For the first time, doctors were able to treat a child who had a life-threatening rare genetic skin disease through a transplant of skin grown using genetically modified stem cells.
The grafts replaced 80% of the boy's skin.
The skin of his arms, legs, back and flanks, and some of the skin on his stomach, neck and face was missing or severely affected due to epidermolysis bullosa.
The compassionate-use experimental treatment is detailed in a case study published in the journal Nature on Wednesday.
Skin as fragile as a butterfly's wings -- that's how children with epidermolysis bullosa are described and why they're often called butterfly children.
The disease, of which there are five major types and at least 31 subtypes, is incurable. People with the condition have a defect in the protein-forming genes necessary for skin regeneration.
About 500,000 people worldwide are affected by forms of the disease. More than 40% of patients die before reaching adolescence.
Their skin can blister and erode due to something as simple as bumping into something or even the light friction of clothing, according to an email from Dr. Jouni Uitto, a professor and chairman of the Department of Dermatology and Cutaneous Biology at the Sidney Kimmel Medical College in Philadelphia. Uitto was not involved with this study.
Epidermolysis bullosa makes the skin incredibly susceptible to infections, and in the case of 7-year-old Hassan, whose treatment was detailed in Nature, those infections can be life-threatening.
A week after he was born in Syria, Hassan had a blister on his back, his father said through an interpreter in an interview provided by the hospital in Germany where the boy was treated.
Hassan's last name, as well as the first names of his family members, are not being disclosed to protect the privacy of the family.
In his first few weeks of life, Hassan was immediately diagnosed with epidermolysis bullosa, and their doctor in Syria told Hassan's family that there was no cure or therapy.
Over the years, their efforts to find help for their son's disease led the family to the Muenster University hospital in Germany in 2015, when Hassan was 7. His condition worsened, and he struggled with severe sepsis and a high fever. He weighed just over 37 pounds.
They didn't think he would make it, and doctors at Muenster decided in summer 2015 to transfer Hassan to the Ruhr-Universität Bochum's University Hospitals, including the burn center -- one of the oldest in the country.
The search for treatment
By the time Hassan arrived at Bochum, he had lost two-thirds of his surface skin.
"We had a lot of problems in first days just keeping him alive," said Dr. Tobias Rothoeft, consultant at the University Children's Hospital at Katholisches Klinikum Bochum.
Doctors tried to promote healing by changing his dressings and treating him with antibiotics, as well as putting him on an aggressive nutrition schedule, but nothing helped. They even tried transplanting skin from Hassan's father.
"By that time, he had lost 60% of his epidermis, the upper skin layer, and had 60% open wounds all over his body," said Dr. Maximilian Kueckelhaus of the Department of Plastic Surgery at Bochum's Burn Center.
Every approach failed, so the doctors prepared Hassan's family for what end-of-life care would entail. But the parents pleaded, asking the doctors to consult studies and research for experimental treatments that might help.
They found Dr. Michele De Luca at the University of Modena's Center for Regenerative Medicine in Italy. His publications described an experimental treatment transplanting genetically modified epidermal stem cells that healed small, non-life-threatening wounds in adults.
The medical team reached out to De Luca, asking whether he could help them replicate the procedure on a larger scale to help Hassan, and he agreed. De Luca told Hassan's parents that he believed there was a 50% chance of the treatment being successful.
They were more than willing to accept the risk, to do anything to help their son have a chance at a normal life.
Hassan "was in severe pain and was asking a lot of questions: 'Why do I suffer from this disease? Why do I have to live this life? All children can run around and play. Why am I not allowed to play soccer?' I couldn't answer these questions," his father said. "It was a tough decision for us, but we wanted to try for Hassan."
Growing sheets of skin
To obtain the skin's stem cells, the doctors took a small biopsy -- only accounting for 1½ square inches -- from an unaffected part of Hassan's skin. The stem cells were processed by De Luca in Italy. A healthy version of the gene that is normally defective in epidermolysis bullosa patients was added to the cells, along with retroviral vectors: virus particles that assist the gene transfer.
This genetic transfer would essentially "correct" the cells.
The single cells were grown and cultivated on plastic and fibrin substrate, which is used to treat large skin burns, to form a large piece of epidermis. This method enabled the researchers to grow as much skin as they needed. The whole process took three to four weeks, Kueckelhaus said.
Once the sheets were ready, they were transferred from Italy to Germany and transplanted onto the well-cleaned wounds right away during two surgeries. The first procedure in October 2015 applied the sheets to Hassan's arms and legs. The second surgery, in November, grafted the sheets to Hassan's entire back and the other affected areas.
