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Mutation-independent therapeutic targets for treatment of epidermolysis bullosa simplex

Completed
Project leadProf. Brigitte Ellen Lane
Organisation IMB - Institute of Medical Biology
Project budgetUSD 209,958.00
Start date / Duration01. Apr 2012 / 36 months
Funder(s) / Co-Funder(s) DEBRA Austria
Research area Molecular therapy

Project details

Short lay summary

People suffering from severe (Dowling Meara type) epidermolyis bullosa simplex have very
fragile skin that blisters easily upon mechanical stress. We have developed cell lines and cell culture stress assays to generate systems in which we can model the disease before direct patient testing. Using these tools, we discovered that EBS cells with the disease-causing keratin mutations are continuously in a stressed state, as seen by activation of stress-associated indicator responses by the cells, even when they are not directly under mechanical stress. Our most recent experiments now suggest an exciting mechanism that directly links the most common Dowling-Meara EBS mutations (damaging keratin filaments in the skin cells) with the clustered and spreading blistering seen in patients. We believe that the problem is due to the combined action of the keratin mutation plus the activation of a stress signal normally used to trigger wound healing. We have observed that if we block this signal, the skin cells are rescued from the EBS state - they now adhere closely to each other and form normal reinforcing keratin filaments. From this, we have identified some candidates for signal-blocking drug that may reduce or even prevent the skin blistering of EBS. We will now test this hypothesis, and optimize the drug candidate selection to increase the skin-targeted effect and reduce the possibility of unwanted side effects for the patient.

What did this project achieve?

People with Epidermolysis Bullosa (EB), especially the severe Dowling Meara type, have very fragile skin that blisters easily on mechanical stress. Our lab has developed several disease model cell lines and cell culture stress assays which we have been using to study and model EBS in the lab, without the need for direct patient testing. 

We discovered that EBS-mimicking cells, that have the same disease-causing keratin mutations as the patients, exist in a continuously stressed state, even before additional mechanical stress. This led us to the idea of a mechanism that may direclty link Dowling-Meare EBS mutations that cause damage keratin filaments inside the skin cells with the clustered and spreading blisters that affect the patients. We fouond evidence suggesting that if we could reduce the formation of the abnormal microscopic keratin lumps, or aggregates, that form inside EBS cells, we should be able to reduce the cell stress and return the skin cells to a much more resilient state.

The aim of the project we have undertaken here was therefore to search for drugs and comounds that could reduce these protein aggregates that are the hallmark of severe EBS. We based our research on testing the EBS model cell lines, grown in the lab in tissue culture, with possible candidate chemicals. We analysed the protein aggregates in detail, looking at where, when and how they are formed in the EBS cells, scrutinizing in detail the effects of any comounds that appearded to affect or reduce the distribution of the aggregates. When a keratin carries an EBS mutation, the affected cell starts to make small lumps of keratin protein around the cell edges where the cells begin to stretch out in preparation for cell migration - for example, aggregates made, of serveral different types of chemicals that redue the number of aggregates made, of several different kinds of molecules: some are enzyme inhibitors already in use to treat diseases like cancer, or inflammation, wherease some are only ever used in biochemistry labs as they are thought to be too toxic for use on people. We extended the analysis of these moleculres, especially ones that are already approved for human use: even if we have to obtain approval to use these for a different medical use, it is likely that their use in one human application will make it easier to get approval to use them to treat EBS. In another part of this project we have developed a robust system for testing candidatae compounds in a more complex, three-dimensional skin-like environement, which can be used for pre-clinical validation before a comound is used in a clinical trial. This helps to de-risk new drugsw to make it easier for pharmaceutical companies to work with us when their help becomes necessary. With this project we have succeeeded in finding several Mutation-independent therapeutic targets for EBS, and we are now proceeding to refine these compounds for a clinical trial.


Keywords

EBS
Lane
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