Epidermolysis bullosa is a genetic disease which causes severe skin damage. There is no cure for it and about four in 10 patients do not reach adolescence. Recently, in a project funded by the Austrian Science Fund FWF, a research team from Salzburg developed an ointment for the treatment of butterfly children. In Germany, a boy was given a new genetically modified skin that covered 80% of his body, in a series of lifesaving operations. Read on to find out the advances in the treatment of this genetic disease.
The Greek term lysis means "dissolution" and is familiar from words such as "electrolysis". In the case of the genetic disease, epidermolysis bullosa, 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, which holds the different layers of skin together. When the protein is missing, the epidermis (surface layer) does not stick to the dermis (the next one down), causing the skin to be weakened and form blisters. There is no cure for EB and about four in 10 patients do not reach adolescence.
A 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 to treat only 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 of 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 onto the skin. "We studied whether it was possible to incorporate the agent in an ointment that can be applied directly 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", 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 in 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."
Two years ago, Hassan, a seven-year-old boy was suffering from junctional epidermolysis bullosa. He was born in Syria, but lives in Germany and has had blisters and wounds all over his body since he was a few days old. In June 2015, Hassan was admitted to the Children's Hospital at Ruhr-University, in Bochum, Germany. He was missing a massive amount of epidermis and most of his body looked like a red-raw open wound.
Dr Tobias Hirsch, from the hospital, said, "We initially decided to provide palliative care because we had no chance to save the life of this child".
But a team of biologists specialising in gene therapy were brought in from the University of Modena and Reggio Emilia, in Italy - and his parents gave approval for them to try an experimental therapy.
In September 2015, a 4 sq cm (0.6 sq inches) piece of skin was taken from an area where the epidermis was still intact. The biopsy was then infected with a customised virus. Viruses are good at getting inside cells, and this one was used like a postman to deliver the missing instructions for binding the layers of skin together.
The genetically modified skin cells were grown to make skin grafts totalling 0.85 sq m (9 sq ft). It took three operations to cover 80% of Hassan’s body in the new skin.
21 months later, the new skin is functioning normally with no signs of blistering. Dr Hirsch said, "The kid is now back to school, he plays soccer, so there was a tremendous increase in quality of life". Hassan’s skin which was once as fragile as a butterfly’s wings, Hassan’s father said the transformation was “like a dream”. The family is glad he can enjoy life the way he has not been able before.
Dr Anna Martinez, who leads the national epidermolysis bullosa service at Great Ormond Street Hospital said, "Today, this treatment is not available, and it is not going to be available in the next few months, but this is a massive advance in research and is going to give us hope going forward with gene therapy".
Epidermolysis bullosais is rare, but the charity DEBRA, which campaigns for EB patients, estimates half a million people are affected around the world. There are different forms of epidermolysis bullosa, including simplex, dystrophic and, as in Hassan’s case, junctional. Each is caused by different genetic faults leading to different building blocks of skin being missing.
Prof Michele De Luca, from the University of Modena and Reggio Emilia said, "The gene is different, the protein is different and the outcome may be different [for each form of EB] so we need formal clinical trials." But if they can make it work, it could be a therapy that lasts a lifetime.
An analysis of the structure of Hassan's skin, detailed in the journalNature, has discovered a group of long-lived stem cells are that constantly renewing his genetically modified skin.
- Bauer, Johann., Jochum, Manuela., and Ladner, Ingrid. “New hope for butterfly children”.scilog. 2 Oct. 2017. Biology and Medicine. Web. 13 Nov. 2017.
- Gallagher, James. “'Butterfly child' given life-saving skin.”BBC News. 8 Nov. 2017.Health. Web. 13 Nov. 2017.
- Wally, V; Kitzmueller, S; Lagler, F; Moder, A; Hitzl, W; Wolkersdorfer, M; Hofbauer, P; Felder, TK; Dornauer, M; Diem, A; Eiler, N; Bauer, JW: Topical diacerein for epidermolysis bullosa: a randomized controlled pilot study.Orphanet Journal of Rare Diseases, 2013, DOI: 10/f4wrqp