Junctional epidermolysis bullosa(JEB) caused by mutations in basement membrane genes such as Laminin332 is among the most severe form of EB.Affected individuals suffer from blistering from birth leading to scarring, granulation tissue and susceptibility to infection. We have identified a new pathway altered in JEB,the regulation of cholesterol biosynthesis.The loss of Laminin 332 results in reduced lipid barrier due to loss of cholesterol transport within keratinocytes.Cholesterol biosynthesis and trafficking are fundamental processes in a wide range of cells and tissues especially in formation of the epidermal barrier. We have developed a cholesterol transport screening assay to analyse the ability of ten selected compounds to restore cholesterol transport in our in vitro model of JEB. Results of this small-scale screen identified 9 drugs that were able to restore cholesterol transport up to 50% of control. 6 drugs were selected for further analysis within our 3D skin equivalent model of JEB. Skin equivalents of normal skin and JEB skin were treated daily for 7 days with either DMSO or 1µM of selected drugs. In 3D 4 drugs displayed an increase in stratum corneum lipids shown by Nile Red staining above levels seen in the untreated JEB organotypics. Further analysis of skin differentiation by keratin, involucrin and tranglutaminase staining were assessed to narrow drug selection for further testing. These data also suggest that JEB is not just a disorder of epidermal-dermal adhesion, but a disorder of aberrant cholesterol trafficking causing a markedly impaired skin barrier. These findings suggests that drugs to target cholesterol transport within keratinocytes could be a beneficial treatment for JEB, helping to improve the crucial epidermal lipid barrier and prevent water loss and infection at the early stages of life.

ESDR191 - Junctional Epidermolysis Bullosa:Repairing The Epidermal Skin Barrier

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.