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They’re known as butterfly children, people born with skin so fragile that a simple touch can create wounds that may never fully heal. Now, in a small study of patients with the rare inherited disease epidermolysis bullosa (EB), researchers have used a DNA-carrying gel to help mend their skin.
The approach is just one of several new experimental gene therapies for the condition. But it is by far the simplest: A gel loaded with viruses ferrying a therapeutic gene is spread on the skin, like an ointment. Its developers say it is the first topical gene therapy to clear clinical testing, and it is “arguably the most successful [such therapy] to date,” says bioengineer David Schaffer of the University of California, Berkeley, who was not involved with the study.
People with EB have mutations that disable genes for proteins that anchor together the layers of skin and the linings of some internal organs. Their skin tears easily, and blisters form in friction-prone areas such as the elbows, knees, and esophagus. Such tearing can result in painful open wounds, persistent infections, scars, skin cancer, and death by early adulthood.
Experimental treatments include skin grafts or stem cells engineered to make the protein missing in a specific form of EB. (Different mutations can give rise to the disease.) In one dramatic 2017 case, lab-grown sheets of stem cells saved the life of a boy who had lost most of his skin. But these treatments require hospital stays and anesthesia, and would likely be unaffordable in many countries.
In the new study, patients had recessive dystrophic EB (RDEB) and lacked a skin protein called collagen VII. To treat their wounds, a team led by Stanford University School of Medicine dermatologist Peter Marinkovich developed a gel containing herpes simplex virus 1–best known for causing cold sores—modified to carry the gene for collagen VII and engineered so that it cannot replicate.
One advantage to herpesvirus is that its genome is roomy enough for collagen VII’s large gene. Another is that the virus has evolved to avoid raising an effective response by the human immune system—the reason most herpes infections never go away. “When you have herpes disease, it’s very troublesome, but as a gene therapy vector it can be quite an advantage,” Marinkovich says. That means that, unlike most viral gene therapies, patients can receive multiple treatments with herpesvirus vectors.
Marinkovich and colleagues first showed treatment with the gel prompted collagen VII production in skin from RDEB patients and mice with the same mutation. In 2018, they launched a clinical trial funded by the company Krystal Biotech Inc. Nine patients, three of them children, had wounds sprinkled with drops of the gel, which was then spread by a bandage. The patients were treated every 1 to 3 days, for 25 days.
In all but one case, wounds healed within 3 months after the treatment ended, the researchers report today in Nature Medicine. One patient’s 5-year-old foot wound needed two cycles of treatment, but ultimately healed for 8 months. By comparison, wounds treated with a placebo gel sometimes healed but reopened. Not every wound treated with the new gel fully healed, but “the results are quite good,” Marinkovich says.
The viral vector doesn’t penetrate far into intact skin, so it can’t prevent blistering altogether. And because collagen VII degrades—and the treated skin cells eventually slough off—the gel has to be reapplied. “It’s not a permanent cure, but it’s a way to really keep on top of the wounds,” Marinkovich says. “It significantly improves patients’ quality of life.”
His team now plans to test the gel on other wounds typical in RDEB patients, in corneas, the esophagus, and around the anus.
The new study is “quite nice,” says stem cell biologist Michele de Luca of the University of Modena and Reggio Emilia, whose stem cell treatment that saved the boy in 2017 appears to be long-lasting. Given the complexity of his treatment, de Luca suggests the two therapies can be combined, with gel treatments for small wounds, and stem cell or skin grafts for larger areas.
Last week, Marinkovich presented positive results from a larger trial of the gel; Krystal Biotech plans to seek regulatory approval this year. The company is also testing two similar gene therapy treatments: a gel for patients with ichthyosis, a disease that causes dry, scaly skin, and an injection for healthy aging people, to see whether delivering a collagen gene could smooth wrinkles.