Towards a personalized medicine approach for atopic dermatitis

Grantee: Dr Emma Guttmann, Icahn School of Medicine at Mount Sinai, New York

Amount: DKK 4,700,000

Grant category: Research grants in open competition

Year: 2017

Geography: USA

Atopic dermatitis (AD) is the most common inflammatory skin disease, with a prevalence in adults of 3% to 10% and a large unmet need for effective therapeutics.

Current clinical trials for AD patients assume a common disease mechanism. However, based on preliminary data, different therapeutics may be required to effectively treat different subsets of AD patients.

Biomarker-based studies show distinct clinical, and particularly molecular and cellular differences between different AD subpopulations such as African American, Chinese, and Indian AD patient populations.

However the characterization of the different and distinct clinical AD phenotypes is still at its very beginning. Indeed, there is high need of appropriate mechanistic studies to create a complete “molecular map” of AD across its different variants and hence to get a step closer for a personalized treatment approach.

Dr. Emma Guttman and her team at Icahn School of Medicine at the Mount Sinai Medical Centre, NY, USA, will seek a first time investigation to provide a systems biology approach for AD aiming to produce a molecular map of AD across its different subtypes.

The project integrates cellular and molecular biomarkers of lesional, but also non-lesional, skin and systemic inflammation to classify adult AD patients based on ethnic phenotypes, disease severity and age differences.

The proposal will set the stage for personalized therapy approach for AD based on skin and blood biomarkers and pathogenic variation of AD phenotypes related to severity, race/ethnicity and age.

Epidermal and Dermal Stem Cells in Psoriasis

Grantee: Markus Frank, MD, Associate Professor, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts; Christine G. Lian, MD, Assistant Professor, and George F. Murphy, MD, Professor, both Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts

Amount: DKK 3,000,000

Grant category: Research grants in open competition

Year: 2017

Geography: USA

Despite decades of research, the root cause of psoriasis remains unknown and targeted approaches to cure psoriasis have to date been elusive.

Psoriasis is a physically and psychologically devastating skin disorder affecting more than 7.5 million Americans, with global prevalence ranging up to 4.6%. The disease causes profound physical, emotional, and social burdens translating into massive healthcare costs.

Theories of the biological mechanisms behind the disease range from genetic and epigenetic deviations to acquired defects involving a plethora of cellular and mechanistic culprits, including epidermal cell kinetics, endothelial-leukocyte interactions and perturbations in dermal nerve fibres, mast cells, lymphocytes and dendritic cells.

However, even if it is clear that a multiplicity of cellular pathways is involved, the primary events that initiate and drive disease remain unknown.

The team behind this study proposes a novel hypothesis that psoriasis is driven by immune-mediated dysregulation of stem cells within the epidermal and dermal compartments.

In the course of the study, the team will, for the first time, test the skin stem cell hypothesis of psoriasis causation with a highly-focused goal of defining the primary event(s) in lesion formation, thus providing a foundation for future pre-clinical targeted therapeutic approaches designed to actually cure psoriasis.

Regulation of immunity by Calcitonin Gene-related Peptide through effects on endothelial cells

Grantee: Richard D. Granstein, MD, George W. Hambrick, Jr. Professor and Chairman, Department of Dermatology, Weill Cornell Medical College, NYC

Amount: DKK 3,252,204

Grant category: Research grants in open competition

Year: 2017

Geography: USA

Many observations suggest interactions between the skin immune system and the nervous system. Psoriasis and atopic dermatitis (AD), as examples, are believed to worsen with stress.

It has furthermore been shown that denervation of areas of human skin bearing psoriasis leads to improvement or resolution of the disease – and studies on mice have shown that an intact nerve supply is necessary for development of murine psoriasiform dermatitis.

The underlying mechanisms addressed in this project revolve around the Calcitonin Gene-related Peptide (CGRP) and the use of a novel, specifically targeted murine model.

Psychological stress increases the CGRP content of cutaneous nerves and dorsal root ganglia, and the team behind the project suggests that CGRP effects on the dermal microvascular endothelial cells may, at least in part, explain stress-exacerbation of Th17-mediated skin diseases such as psoriasis.

The LEO Foundation believes that the project can provide relevant insights into the role of the nervous system in regulating skin immune responses and thus provide a rational basis for developing novel drugs for modulation of skin immune responses.