Hassan began to improve immediately. The researchers noticed that the grafts were not rejected; they bound to all of the areas they were transplanted.
"For everyone that was involved, taking off the bandages and seeing for the first time that this is working out, that the transplants are actually attached to the patient and growing skin, that's an incredible moment," Kueckelhaus said.
Hassan was discharged from the hospital in February 2016.
After steady followups over 21 months, the researchers found that Hassan's new skin healed normally, didn't blister anymore, and was resistant to stress. It was even growing hair. Unlike some skin graft patients, he doesn't require any ointment to keep his skin smooth and hydrated. And like any growing kid, he bruises and recovers normally.
They also learned that only a few stem cells contribute to the long-term maintenance of the epidermis, shedding light on cellular hierarchy in this regard.
"The investigators removed of small piece of patient's skin, isolated cells with stem cell potential for growth, introduced a normal copy of the mutated gene to the cells, propagated a large number of these cells in culture and then grafted them back to the skin," Uitto said. "This concept is not new, but what is remarkable here is that they were able to change essentially the entire skin of the patient with normal cells."
Hassan's family is currently living in Germany. Hassan, now 9, is able to go to school and play sports, but he maintains a schedule of frequent monitoring at the hospital to ensure that the initial success of the treatment continues. The area of his skin that was not treated sometimes shows small blisters, and if it worsens, he may receive transplants there as well.
"Seeing him 18 months after the initial surgery with an intact skin is incredible because he has been in the ICU for so long," Kueckelhaus said. "He had bandages all over his body except his hands, feet and face. He was on extremely strong pain medication. So the quality of life was really, really bad for him. Seeing him play soccer, play sports, play with other kids, that is just amazing because that's something he couldn't do before."
"It felt like a dream for us," the boy's father said. "Hassan feels like a normal person now. He plays. He's being active. He loves life."
A future treatment?
Everything points to a good long-term outcome for Hassan.
The researchers will continue to monitor him for complications. Sometimes, genetic modifications can cause malignancies in cells.
"That is of course one thing we really have to be aware of," Kueckelhaus said. "However, analyzing the integration profile of that gene into the boy's DNA, which we did, we saw that it's mostly in areas that don't cause too much concern about developing malignancies."
Epidermolysis bullosa patients can be at a very high risk of developing skin cancer simply because of the disease. Because Hassan now has intact skin and intact DNA, this risk might even decrease, but that will have to be proved through follow-up, Kueckelhaus said.
Given that this was one successful outcome for one patient, the experimental treatment can't be applied for other patients just yet. De Luca is conducting clinical trials using the treatment.
"This is one case with a distinct type of EB, and further studies will show whether this approach is applicable to other forms of EB as well," Uitto said. "It should be noted that in some severe forms of EB, the patients also suffer from fragility of the gastrointestinal and vesico-urinary tract, and some forms are associated with the development of muscular dystrophy. Obviously, gene therapy of the skin cannot correct them, and these issues have to be addressed in further studies."
Hassan's treatment also cost hundreds of thousands of dollars. Although the process could be optimized, doctors would still have to individually grow transplants for each patient, which could get very expensive.
But for patients' families, epidermolysis bullosa is already expensive.
"Standard maintenance treatment of patients with EB, including daily bandaging, antibiotics and special moisturizer, as well as frequent hospitalizations, can be extremely costly, and gene correction as described in this paper may well be cost-effective over the lifetime of these patients," Uitto noted.
Brett Kopelan, executive director of the Dystrophic Epidermolysis Bullosa Research Association of America, has a 10-year-old daughter, Rafi, with recessive dystrophic EB. Between January and August, $751,1778 for wound/burn dressings was charged to Kopelan's insurance company, he says. That doesn't account for drugs or hospital visits and surgeries.
Kopelan's nonprofit sends free supplies and bandages to families. The nonprofit can provide its employees with insurance that covers the medical equipment, but that isn't the case for everyone impacted by the condition, he said.
Kopelan is hopeful about the results of the study. The baths and bandage changes that are necessary for epidermolysis bullosa patients to stave off life-threatening infections can last hours and feel torturous.
"Do you remember the last time you got a paper cut and put Purell on it? It burned, right? Now think of 60% of body being an open wound, and opioids don't really work for this kind of pain," Kopelan wrote in an email. "This is what make EB kids and adults the strongest people on Earth."
The study "confirms our hopes that gene therapy is potentially the most efficacious path forward to providing a significant treatment option for those with epidermolysis bullosa," Kopelan said. "While it's important to remember that this is only one patient and more work needs to be done to demonstrate how effective this gene therapy platform may prove to be, I am very enthused."
"I wish that all children with the same disease could be treated in this way," Hassan's father said.