient group.

“Inflammation has been proposed as a part of the explanation for the association between psoriasis and CVD. However, when we look at the underlying pathophysiology and molecular drivers of this connection, they are unclear. It is also unresolved whether treatment responses for psoriasis alter the course of CVD. To us, this suggests that the connection with inflammation might be more complex than currently appreciated,” said Joel Dudley, Director of Biomedical informatics at Icahn School of Medicine, Mount Sinai in New York.

Together with Peter Riis Hansen, Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark, Dudley will lead a team focused on developing a much needed understanding between the molecular mechanisms of psoriasis and the increase in CVD comorbidity. Understanding these complex interactions between skin and cardiovascular health will lead to insights for future preventive treatments and improved prognosis.

The team will employ an array of modern high throughput technologies to bring together information about genetics, immunology, local gene expression, microbiomes, and more standard clinical measures to develop an unprecedented map of factors impacting cardiovascular health in psoriatic patients.

“We will apply sophisticated bioinformatics and network biology techniques to integrate the data and develop a disease network model that will enable both discovery and testing of novel hypotheses concerning biomarkers and pathogenic mechanisms. We believe that this disease network model will serve as a powerful and unprecedented resource for the dermatology, cardiology, and immunology research communities,” said Peter Riis Hansen.

More specifically, the model may facilitate the re-interpretation of data from previous studies and clinical trials, be queried by scientific and clinical investigators to evaluate novel clinical and molecular hypotheses, and inform new understanding of fundamental molecular mechanisms underlying the interplay between skin biology, immune function, and the immune-metabolic-cardiovascular axis.

The resulting disease network model may also uncover molecular mechanisms contributing to increased CVD risk in other immune disorders, such as rheumatoid arthritis, atopic dermatitis, and inflammatory bowel disease.

“We believe that the data generation activities alone would provide tremendous value to the research community, and that developments in data analysis and bioinformatics has the potential to increase exponentially our understanding of molecular mechanisms underlying CVD risk in inflammatory skin disease,” said Peter Riis Hansen.

Defining the epigenetics of rosacea

Grantee: Luis Garza, Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD

Amount: DKK 330,000

Grant category: Research grants in open competition

Year: 2016

Geography: USA

Rosacea affects many people around the globe and treatments could be better and more efficient. Defining new possible treatments will not only satisfy this clinical need, but also offer the opportunity to learn about the pathogenesis of rosacea and subsequent basic knowledge about skin biology.

The discovery of the role of the innate immunity in rosacea has generated many interesting new avenues for investigation.

The team led by Luis Garza points to the fundamental role of keratinocytes in disease pathogenesis as a critical insight given that keratinocytes, more than fibroblasts for example, contribute to innate immunity pathways.

This, they say, begs an interesting question: if keratinocyte turnover is so rapid such that entirely new cells are present every several months, how is the propensity for rosacea so robustly inherited from ‘mother’ to ‘daughter’ keratinocyte?

The team hypothesises that epigenetic lesions are more likely to explain the mostly adulthood acquisition of rosacea and the stability of disease in adulthood rather than DNA mutations. With this project, the team has the potential to generate data that can be used in academics and industry to measure improvements and severity of rosacea through its epigenetic profile.

LEO Foundation SPARK grants at Stanford

Grantee: Kevin Grimes, Director, SPARK Programme, Associate Professor, Chemical and Systems Biology, Stanford University, California

Amount: DKK 4,500,000

Grant category: Research grants in open competition

Year: 2016

Geography: USA

Bridging the gap between early research and clinical development is a challenging endeavour. There is an inherent risk that early-stage programs will fail during development, no matter how promising the science is.

Such nascent programs are unlikely to attract interest from industry until they have reached significant milestones, and very little funding is available from the NIH, foundations, or private enterprise for this critical transition.

The LEO Foundation SPARK donations at Stanford will help incubate and accelerate dermatology projects. SPARK is a unique partnership between university and industry targeted advancement of Stanford research towards development of new breakthrough therapies. SPARK provides access to specialised knowledge and technical expertise regarding drug and diagnostic development, dedicated core laboratory facilities, and sources of funding to support translational efforts.

The donations will be awarded as a supplement to the existing suite of support and funding from Stanford and will ensure that as many as 15 Stanford dermatology projects will be progressed towards human proof of concept.

It is expected that the grant will foster a renewed and unique focus on dermatology at Stanford University and enable a larger number of orphan drug research projects to reach actual clinical development.

The grant from the LEO Foundation is paid out in three equal portions in 2016, 2017 and 2018.

