Genetically modified skin grafts help heal chronic wounds in patients with epidermolysis bullosa

Genetically modified skin grafts help heal chronic wounds in patients with epidermolysis bullosa

Skin grafts genetically engineered from a patient's own cells can heal persistent wounds in people with an extremely painful dermatological disorder, a Stanford Medicine-led clinical trial has shown. The transplants treat severe dystrophic epidermolysis bullosa, or EB, a genetic disorder in which the skin is so fragile that the slightest touch can cause blisters and sores, eventually leading to large, open lesions that never heal and are immensely painful.

A Phase 3 clinical trial showed that EB patients experienced significantly better healing, less pain, and less itching from wounds treated with the genetically modified grafts compared to skin wounds that were not grafted. The results will be published on June 23rdThe Lancet. The skin grafts were approved as EB therapy by the U.S. Food and Drug Administration on April 29.

"Using our novel gene therapy technique, we successfully treated the toughest to sacred wounds, which were also typically the most painful for these patients," said study lead author Jean Tang, MD, professor of dermatology, who treats children with EB at Lucile Packard Children's Hospital. “It is a dream come true for all the scientists, doctors, nurses and patients involved in the long and difficult research process.”

Twenty-year-old Charlotte Brown from Birmingham, Alabama, is experiencing much less pain from her EB than before when she entered the Phase 3 trial in 2021. She can even hold on to a job she loves.

“It’s honestly, life-changing,” Brown said. “I feel so much better.”

Brown is one of 11 patients who took part in the study, most of whom received the new treatment on multiple sites on their skin.

The new skin grafts are part of a larger effort to improve treatment options for EB patients. 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 larger, 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 personalized therapy for EB patients?” she said. “Now there is a lot of hope.”

Starting in the early 2000s, research teams at Stanford Medicine conducted a series of studies showing that a corrected gene could be engineered into skin cells, that the engineered skin grafts work in a mouse model of the disease, and that the grafts are safe and effective for people with EB. The treatment was then licensed by Abeona Therapeutics Inc. at Stanford University, which will produce transplants for patients. The transplants 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 500,000 people. Those with the disease have a defect in the gene for collagen VII, a protein that normally holds 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 skin layers separate in response to light friction, even a light touch. This causes sores that can last for years, as well as extreme pain and itching.

These children are wrapped almost head to toe in wound dressings to protect their delicate skin. They are known as butterfly children because their skin is as fragile as butterfly wings. “

Jean Tang, MD, PhD, lead author

The wounds are susceptible to infection, and even bathing is painful. Over the course of their lifespan, EB patients are at high risk of skin cancer due to the constant inappropriate wounds and inflammation.

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 of Dermatology at 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 of functioning collagen VII and safely grafted onto mice. This work led to Stanford Medicine trials over the next two decades developing skin grafts for gene therapy for humans, including a Phase 1 clinical trial led by Alfred Lane, MD, now professor emeritus of dermatology, and Peter Marinkovich, MD, associate professor of dermatology, which showed early signs of safety and effectiveness Griffen and the effectiveness of the handles, and in 2016 showed.

To make the skin grafts, which are grown individually for each patient, a doctor collects a small biopsy of the patient's unwounded skin. The biopsy is taken to a laboratory where a retrovirus is used to introduce a corrected version of the collagen VII gene.Col7aito the skin cells. The genetically modified cells are grown into sheets of skin, each about the size of a credit card. Preparation of the transplants takes approximately 25 days, after which a plastic surgeon sews the genetically modified skin onto a wound. Patients stay in the hospital for about a week before returning home. Because each transplant is created from the patient's own skin, the treatment provides healthy skin that matches the patient's own immune markers and prevents rejection of the transplants.

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. Each patient could contribute multiple pairs of wounds; The study ultimately included 43 pairs of wounds.

After the grafts were applied, the research team monitored wound healing, pain and itching at regular intervals over six months. At 24 weeks after transplantation, 81% of treated wounds were at least half healed, compared to 16% of control wounds. At the same time, 65% of treated wounds were at least three-quarters healed compared to 7% of control wounds, and 16% of treated wounds were completely healed compared to none of the control wounds. Additionally, patients' reports of pain, itching, and blistering in the grafted areas were better than control wounds, as they improved more from baseline.

The skin grafts were safe and adverse events patients experienced with the treatment were not serious, the study reported. Two patients had pain with the transplant procedure, one had muscle spasms and one had itching. All these problems have certainly been solved. Some patients had mild or moderate infection in wounds treated with the skin grafts.

A better life for patients

Brown joined the Phase 3 trial in 2021 while she was still in high school. She describes the feeling from EB wounds that were not treated with the skin grafts as “like being burned all the time, almost like being dunked in lava.”

The transplants she received in the clinical trial helped heal several large, open wounds on her thigh, hip, abdomen and back. The wounds now remain mainly or completely closed.

“I’m not in as much pain anymore,” Brown said. “I don’t have to wear as many bandages, so I feel a lot lighter physically.”

Brown told Tang that she felt comfortable no longer having wounds that needed to be covered with thick dressings, wearing a dress with the dress, and having the confidence to attend her high school prom.

Brown's parents are both nurses, and one of her grandfathers is a scientist. Now that her EB requires less of her focus, she has joined the family tradition of working in a health-related field with a job she loves: She is a pharmacy technician.

“I’ve never imagined this,” she said.

The transplants have also received rave reviews from other study participants.

"Other patients have told me how much of their life and attention has been focused on these painful wounds," Tang said. "Not having them is very freeing."

The research team follows patients in the clinical trial for up to 15 years to monitor the continued success of the transplants. Researchers hope the grafts will reduce the long-term risk of infections and skin cancer in the areas where they are applied.

“It's important to let patients know: This can give you a chance,” Brown said. "If you're afraid that you can't do things, it will help you live a normal life or give you a better quality of life than you have before."

Tang is excited to see how the therapies help when they become available to very young patients.

"I hope that if these patients are diagnosed as infants and start the gene therapy gel, they may not develop large wounds," Tang said. "But if the gels don't work and a wound expands, 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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