Repairing the skin barrier in Junctional Epidermolysis Bullosa (Caley 1)
Completed| Project lead | Dr Matthew Caley |
| Organisation | Queen Mary University of London, Centre for Cell Biology and Cutaneous Research, London, UK |
| Partner organizations & collaborators | Prof. Edel O’Toole, Queen Mary University London, UK |
| Project budget | GBP 152,122.00 (main funding provided by LifeArc, co-funding of EUR 25,000.00 by DEBRA Austria) |
| Start date / Duration | 01. Sep 2020 / 28 months |
| Funder(s) / Co-Funder(s) | DEBRA Austria, LifeArc |
| Research area | Symptom prevention & relief |
Project details
Short lay summary
Junctional epidermolysis bullosa (JEB) is a rare genetic skin disorder leading to severe skin fragility from birth, caused by the loss of skin basement membrane proteins that anchor the outer layer of the skin to the rest of the body. The most severe form, JEB generalised severe, is caused by complete loss of one of the parts of laminin 332 a key component of the basement membrane. Babies diagnosed with this form of JEB do not survive beyond their first birthday.
We have discovered a previously unreported characteristic of JEB skin, a loss of cholesterol from the skin of JEB patients. Within the skin, cholesterol plays an important role in maintaining the skin barrier preventing water loss, skin infection and dry skin-related itch.
Scientific summary
Our recent work demonstrated that JEB cells can make cholesterol but are unable to transport it out of the cell which leads to the loss of lipids within JEB skin. The loss of laminin 332 from the skin basement membrane disrupts the actin cytoskeleton which is vital for the movement of cholesterol within the skin. We have developed models of JEB skin that allow us to investigate cholesterol transport. We propose to use these models to identify drugs that are able to restore cholesterol transport in JEB. We will then test these positive hits in more complex 3D JEB skin models and finally, we will use a JEB mouse model to identify future treatments for JEB patients.
Strategic relevance
Blistering in JEB patients may lead to scarring which, over time, can result in granulation tissue — red, bumpy skin that is easily damaged and can bleed profusely, increasing the risk of infection, dehydration, and the loss of other essential proteins and minerals. This project explores at the pre-clinical stage, the potential of drugs to restore cholesterol in JEB skin and reconstitute a functional skin barrier that would minimise water loss and infection.
What did this project achieve?
The research project developed pre-clinical data demonstrating that the skin barrier in JEB is disrupted and that it can be restored through use of a repurposed drug. In addition to restoration of the skin barrier the group demonstrated reductions in proliferation and inflammation after drug treatment.The research team continues to investigate the potential of restoring the skin barrier as a treatment for JEB.
The project allowed the group to establish a drug testing pipeline for JEB which includes 2D high throughput screening, large scale 3D in vitro JEB skin models and in vivo testing in an inducible mouse model of JEB. They are using this pipeline to test other repurposed drugs as well as recombinant protein treatments for JEB. The tools developed in this project are being used in five research projects investigating EB (£850,000 of funding), three PhD studentships and two postdoctoral research projects. The strength of research in EB at QMUL has led to the establishment of a EB Research Hub at QMUL, developing our research collaborations and ensuring sharing of data and research resources.