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Gene therapy gel heals decades-old wounds in trial for blistering skin disease

Researchers find that a gel tested in patients with a life-threatening blistering skin disease helps wounds heal. The gel — the first topical gene therapy — awaits FDA approval.

- By Krista Conger

Vincenzo Mascoli, at left with his parents and Peter Marinkovich, has dystrophic epidermolysis bullosa, a genetic skin disease that leads to painful wounds. A gel that helped Mascoli's wounds heal was developed at Stanford Medicine.
Courtesy of the Mascoli family

People with a blistering skin disease called dystrophic epidermolysis bullosa often suffer from large open wounds that last for years or decades. It’s an intensely painful condition, and medical treatment for it has been limited largely to palliative care.

Now, a double-blind, placebo-controlled clinical trial of a gene therapy gel developed at Stanford Medicine shows improved wound healing in 31 people with the disease, including 19 who were 18 years old or younger. Sixty-seven percent of wounds treated with the gel, which is applied to the skin during bandage changes, completely healed after six months of weekly applications, while only 22% of wounds treated with a placebo did so.

“After four months, I saw an improvement on a large wound on my back that I had for 20 years,” said trial participant Vincenzo Mascoli, 22. “After six months, the wound had healed completely and was much less painful.”

“This was a life-changing event for Vincenzo,” said Peter Marinkovich, MD, director of Stanford Medicine’s Blistering Disease Clinic. “Now he can bathe and sleep on his back without pain. This treatment made a huge difference in quality of life for Vincenzo and other trial participants.”

Marinkovich, an associate professor of dermatology, is the senior author of a study detailing the clinical trial results that was published Dec. 15 in The New England Journal of Medicine. Shireen Guide, MD, a pediatric dermatologist at Children’s Hospital of Orange County, California; Mercedes Gonzalez, MD, a pediatric dermatologist at Florida-based Pediatric Skin Research; and Isin Sinem Bağcı, MD, a basic life research scientist at the Stanford School of Medicine, are the lead authors of the study.

Marinkovich and his colleagues have applied to the Food and Drug Administration for approval of the gel, which is called B-VEC, as a treatment for dystrophic epidermolysis bullosa. It would be the first topical gene therapy treatment approved for use in the United States. The study was funded by Pittsburgh-based Krystal Biotech Inc., which is testing and developing the gel for clinical use.

The late-stage trial results mirror those seen in an earlier, smaller trial in nine patients conducted at the Stanford School of Medicine and published in Nature Medicine in March of 2022. That trial was the first to show that gene therapy vectors for skin diseases can be effective when applied topically and was the first trial of gene therapy in children with epidermolysis bullosa.

A missing protein

People with recessive dystrophic epidermolysis bullosa have a genetic mutation that renders them unable to make a protein called collagen VII, which binds the middle and outer layers of the skin together. Without this protein, the layers slide across each other, causing blisters that progress to severely painful open wounds. People with the condition are vulnerable to infections and skin cancer, and they often die in early adulthood.

Five-year-old Rowan Millner has dystrophic epidermolysis bullosa.
Courtesy of the Millner family

The gel uses a modified herpes simplex virus to deliver a copy of the collagen VII gene to the surface of the skin, which makes the missing protein and stabilizes the skin’s structure. Because the herpes virus has evolved to evade the human immune system, the gel can be applied repeatedly without triggering an immune response that has stymied previous gene therapies using other viruses to deliver corrective genes to the body.

“We saw no inflammation, significant side effects or immune neutralization of the drug, even with repeated administration of the gel over the six months of the trial period,” Marinkovich said.

The researchers hope that the results with the modified herpes virus will advance gene therapy for other diseases in which genes are missing or damaged.

Marinkovich said that while the previous trial was designed to show that gel-treated skin could make collagen VII, the new trial focused mainly on wound healing. “We set a goal for 100% healing within six months of treatment,” he said. “That’s a high bar, but we very clearly met the primary objective.”

After the trial period ended, most participants continued to receive the gel treatment at home under medical supervision as part of an open-label extension of the trial.

Mascoli, who lives in Italy, and his parents stayed in the Palo Alto area for about nine months to participate in the trial, which ended in late 2021. Now that he is home, Mascoli, who is training to be a pharmacist, no longer has access to the gel, although Marinkovich and his colleagues are trying to get him access though a compassionate use authorization in Italy.

Now off therapy for 10 months, Mascoli noted, “Unfortunately, the wounds don’t always stay closed, and new ones can open. I hope that I and other patients can soon use the gel again, because the wounds are much less painful when they are closed.”

Marinkovich traveled to southern Italy in the late 1990s, when he was invited to advise local pediatric dermatologists how best to care for a newly diagnosed child in the region. “I would travel to Italy for a few days each year to consult with their doctors and spend time with their family,” Marinkovich said. “We developed a rapport, and over the years, as I and my colleagues at Stanford Medicine worked to understand the disease and develop treatments, I always had them in the back of my mind. I really wanted to be able to do something to help epidermolysis patients throughout the world. It’s a terrible disease.”

He added that the next steps for researchers will be to try the gel on patients’ hands as well as mucosal surfaces including the mouth, throat, eyes, esophagus and anus.

Researchers from Delaware-based Savio Group Analytics and Maryland-based Kammerman Consulting also participated in the study.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu.

2023 ISSUE 1

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