The surgical team in Germany quickly exhausted conventional skin graft techniques — skin from the boy’s father was rejected — and were ready to give up when they came upon an experimental gene therapy in Italy. The method, which had only been used twice on much smaller grafts, used genetic editing to correct a mutation that prevented the epidermis from properly binding to the underlying dermis.
As the surgeons and researchers reported in an article published in the journal Nature, the boy underwent three skin graft surgeries in late 2015 and early 2016 using sheets of his own genetically corrected skin grown in the Italian lab. At the time of the first surgery, he had lost 80 percent of his total epidermal skin layer and the prognosis was dire. Just eight months later, he walked out of the intensive care unit with a completely healthy, self-renewing, and stretchable epidermis.
“To make it clear, we didn’t have any options to treat this child,” Tobias Hirsch, a surgeon with the burn center at the Ruhr University Hospital in Bochum, Germany, told journalists during a press briefing. “We initially decided to do palliative care, because there was no chance to save his life. And now the kid is back to school, he’s playing soccer, and spending holidays with his siblings. There’s a tremendous increase in quality of life.”
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The experimental gene therapy treatment was developed by Michele De Luca at the Center for Regenerative Medicine at the University of Modena and Reggio Emilia in Modena, Italy. Patients suffering from JEB have a mutation in one or more of three genes (LAMA3, LAMB3, or LAMC2) that disrupts the production of laminin 5, a protein that’s critical to forming the bottom-most layer of the epidermis.
An estimated 500,000 people worldwide suffer from various forms of epidermolysis bullosa. Without a cure, 40 percent of individuals with JEB don’t survive past early childhood, primarily due to skin cancers that are also strongly associated with the disease.
Even though the 7-year-old boy was stricken with a particularly severe form of JEB, surgeons were able to salvage a small biopsy of healthy skin tissue and send it to De Luca’s lab in Italy, where he used a retroviral vector to replace the boy’s faulty LAMB3 gene with a fully expressed version.
The new skin cells were then grown out on fibrin protein scaffolds that were shipped in sheets to the hospital in Germany. In total, the new epidermal sheets needed to cover more than nine square feet (0.85 square meters) of the boy’s body, far more than had ever been attempted with a JEB patient.
Just a few weeks after the first operation, in which all four of the boys limbs were grafted with the genetically altered skin, the new epidermis had stabilized and stratified, said De Luca in the press briefing. The second operation, which grafted the remaining skin on the back and torso, was equally successful. However, the boy needed to immobilized and fed through a tube throughout the months-long ordeal.
Nearly two years later, the boy’s new skin has gone through 20 monthly renewal cycles, and heals and stretches just like a healthy epidermis. While doctors want to avoid excessive biopsies, genetic testing shows that the regenerating skin cells all carry the fixed gene. What’s amazing, said the boy’s surgeons, is that his skin doesn’t even need to be treated with any special creams or ointments, which are a daily requirement for most burn grafts. The boy, who had once been on a constant morphine drip, doesn’t even take any medications.
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De Luca was quick to point out that the boy’s success story was only one test case and that further clinical trials would determine the gene therapy’s effectiveness with other forms of epidermolysis bullosa and different target genes.
An additional discovery from the boy’s experimental procedure related to the role of stem cells and progenitor cells (cells that are more specialized than “blank-slate” stem cells) in the ongoing regeneration of epidermal tissue. De Luca said that his analysis answered an “open question in the field” about how the skin regeneration process happens on a cellular level.
De Luca found that the progenitor cells responsible for differentiating into various cell types in the skin die off fairly quickly and need to be constantly replaced by long-lived, self-renewing stem cells call holoclone-forming cells. For future grafts to be more successful, including burn grafts, the cultured skin must preserve the right number of these long-lived stem cells to continuously regenerate.
WATCH: How Does Gene Therapy Work?