A Dying Boy Gets a New, Gene-Corrected Skin

Doctors took his stem cells, corrected a faulty mutation within them, and used them to replace 80 percent of his skin.

A little boy playing soccer next to a colorful statue of a cow
Hassan, playing soccer after his operation (University of Modena and Reggio Emilia)

At the age of 7, Hassan had already seen more than his fair share of hardship. A week after he was born in Syria, a blister appeared on his back. The doctors there diagnosed him with a genetic disorder called epidermolysis bullosa, or EB, which leaves one’s skin extremely fragile and prone to tearing. There was no cure, they said. When Hassan’s family fled Bashar al-Assad’s regime and moved to Germany as refugees, the doctors there said the same thing. Meanwhile, the blisters were getting bigger.

In June 2015, Hassan was admitted to the burn unit of a children’s hospital in Bochum, Germany. By that time, around 60 percent of his epidermis—the top layer of his skin—was gone. His back, flanks, and limbs had become a continuous landscape of open wounds, red and raw. Much of it was badly infected. The pain was excruciating. “Why do I have to live this life?” he asked his father.

Five weeks later, Hassan’s doctors had run out of options, and were planning to start end-of-life care. But after his father asked about experimental treatments, they contacted Michele de Luca, a stem-cell biologist at the University of Modena and Reggio Emilia. Over the past decades, de Luca had been working on a way of giving EB patients fresh skin. He would collect stem cells from their body, edit the faulty genes that were causing their condition, use the corrected cells to grow healthy epidermis, and graft these new layers back onto the patients.

He and his colleague Graziella Pellegrini had tried this once before in 2006, but on a smaller scale. Back then, they successfully treated a 49-year-old woman with a large EB-induced wound on her right leg. Hassan’s condition was much worse—and he was just a child. Still, there was nothing else to try.

In August, De Luca and Pelligrini got the green light to try their technique. In September, they collected a square inch of skin from Hassan’s groin—one of the few parts of his body with intact skin. They isolated stem cells, genetically modified them, and created their gene-corrected skin grafts. In October and November, they transplanted these onto Hassan, replacing around 80 percent of his old skin.

It worked. In February 2016, Hassan was discharged from the hospital. In March, he was back in school. He needs no ointments. His skin is strong. It doesn’t even itch. “He hasn’t developed a single blister,” says de Luca, who shared the details of Hassan’s story with me. “He’s gaining weight. He’s playing sports. He’s got a normal social life.”

EB has been called “the worst disease you’ve never heard of.” In the United States, it affects around one in every 20,000 people, and the many types and subtypes are caused by mutations in at least 18 possible genes. But all of these mutations have one thing in common: They impair the molecules that strengthen skin, making it extremely fragile. For some people, the symptoms are mild, while others are afflicted with massive wounds and blisters. When it comes to junctional EB—one of the most severe types, and the one Hassan had—around 40 percent of people die before adolescence.

“Whenever I speak about EB, I find myself saying: until there is a cure ...” says Kimberly Morel, who directs an EB clinic at Columbia University. “Now it seems there is more hope on the horizon for this terrible disease.”

Hassan’s treatment is “a sea change to the world of EB,” says Brett Kopelan, the executive director of the Dystrophic Epidermolysis Bullosa Research Association of America. Even though it’s only one instance of success, “it’s made such a change in that one subject that I think it’ll be very much welcome by the EB community. You’re looking generally at a desperate patient population. I have a daughter with recessive dystrophic EB. If something like this were to be commercially viable, it’s certainly something we would pursue.”

One of the gene-corrected skin grafts (University of Modena and Reggio Emilia)

Hassan’s miraculous recovery mirrors that of two young boys who, in 1983, accidentally set themselves on fire and burned the skin off more than 97 percent of their bodies. Their lives were saved by the physician Howard Green, who had inadvertently discovered a way of regenerating skin so it could be grafted onto burn victims. Green’s technique has since saved countless lives, and fueled the entire fields of stem-cell biology and regenerative medicine.

De Luca studied with Green in his early career, and his procedure is almost identical to the one his mentor developed, except for one crucial part: He added gene therapy to the mix, modifying the stem cells behind the regenerating skin to correct the mutations behind Hassan’s condition.

“It’s a landmark in the field of stem-cell therapy,” says Elaine Fuchs, from The Rockefeller University. It also helps resolve what she calls “a brewing controversy in the field” about the exact nature of the stem cells behind the substitute skin. In some cases, burn victims who are treated with regenerated skin do really well. In others, the new skin proves to be unstable. By analyzing the DNA in Hassan’s new skin, de Luca’s team showed why: Almost all of the new cells are produced by a small but elite group of long-lived stem cells. In the future, scientists like de Luca would need to check for such cells when they grow their grafts.

A second group led by Peter Marinkovich and Jean Tang, both from Stanford University School of Medicine, have also tried to use gene-corrected skin grafts to treat four patients with a different type of EB. They replaced smaller patches of skin with variable degrees of success, but their results were promising enough to start recruiting for a larger clinical trial.

So far, both teams haven’t seen any negative side effects in their patients—a real concern, when it comes to gene therapy. Hassan’s EB was caused by a faulty version of a gene called LAMB3, and de Luca’s team used a virus to insert the normal version of the gene into the DNA of the boy’s stem cells. But if the virus inserts the gene into the wrong place, it could cause new mutations that might ultimately lead to cancer. Fortunately, when de Luca’s team sequenced DNA from Hassan’s new skin, they found that the normal LAMB3 gene had landed in safe zones. There were no signs of any potentially cancerous changes in either Hassan’s new skin cells or those from de Luca’s earlier 2006 patient.

De Luca’s team is now running two separate clinical trials to test their gene-corrected skin grafts on around two-dozen children with EB. His ultimate goal is to develop an effective and standardized procedure that could be carried out during early childhood, to prevent the painful blisters before they happen, rather than restoring lost skin after the fact. “It will take years to get there but it’s clearly doable,” he says. “Maybe this will be the last thing I’ll do in my career.”