Learn more about the SPARK Program at Stanford University here.

Epithelial Differentiation and Keratinization Gordon Research Conference (GRC) and Gordon Research Seminar (GRS)

Grantee: Prof. Catharina (Carien) Maria Niessen, Department of Dermatology, University of Cologne, Germany; and Brenda Figueroa, Gordon Research Conferences, West Kingston, Rhode Island, USA

Amount: DKK 149,099

Grant category: Research grants in open competition

Year: 2016

Geography: Germany, USA

The 2017 Gordon Research Conference on Epithelial Differentiation and Keratinization (GRC-EDK), to be held May 6-12 in Italy, is the premier international meeting in epithelial biology.

It has been held biennially since 1979 with attendance from leading epithelial biology researchers, leaders from other fields, and early career scientists with innovative and exciting research programs to present and promote the latest conceptual, translational and technological advances in epithelial biology.

Today, the meetings take on stem cell biology, regenerative medicine, inflammatory skin diseases, skin cancer, epigenetics, and global genomics, and the program moreover explores developments in gene therapy, genome organisation, cell competition, stress responses as well as cutting edge advances in intravital imaging.

A third of the speakers are from outside the area in order to fuel new concepts and promote discussion of novel ideas, and more than a third of the oral presentations come from submitted abstracts to accommodate late breaking exciting stories and ensure speaking opportunities for young investigators.

To promote collaboration between academic medicine and industry the meeting also invites speakers from biotech and other academic scientists with strong industrial ties. Finally, the meeting will continue the commitment to trainee mentorship, including a career mentoring panel discussion with special emphases on careers in academia versus industry, and the importance of diversity within science.

Link to the meeting homepage.

Full thickness skin models from human pluripotent stem cells for identification and testing effectiveness of personalised therapies in atopic dermatitis

Grantee: Dr Dusko Ilic, MD, PhD, Reader in Stem Cell Sciences, Kings College London, Dr Reiko Tanaka, Lecturer, Department of Bioengineering, Imperial College, London, Dr Patrick Harrison, Senior Lecturer, Department of Physiology, University College Cork, Ireland, and Professor Theodora Mauro, MD, Professor of Dermatology, San Francisco Veterans Affairs Medical Center, USA

Amount: DKK 9,980,000

Grant category: Research grants in open competition

Year: 2016

Geography: Ireland, United Kingdom, USA

This is an exciting project that, with the international group’s extensive research and know-how in mind, has the potential to create an intriguing base for novel personalised treatments for atopic dermatitis (AD). The project moreover holds an innovation potential that may make it stand out in the emerging global bio-economy.

The prevalence of AD, an inflammatory skin disease resulting in itchy, red, swollen and cracked skin, is constantly increasing. Today, it affects 15-30 percent children and 2-10 percent adults worldwide, presenting a significant economic burden to healthcare systems.

There is no cure for AD, only soothing of the symptoms. In the majority of AD patients, the disease is a consequence of a blend of genetic defects of the skin barrier defects and abnormal immune responses influenced by environmental factors.

Until now, the models used to assess the interplay are not particularly predictive. The group behind this project aims to change this by using the latest advances in stem cell science, gene editing and tissue engineering to develop and validate innovative 3D in vitro models of skin – making the models similar to skin in AD patients by emulating full thickness skin of varying barrier integrity; faulty, partially repaired or intact, and immune response composition.

As part of the project, the group will also develop mathematical computer models to accurately address the predictive, prognostic and therapeutic outcome of personalised AD therapy – in order to address co-dependence of the quantitative and qualitative changes in skin barrier and activation of immune cells.

The 3D models will also be made available to test various novel therapeutic approaches for AD treatment in a patient specific manner.

Melanocyte stress response pathways and their role in the onset of vitiligo

Grantee: Prashiela Manga, PhD
, Associate Professor Dermatology and Cell Biology, New York University School of Medicine

Amount: DKK 5,037,192

Grant category: Research grants in open competition

Year: 2016

Geography: USA

Vitiligo, an acquired skin disease in which pigment cells, melanocytes, are destroyed, affects 1-2% of people worldwide. The disease deprives the skin of photoprotection leaving it more susceptible to solar damage and compromised cutaneous immunity – and the disease impacts physical and mental health.

Vitiligo is thought to occur in genetically susceptible individuals after being exposed to environmental triggers. Some individuals develop contact vitiligo after direct exposure to certain chemicals. As disease progression in vitiligo is independent from initiating factors, this subset of individuals makes it possible to study vitiligo at large.

