12 Jun Atopic Dermatitis- Eczema: New Therapeutic Approach Blocks Protein That Breaks Down Skin Barrier
MedicalResearch.com Interview with:
David Granville PhD, FAHA
Professor, Pathology and Laboratory Medicine, UBC
Associate Director, Vancouver Coastal Health Research Institute, VGH-UBC
Associate Director, BC Professional Firefighters Burn & Wound Healing Group, Department of Surgery, UBC
Principal Investigator, iCORD and UBC Centre for Heart Lung Innovation
MedicalResearch.com: What is the background for this study?
Response: Atopic dermatitis (aka. eczema) is a chronic inflammatory skin condition characterized by patches of dry, red, itchy skin. These patches can come and go – a process often referred to as ‘flare ups’. Often when these flare ups occur, people avoid going out, or to work, resulting in lost productivity and reduced quality of life. While the cause of these flare-ups is not completely understood, a loss of the skin’s protective barrier function is believed to be a triggering event. This is because the outer layer of skin (epidermis) acts as a barrier to allergens and other foreign entities from getting into the skin. When this outer barrier is lost, allergens are able to cross and penetrate the deeper layers of skin. This triggers an inflammatory response. The inflammatory response, in turn, can release factors that cause further disruption of the barrier thereby exacerbating the flare up.
The outer skin barrier can be thought of in terms of a brick wall in which the ‘bricks’, or skin cells in this case, are held together by a molecular ‘grout’ known as adhesion proteins. If these adhesion proteins, which tightly anchor the skin cells together, are lost, the skin becomes more permeable to the outer environment, allowing foreign antigens to enter in, and conversely, moisture to escape out resulting in skin dryness and shedding
MedicalResearch.com: What are the main findings?
Response: In the present study, published in the Journal of Investigative Dermatology, Dr. David Granville (Professor and Associate Director, University of British Columbia and Vancouver Coastal Health Research Institute) and colleagues identify an enzyme, Granzyme B, that accumulates specifically in the lesional skin of patients with atopic dermatis. This enzyme, called a protease, cleaves key proteins are essential for holding the skin together. When these proteins are cut by Granzyme B, the protective skin barrier function is lost. While a previous study by Kamata et al., (J. Dermatol. Sci. 2016) had reported that Granzyme B levels are positively correlated with increased itchiness and overall disease severity in patients with atopic dermatitis, they did not assess whether Granzyme B contributed to the disease. To further explore the role of Granzyme B in dermatitis, lead author Dr. Chris Turner, a post-doctoral fellow in Dr. Granville’s laboratory, set out to assess whether inhibition of Granzyme B would affect disease severity. What he found was that genetically knocking out the enzyme, or preventing its activity with a topical drug, prevented the loss of epidermal barrier function and significantly reduced disease severity. The study also showed that the topical drug could prevent the breakdown of proteins that are known to be reduced in dermatitis such as E-cadherin and filaggrin.
MedicalResearch.com: What should readers take away from your report?
Response: Granzyme B levels are correlated with itchiness and disease severity in eczema. The present study provides evidence supporting a new therapeutic approach for the treatment of dermatitis. While corticosteroids are sometimes used for this condition, long-term use is highly discouraged as they promote skin thinning and other serious side effects. The present work suggests topical Granzyme B inhibition may be safer alternative to corticosteroids.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Future studies will be aimed towards developing further proof-of-concept, safety data and clinical trials. Given the link between atopic dermatitis, asthma and hay fever, we are also excited by a recent study in the Journal of Clinical Investigation (May, 2020) in which extracellular Granzyme was proposed as a causative factor in childhood asthma. This could suggest that Granzyme B could play a larger, primary role in atopic march as an underlying factor linking the pathologies of these conditions.
Dr. Granville is a Co-Founder and serves as the Chief Scientific Officer of viDA Therapeutics. None of the other authors have any disclosures to declare. This work was supported by the Canadian Institutes for Health Research, Eczema Society of Canada and Michael Smith Foundation for Health Research.
Christopher T. Turner, Matthew R. Zeglinski, Katlyn C. Richardson, Stephanie Santacruz, Sho Hiroyasu, Christine Wang, Hongyan Zhao, Yue Shen, Roma Sehmi, Hermenio Lima, Gail M. Gauvreau, David J. Granville. GRANZYME B CONTRIBUTES TO BARRIER DYSFUNCTION IN OXAZOLONE-INDUCED SKIN INFLAMMATION THROUGH E-CADHERIN AND FILAGGRIN CLEAVAGE. Journal of Investigative Dermatology, 2020; DOI: 10.1016/j.jid.2020.05.095
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