The Greek term lysis means “dissolution” and is familiar from words such as “electrolysis”. In the case of the genetic disease epidermolysis bullosa it refers to severe skin damage. Sufferers are called “butterfly children” because their skin is as sensitive as the wings of a butterfly. Currently, treatment is limited to wound care, and the ailment cannot be cured. Potential treatment via genetic therapy is under investigation in clinical studies, but even if the studies show promise, the treatment will not be applicable to all variants of the disease. Now there is fresh hope for one of these variants. Pilot studies with a new drug promise a significant, long-term reduction of symptoms.
Inflammation caused by a genetic defect
A factor common to all variants of epidermolysis bullosa (EB) is the impaired production of an important skin protein. When the protein is missing, the skin is weakened and forms blisters. The new treatment method developed by the research group of Johann Bauer at the EB House Austria, University Clinic for Dermatology at the Paracelsus Medical University (PMU) is designed for treating a variant of EB that carries the addition “simplex”. “In the other forms of EB, the blisters are a direct consequence of the weakened skin”, explains Johann Bauer. “But in the simplex variant that we are targeting this weakness is less pronounced. While the protein is still present, it mutates and clumps within the cells. This triggers inflammatory reactions”, Bauer adds.
Bauer’s group investigated these inflammations and noted that certain inflammation products appear with particular frequency. “This is the result of basic research in the laboratory of the EB House Austria with initial financial support of DEBRA Austria, the patient organization for EB patients. We wondered how we could apply it, and one of my team members, Verena Wally, had the brilliant idea that an approved medication which suppresses one of these inflammatory markers does already exist. The substance is diacerein, a commercially available medication for the treatment of osteoarthritis.” The drug containing diacerein is produced in the form of tablets, but in the case of butterfly children the active agent needs to be applied directly to the skin. “We studied whether it was possible to incorporate the agent in an ointment that can be applied to the skin, and our pharmacist at the University Clinic Salzburg was actually able to produce such an ointment”, reports Bauer.
Motivated by this achievement, the researchers conducted a small pilot study with five participants. “We were astonished by the success”, says Bauer. “Within two weeks we observed a reduction of 80% of the blisters. And to our surprise – we still don’t really know why – we brought about a very lasting effect. The blisters did not reappear even without treatment.”
The team received funding from the Austrian Science Fund FWF for a larger study. The results of the study have been submitted for publication. The interim results were so promising that the scientists already applied for a patent as a so-called “orphan designation” at the European Medicines Agency in a programme focusing on medication for particularly rare diseases – only one in 50,000 children suffers from EB simplex. In order to alleviate economic pressure in the development of such medication, orphan drugs enjoy special protection, granting a ten-year exclusivity period to the developer for marketing the drug.
“We then had to decide how to proceed. We considered developing the drug by ourselves in Austria, but we quickly saw that we did not have the necessary know-how. Our shortcoming was less related to molecular biology and more to the regulatory aspects, which are very important if you aim at drug approval – and global approval, at that”, notes Bauer. “Therefore, we looked around at the international level for a partner company and received an inquiry from a small US start-up named Castle Creek Pharma. After some negotiations, we licensed the drug to them and initiated an approval trial which is currently running at global level.” According to Bauer, everything is on track: “We hope that it all goes well and that we receive approval soon, first in the USA and then in Europe.” Such fast approval is unusual in the pharmaceutical sector, the lead time for new medication being normally much longer. “We have the advantage that the active agent already has market approval, which is why many pharmacokinetic studies already existed”, explains Bauer.
Interface between research and therapy
Bauer’s research belongs to what is called translational medicine. “We do blue-sky research without a specific goal in mind. When something interesting comes up we study how we can use it for the benefit of patients.” According to the dermatologist, who has been researching EB since the 1990s, approval procedures and everything that follows are a completely different story. Now, a real breakthrough seems to have been achieved. “At present, there is nothing comparable on the market”, says Bauer and notes that drugs from Austria are rare on the world market. “The drug is now being developed further in the US, but the ideas and the context come from Austria.”
Johann Bauer is the Head of the University Clinic for Dermatology at the Paracelsus Medical University (PMU) and Medical director of the EB House Austria in Salzburg. His scientific career took him from the pharmacology of neuropeptides to research on genetic diseases, particularly involving butterfly children. His research took Bauer to Philadelphia and Atlanta, the latter in the context of an international mobility grant from the FWF (Erwin Schrödinger Fellowship). His field is translational research which builds a bridge between basic research and the development of new treatment methods.