Determining the role of retinoic acid metabolism in acne treatment: Genetic and small molecule blockade of CYP26 in the Rhino mouse model of cystic acne

Grantee: Professor Martin Petkovich, PhD
, Cancer Research Institute Queen’s University, Kingston, Ontario

Amount: DKK 2,180,000

Grant category: Research Grants in open competition

Year: 2017

Geography: Canada

Retinoids have been used in the treatment of skin disorders for many years, particularly for hyperkeratotic diseases such as ichthyoses, psoriasis, and severe acne. Retinoid agonists are potent modulators of epidermal proliferation and differentiation, but are also associated with several side effects including hypertriglyceridemia, fatty liver, and teratogenicity.

In this project, it is believed that selective modulation of the activity of the so-called CYP26 enzymes present in skin cells and involved in inactivation of retinoic acid (RA) could provide a route to safer, equally effective treatments.

More specifically, the project uses a two-pronged approach in which:

1) The role of CYP26 is evaluated by genetic knock-out, and

2) The effect of topical administration of CYP26 inhibitors is investigated, arguing potential advantages over existing therapies by limitation of systemic increase in RA since inactivation of the enzyme is limited to the target tissue

Moreover, the project aims at showing that topical CYP26 inhibitor application is superior to topical RA agonists as the latter may induce CYP26 expression that, on repeated dosing, can limit their effectiveness; this would not be the case for CYP26 inhibitors.

Replicating peeling skin diseases in a living skin model

Grantee: Professor Peter R Hull, PhD (Med) FRCPC. Head, Division of Clinical Dermatology and Cutaneous Science, Dalhousie University, Halifax, Nova Scotia

Amount: DKK 2,180,881

Grant category: Research Grants in open competition

Year: 2017

Geography: Canada

A number of chronic skin conditions have peeling of the skin as the dominant expression; akin to skin peeling following severe sunburns. In the chronic conditions, peeling is cyclical or continuous, often affecting hands, feet, or the body. Today, there is no effective treatment for these conditions, leaving patients subjected to trial and error with a variety of non-effective and often also expensive therapies.

A number of abnormal gene variants have been found to disrupt the normal maturation of the skin. Using a gene manipulation tool known as CRISPR, the team led by Dr Hull will build understanding of the role of four known genes causing skin peeling syndromes. This will be done by replicating the diseases in cell cultures grown into full thickness skin and studying the cellular and biochemical changes caused by the induced gene modifications.

Of particular interest is cathepsin B, an enzyme that has been found to play an important role in peeling associated with the skin disorder, keratolytic winter erythema.

The team’s hypothesis is that there is an important and dynamic interplay and balance between a number of enzymes in the outer layers of the skin and that if this balance favours the activity of cathepsin B, peeling results.

If this is shown, it may be clinically very relevant as there are a number of known compounds that inhibits cathepsin B and which then could be used to treat patients with chronic peeling as a consequence of their skin disorder.