A phase 3 clinical trial showed that EB patients experienced significantly better healing, less pain and less itching from wounds treated with the genetically engineered grafts compared with skin wounds that were not grafted. The results are being published June 23 in The Lancet. The skin grafts were granted approval as an EB therapy on April 29 by the U.S. Food and Drug Administration.
“With our novel gene therapy technique, we successfully treated the hardest-to-heal wounds, which were usually also the most painful ones for these patients,” said the study’s lead author, Jean Tang, MD, PhD, a professor of dermatology who treats children with EB at Lucile Packard Children’s Hospital Stanford. “It’s a dream come true for all the scientists, physicians, nurses and patients who were involved in the long and difficult research process.”
Twenty-year-old Charlotte Brown of Birmingham, Alabama, experiences much less pain from her EB than before she joined the phase 3 trial in 2021. The genetically engineered grafts she received in the trial have greatly reduced the severity of several chronic wounds. She is even able to hold down a job she loves.
“It’s honestly life-changing,” Brown said. “I feel so much better.”
Brown is one of 11 patients who participated in the study, most of whom received the new treatment at multiple sites on their skin.
The new skin grafts are part of a larger effort to improve EB patients’ treatment options. Another treatment, a gene therapy gel that can be applied to the skin, has been available to EB patients since 2023. The gel helps prevent and heal smaller wounds, but patients still need an effective way to treat bigger, more persistent wounds. Skin grafts fit the bill, and as a product of more than two decades of Stanford Medicine research, the development has Tang and her collaborators “super excited.”
“Who would have thought that an experiment in a Stanford lab would lead to a personalized therapy for EB patients?” she said. “Now there’s a lot of hope.”
Starting in the early 2000s, Stanford Medicine research teams conducted a series of studies showing that a corrected gene could be engineered into skin cells, that the engineered skin grafts would function in a mouse model of the disease, and that the grafts are safe and effective for people with EB. The treatment was then licensed from Stanford University by Abeona Therapeutics Inc., which will manufacture grafts for patients. The grafts will be available at five hospitals across the country, including Lucile Packard Children’s Hospital Stanford.
Skin as fragile as butterfly wings
Severe dystrophic epidermolysis bullosa is very rare, affecting one in every 500,000 people. Those with the disease have a defect in the gene for collagen VII, a protein that normally holds the skin together.
“Collagen VII is like a staple that attaches the top layer to the bottom layer of your skin,” Tang said. Without this molecular “staple,” the layers of patients’ skin separate in response to slight friction, even a light touch. This causes wounds that can persist for years as well as extreme pain and itching.
“These kids are wrapped in wound dressings almost from head to toe, just to protect their delicate skin,” Tang said. “They’re known as butterfly children because their skin is as fragile as butterfly wings.”
The wounds are prone to infection, and even bathing is painful. Over their lifetimes, because of the constant unhealed wounds and inflammation, EB patients are at high risk for skin cancer.
Other parts of the body are also affected, as collagen VII helps hold layers of the digestive tract and eyes together, but the skin problems are the most difficult aspect of the disease.
Two decades of Stanford Medicine research
In 2003, Paul Khavari, MD, PhD, the Carl J. Herzog Professor in Dermatology in the School of Medicine, and Zurab Siprashvili, PhD, senior staff scientist, developed a safe and effective way to genetically engineer EB skin cells with a corrected gene. The team showed that the resulting skin could be grown into small patches that had functioning collagen VII and could be safely grafted to mice. This work led, over the next two decades, to Stanford Medicine studies that developed gene therapy skin grafts for people, including a phase 1 clinical trial led by Alfred Lane, MD, now emeritus professor of dermatology, and Peter Marinkovich, MD, associate professor of dermatology, which showed early signs of safety and effectiveness of the grafts and was published in 2016.
To make the skin grafts, which are grown individually for each patient, a physician collects a small biopsy of the patient’s un-wounded skin. The biopsy is taken to a lab, where a retrovirus is used to introduce a corrected version of the collagen VII gene, COL7AI, to the skin cells. The genetically engineered cells are grown into sheets of skin, each about the size of a credit card. Preparing the grafts takes about 25 days, after which a plastic surgeon sutures the genetically engineered skin onto a wound. Patients stay in the hospital for about a week before returning home. Because each graft is created from the patient’s own skin, the treatment provides healthy skin that matches the patients’ own immune markers, preventing rejection of the grafts.
The phase 3 study included 11 patients with recessive dystrophic EB, all of whom were at least 6 years old. The study compared pairs of wounds in similar locations on the same person: One wound from each pair was treated with a genetically engineered skin graft, and the other was treated with usual care practices. Each patient could contribute multiple pairs of wounds; the study ultimately included 43 wound pairs.
After the grafts were applied, the research team monitored wound healing, pain and itching at regular intervals over about six months. At 24 weeks after grafting, 81% of treated wounds were at least half healed, compared with 16% of control wounds. At the same time point, 65% of treated wounds were at least three-quarters healed, compared with 7% of control wounds, and 16% of treated wounds had completely healed, compared with none of the control wounds. In addition, patients’ reports of pain, itching and blistering were better on the grafted areas than the control wounds, having shown more improvement from baseline.
The skin grafts were safe, and adverse events that patients experienced related to the treatment were not serious, the study reported. Two patients experienced pain with the graft procedure, one had muscle spasms and one experienced itching. All of these problems resolved safely. Some patients experienced mild or moderate infection in wounds treated with the skin grafts.
A better life for patients
Brown joined the phase 3 trial in 2021, when she was still in high school. She describes the sensation from EB wounds that have not been treated with the skin grafts “like being burned all the time, almost like being submerged in lava.”
The grafts she received in the clinical trial have helped heal several large, open wounds on her thigh, hip, abdomen and back. The wounds now stay mostly or completely closed.
“I’m not in as much pain anymore,” Brown said. “I don’t have to wear as many bandages, so physically I feel a lot lighter.”
Brown told Tang that because she no longer had oozing wounds that needed to be covered in thick dressings, she felt comfortable wearing a dress and had the confidence to attend her high school prom.
Brown’s parents are both nurses, and one of her grandfathers is a scientist. Now, with her EB demanding less of her focus, she has joined the family tradition of working in a health-related field with a job she loves: She’s a pharmacy technician.
“I never imagined that before,” she said.
The grafts have received enthusiastic reviews from other study participants, too.
“Other patients have told me just how much of their life and attention had been focused on these painful wounds,” Tang said. “To not have them is very freeing.”
The patients in the clinical trial will be followed by the research team for up to 15 years to check on the continued success of the grafts. The researchers hope that the grafts will reduce long-term risks for infections and skin cancer in the sites where they are used.
“It’s important to let patients know: This may give you a fighting chance,” Brown said. “If you are scared that you can’t do things, it’s going to help you get closer to living a normal life, or give you a better quality of life than you had previously.”
Tang is excited to see how the therapies, when they are available for very young patients, will help.
“I hope that if these patients are diagnosed as infants and start the gene therapy gel, maybe they won’t develop big wounds,” Tang said. “But if the gels don’t work and a wound does expand, the skin graft therapy is the right treatment. The life arc of their disease will, I hope, be modified, with less suffering.”
The phase 3 study was funded by Abeona Therapeutics Inc.
Scientists from the VA Palo Alto Health Care System, the University of Massachusetts Chan Medical School, Abeona Therapeutics Inc. and the University of Colorado Anschutz Medical Campus contributed to the research.
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