The hypothesis in this project is that melanocytes from healthy individuals can withstand exposure to triggers by initiating a stress response regimen that allows the cell to return to homeostasis. These pathways may be disrupted in individuals who develop vitiligo, leaving melanocytes stressed following challenge, causing them to be targeted for removal by the immune system.

In order to investigate this hypothesis, the project will investigate survival pathways in melanocytes cultured from biopsies taken from pigmented skin from individuals who have developed vitiligo.

International Eczema Council

Grantee: Amy Paller, MS, MD, IEC President, Professor of Dermatology and Professor of Pediatrics, Northwestern University’s Feinberg School of Medicine, Chicago, and Emma Guttman-Yassky, MD, PhD, IEC President-Elect, Associate Professor of Dermatology & Immunology, Department of Dermatology, Icahn School of Medicine, Mount Sinai, New York

Amount: DKK 340,000

Grant category: Research grants in open competition

Year: 2016

Geography: USA

The IEC is convening a meeting at the ESDR in September 2015 to write a position paper on Atopic Dermatitis as a systemic disease.

In March 2016, the IEC will hold a session at the Annual AAD in Washington, D.C. focusing on AD phenotyping – starting to use biomarkers to assess subgroups of AD, which may be relevant to the understanding of disease and treatment decision-making.

Identification and Characterization of Key Itch Mediators and Receptors in Human Pruitus

Grantee: Professor Martin Steinhoff, University of California San Francisco

Amount: USD 388,225

Grant category: Research grants in open competition

Year: 2013

Geography: USA

Itch is probably the most common symptom in dermatology and it is associated with a significant impact on the patient’s life.

A team led by Professor Martin Steinhoff, University of California San Francisco, has set out to develop novel targeted therapies for chronic itch in humans.

Besides the lesional and non-lesional as compared to healthy skin, the project team will also identify critical itch mediators and/or receptors that are expressed (and activated) in human dorsal root ganglion (DRG) and spinal cord tissue. To address this, mediators will be identified as well as receptors associated with human itch, and thereby the team will be able to define “biomarkers” for the different pruritic human diseases.

The project will be the first-of-a-kind study to analyse the expression and distribution of key itch mediators and receptors in human skin, human DRG and human spinal cord, and will therefore provide a significant basis for future translational research that targets these mediators/receptors in the different subtypes of itch.

Moreover, it is the first time that it will be tested whether several new itch pathways that have been described in murine skin models are relevant, i.e. can be translated, in human disease state.

Defining the skin and blood biomarkers of pediatric atopic dermatitis

Grantee: Dr. Emma Guttman, MD, PhD, Associate Professor of Dermatology, Director Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine, Mount Sinai, New York

Amount: USD 1,046,400

Grant category: Research grants in open competition

Year: 2013

Geography: USA

Despite considerable impact on quality of life, atopic dermatitis, or eczema, has not been studied extensively in children although as many as one in five experience the condition. Atopic dermatitis, or eczema, is a chronic skin condition, characterised by itching and inflammation, and frequently occurs in people who have other allergic conditions, such as asthma and hay fever.

Dr. Guttman has set out to define the skin and blood biomarkers of atopic dermatitis in children. She and her team will investigate how skin biomarkers compare to disease activity, epidermal barrier function and known biomarkers in adults with atopic dermatitis. They will also investigate whether blood biomarkers could offer a less invasive way to monitor skin changes than a skin biopsy, which can be difficult to perform in children.

With better knowledge of what causes atopic dermatitis in children, the researchers hope to develop more targeted therapies for the disorder as well as for other atopic conditions, such as asthma and hay fever. Together, these three disorders form an “atopic triad”.

Publications:

Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)+ TH2/TH1 cell imbalance, whereas adults acquire CLA+ TH22/TC22 cell subsets

J Allergy Clin Immunol. 2015 Oct; 136(4): 941–951.e3.

Early-Onset Pediatric Atopic Dermatitis Is TH2 but Also TH17 Polarized in Skin

J Allergy Clin Immunol 138 (6), 1639-1651. 2016 Sep 23.

Alterations in B-cell subsets in pediatric patients with early atopic dermatitis

J Allergy Clin Immunol. 2016 Dec 10 pii: S0091-6749(16)31452-X

Accelerated T-cell activation and differentiation of polar subsets characterizes early atopic dermatitis development

J Allergy Clin Immunol. 2016 Nov;138(5):1473-1477.e5

An IL-17-dominant immune profile is shared across the major orphan forms of ichthyosis.

J Allergy Clin Immunol. 2017 Jan;139(1):152-165