A 7-year-old who lost most of his skin to a rare genetic disease has made a dramatic recovery after receiving an experimental gene therapy, researchers announced today. The treatment—a whole-body graft of genetically modified stem cells—is the most ambitious attempt yet to treat a severe form of epidermolysis bullosa (EB), an often-fatal group of conditions that cause skin to blister and tear off at the slightest touch.
The new approach can address only a subset of the genetic mutations that cause EB. But the boy’s impressive recovery—he’s now back in school and is even playing soccer—could yield insights that help researchers use stem cells to treat other genetic skin conditions.
“It is very unusual that we would see a publication with a single case study anymore, but this one is a little different,” says Jakub Tolar, a bone marrow transplant physician at the Masonic Cancer Center, University of Minnesota in Minneapolis who is developing therapies for EB. “This is one of these [studies] that can determine where the future of the field is going to go.”
EB results from mutations to any of several genes that encode proteins crucial for anchoring the outer layer of skin, the epidermis, to the tissue below. The missing or defective protein can cause skin to slough off from minor damage, creating chronic injuries prone to infection. Some forms of EB can be lethal in infancy, and some predispose patients to an aggressive and deadly skin cancer. The only treatment involves painfully dressing and redressing wounds daily. Bandage costs can approach $100,000 a year, says Peter Marinkovich, a dermatologist at Stanford University in Palo Alto, California, who treats EB patients. “They’re like walking burn victims,” he says.
In fact, the new approach is similar to an established treatment for severe burns, in which sheets of healthy skin are grown from a patient’s own cells and grafted over wounds. But stem cell biologist and physician Michele De Luca of the University of Modena and Reggio Emilia in Italy and his colleagues have been developing a way to counteract an EB-causing mutation by inserting a new gene into the cells used for grafts. His group has already treated two EB patients with this approach. They published encouraging results from their first attempt—with small patches of gene-corrected skin on a patient’s legs—in 2006.
In 2015, De Luca’s team got a desperate request from doctors in Germany. Their young patient had a severe form of the disease known as junctional EB, caused by a mutation in a gene encoding part of the protein laminin 332, which makes up a thin membrane just below the epidermis. It was the same gene De Luca’s team was targeting in an ongoing clinical trial, but this case was especially dire: Lacking most of his skin, the boy had contracted multiple infections and was in a life-threatening septic state. The emergency treatment would be the first test of their gene therapy approach over such a large and severely damaged area.
De Luca’s team used a patch of skin a little bigger than a U.S. postage stamp from an unblistered part of the boy’s groin to culture epidermal cells, which include stem cells that periodically regenerate the skin. They infected those cells with a retrovirus bearing healthy copies of the needed gene, LAMB3, and grew them into sheets ranging from 50 to 150 square centimeters. In two surgeries, a team at Ruhr University in Bochum, Germany, covered the boy’s arms, legs, back, and some of his chest in the new skin.
After a month, most of the new skin had begun to regenerate, covering 80% of the boy’s body in strong and elastic epidermis, the researchers report online today in Nature. What’s more, he’s developed no blisters in the grafted areas in the 2 years since the surgery.
Other researchers have long been concerned that using a retrovirus to insert genes at random points in cells’ genomes might cause cancer. (In the early 2000s, five children who participated in a retrovirus-based gene therapy trial for severe combined immunodeficiency developed leukemia.) But the current study found no evidence that the insertion affected cancer genes.
De Luca and colleagues were also able to track which grafted cells regenerated the skin over time by using the different locations of the genetic insert as markers for individual cells and their progeny. They found that most cells from the graft disappeared after a few months, but a small population of long-lived cells called holoclones formed colonies that renewed the epidermis.
That’s an important lesson, Tolar says; it suggests that future attempts to correct genetic skin diseases should focus on culture conditions that nourish these stem cells, and potentially even target them for modification. “If you have a gene correction strategy,” he says, “you’d better have these primitive epidermal stem cells in mind.”
The current results could benefit several thousand EB patients across the world, Marinkovich says, but it won’t work for all of them. More than half have a form of the disease called EB simplex, which is caused not by a missing protein, but by mutations that produce an active but dysfunctional protein. For these errors, correction with a gene-editing tool like CRISPR makes more sense, De Luca says.
The grafts also can’t repair damage to internal surfaces such as the esophagus, Tolar notes, which occurs in some EB cases. Fortunately, that wasn’t an issue for the boy in this study. The treatment is “a good step in the right direction,” he says, “but it’s not curative.”
Both De Luca and Marinkovich’s teams are exploring a similar gene therapy for another major form of the disease, called dystrophic EB, caused by a different genetic error affecting a larger protein. Biotech companies are working with each group to test the approach in larger clinical trials.