The German doctors realized they had to do something drastic or their seven-year-old patient would die. The boy had escaped war-ravaged Syria with his parents, and a rare genetic disease had left him with raw, blistering sores over 80 percent of his body. His doctors in a children’s burn unit tried everything they could to treat his illness, called junctional epidermolysis bullosa—even grafting some skin from his father to see if it would heal the child’s wounds. But his body rejected this. Finally, they e-mailed Michele De Luca, a researcher in Italy, to ask for help.
Twelve years earlier De Luca, director of the University of Modena and Reggio Emilia’s Center for Regenerative Medicine had successfully used gene therapy to restore skin on the legs of someone with a similar disease. No one had ever attempted using gene therapy to replace as much skin as the boy needed, however, and De Luca’s work had been sidelined by bureaucratic hurdles. But after nearly a decade of filing paperwork and improving his skin cell production system, De Luca was ready to try.
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The doctors took a small sample of skin from one of the few places on the boy’s body where it was not flaming red or flaking off, and sent it to De Luca. His team at the center used a virus to insert into the skin cells a correct copy of a gene called LAMB3; the boy’s own defective copy had caused his epidermolysis bullosa. De Luca and his colleagues grew the skin cells over scaffolds in their lab to form large sheets, the way doctors often do for burn patients.
In two surgeries in October and November 2015, the Italian and German teams covered the boy’s limbs, sides and back with these sheets of fresh skin. After being too sick even to get out of bed before his surgeries, “he was standing up already by Christmas,” De Luca says. In January 2016 the boy, whose name is not being released to protect his privacy, received a few more skin patches—and in February he was released from the University Hospitals of the Ruhr University Bochum in Germany.
A year later, the boy proudly showed off his skin to students and researchers in De Luca’s lab. “It was a quite moving moment,” says De Luca, who published a report on the treatment Wednesday in Nature. “After this 10 years of struggling to accomplish all these rules and paperwork and bureaucracy, the moment you see a patient like this, you understand it was worth it to do it.”
The boy’s epidermis—the top layer of skin—totally regenerated itself after the new cells were added, proving for the first time that the entire epidermis is sustained only by a relatively few stem cells in the skin, De Luca says. “Once you have regenerated the epidermis with stem cells, the stem cells behave like they’re supposed to: They adjust their number and they keep making the renewal of epidermis as a normal physiological situation,” he said Tuesday in a news conference.
Other researchers in the field say they are impressed with the team’s results. “It’s a fantastic piece of work,” says Cédric Blanpain, a professor and stem cell biologist at the Free University of Brussels, who wrote an opinion article accompanying the study. “This is a beautiful example of how you can move stem cells into the clinic in a very safe and powerful manner,” he says, also calling the work “a powerful demonstration that only a few stem cells are indeed maintaining the skin epidermis rather than many different progenitors.”
Some unusual pigmentation remains on the boy’s skin because of the earlier damage. But other than that, he is now a normal nine-year-old who is fond of soccer and running, De Luca says. “When we engrafted him he was 17 kilograms [37 pounds],” he adds. “Now, he’s a robust kid.”
His skin no longer blisters or itches, and unlike many burn patients who must apply ointment once or twice a day for the rest of their lives, his repaired skin needs no ongoing treatment. It also heals normally from cuts and bruises and now produces essentially normal levels of the protein laminin 332, which the child had lacked from birth due to his condition. The protein is crucial for, among other things, sticking the epidermis to the underlying dermis. The boy has no scarring, because his disease was literally only skin-deep. It did not affect the deeper dermis, where cuts trigger scars.
In patients with epidermolysis bullosa every skin cell has a genetic disorder that limits its ability to grow healthy skin. This is why De Luca had to correct the gene before growing new skin for the boy. The illness can be caused by one of several mutations. The defect on the boy’s LAMB3 gene gave him a devastating illness—but also may have made it easier to recover after the gene therapy, says Peter Marinkovich, an associate professor of dermatology and epidermolysis bullosa expert at Stanford University, who was not involved in the boy’s treatment. In his own research Marinkovich has used gene therapy to treat four patients with a different genetic form of epidermolysis bullosa. Those patients showed significant improvement but their skin did not engraft as smoothly as the boy’s, he says.
De Luca is collaborating with doctors in Salzburg, Austria, to conduct several early-stage clinical trials, testing his gene therapy approach on 20 more patients with two types of epidermolysis bullosa. The complicated treatment will not be cheap. “That’s the price we have to pay for advanced therapy for a genetic disease,” De Luca says. Caring for children with epidermolysis bullosa is not cheap either, Marinkovich notes, adding that it can cost $100,000 a year to dress their wounds—which is sometimes not covered by insurance.
In the future De Luca hopes to use the therapy on children younger than the boy, even on babies. Children with the most serious form of epidermolysis bullosa often die before they reach school age. Prevention, De Luca says, is better than restoration. “The sooner we do it,” he explains, “the better it is for the kids.” In a younger child who is less critically ill, still-healthy epidermis can be removed much more slowly and replaced in pieces over the course of a year or two, he says.
Because the treatment is still holding up in the patient De Luca worked with 12 years earlier, he is fairly confident the boy’s skin will remain healthy in the long term. But no one really knows, because the approach is so new. De Luca says he will follow the boy’s progress indefinitely to make sure he continues to thrive. Gene therapy, however, carries the risk of cancer, he notes. But he hopes that because this particular treatment involves the skin, any tumors will be easy to spot and can be quickly removed.
The gene therapy approach might also be helpful for other skin diseases someday. De Luca says he has enough work to do fighting epidermolysis bullosa. “It will,” he says, “take more time beyond my working life span.”
Caption: Gene therapy to treat a skin disease.
Credit: Nature, News & Views