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Gene Therapy Skin Grafts Save Boy With Rare Disease

Gene therapy created a whole body skin graft for a 'butterfly' boy. It's a new regenerative medicine approach using both gene therapy and stem cells.
Denuded skin on the patient is represented in red, blistering areas in green.
Denuded skin on the patient is represented in red, blistering areas in green.Center for Regenerative Medicine, University of Modena and Reggio Emilia

Seven-year-old Hassan was dying. An infection had destroyed most of his skin, he was too weak to eat, and he was in agony.

Doctors in Germany were planning to provide palliative care — keeping the child as comfortable as possible while he died. But there was another option: an experimental skin graft made using gene therapy to correct the faulty DNA that gave the boy his delicate, blister-prone skin.

It worked. The graft replaced 80 percent of Hassan's skin, and he’s back at school, leading a normal life, the researchers reported Wednesday in the journal Nature.

"The amount of coverage that (the team) was able to achieve on this patient and the impact that this has had on the patient's life is really incredible," said Dr. Peter Marinkovich of Stanford University, who also uses skin grafts to treat similar patients.

"It shows the promise of what we are doing."

Hassan, identified only by his first name, has a rare genetic condition called junctional epidermolysis bullosa. This particular type of epidermolysis bullosa (EB) is caused by defects in genes that control development of a membrane in the epidermis — the top layer of skin.

Kids with EB, sometimes called “butterfly children” because their skin is as fragile as butterfly wings, develop painful blisters when their skin layers rub against one another with any movement. They are vulnerable to infections and skin cancer and often die before age 30. There is no cure.

European researchers used genetic engineering to grow skin grafts that replaced 80 percent of the skin on a 7-year-old boy with a rare genetic disease.Michele De Luca / Center for Regenerative Medicine

“Since birth, the patient had developed blisters all over his body, particularly on his limbs, back and flanks,” the researchers wrote. His blistered skin had been attacked by two bacterial infections that destroyed most of it.

Related: Helping 'butterfly children'

Skin grafts usually don’t work for these patients because of the genetic mutations controlling how the skin grows. The boy had been given skin grafts from his father, but they did not last.

However, some earlier experiments had shown it might be possible to take some skin from a patient, replace the faulty gene using gene therapy, grow the skin into sheets in the lab, and then graft it back.

But this approach had only been tried on two children and only replacing small patches of skin. And the treatment itself could kill Hassan.

The desperate parents asked to try it, anyway.

“His epidermis is currently stable and robust, and does not blister, itch, or require ointment or medications."

The team at Children’s Hospital at Ruhr University in Bochum, Germany teamed up with specialists across Europe, led by Dr. Michele De Luca of the University of Modena and Reggio Emilia in Italy, a specialist in regenerative medicine.

They took a patch of non-blistered skin from Hassan's leg and used a virus to carry a corrected version of the bad DNA into his skin cells.

They grew grafts of the corrected skin and, in three separate operations over several months, replaced the missing skin.

Related: Regenerative Medicine Grows New Organs in the Lab

Hassan was in terrible shape. He’d lost much of his body weight and was kept sedated at first because of the agonizing treatment.

But the grafts took, and grew, the team reported.

“He was discharged from the hospital in February , 2016,” De Luca told reporters in a telephone briefing.

“His epidermis is currently stable and robust, and does not blister, itch, or require ointment or medications,” the team wrote. “The child returned to regular elementary school in March 2016.”

Denuded skin on the patient is represented in red, blistering areas in green.Center for Regenerative Medicine, University of Modena and Reggio Emilia

Tests showed that the gene therapy corrected immature cells known as stem cells. These stem cells replenished the skin cells with normal, healthy skin.

“The paper was able to show that in fact it is a specific cell population that gives rise to the continued regeneration,” said Dr. Anthony Atala, a specialist in regenerative medicine at Wake Forest University who was not involved in the research.

“It’s a small population of those cells. It is not all the cells we put in there,” Atala added. “The advantage is that even long-term those cells that have that (corrective) gene remain and are able to keep repopulating the skin over and over again for long periods of time.”

Gene therapy has its own risks, including the possibility that tumors might form, but there’s no evidence this has happened in the boy, the team reported.

“The authors’ work marks a major step forward in the quest to use stem-cell therapies to treat disease,” Mariaceleste Aragona and Cédric Blanpain, who work at the Laboratory of Stem Cells and Cancer at the Université Libre de Bruxelles in Belgium and who also were not involved in the experiment, wrote in a commentary.

"You can get to the patients early before they have all the complications and suffering."

It’s one of several approaches being tried to help children and adults with EB. About 20 in every 1 million babies born in the U.S. have one of the various forms of the condition and advocacy groups estimate between 25,000 and 50,000 people in the U.S., mostly children, currently have EB.

Last year Marinkovich's team at Stanford used gene therapy to treat four adults with a form of EB that is a little different from the case of the boy in Germany. But they only replaced patches of skin the size of playing cards, Marinkovich said.

They are now recruiting patients for a bigger experiment to prove it's safe to do in children.

"This is really the way to go. You can get to the patients early before they have all the complications and suffering," Marinkovich said.

Because gene therapy is uncertain, Marinkovich said his team is also testing out a more direct treatment. Instead of replacing the gene, they inject the protein that the gene codes for into the skin of patients. It's not as permanent a solution, but the protein can help normalize the skin for a few months, he said.

"It bypasses some of the safety issues," Marinkovich said.

A team at the University of Minnesota has been trying a different tactic, using bone marrow transplants to help patients, and they’ve moved on to advanced gene-editing methods to try to create corrected skin grafts for patients.

Related: 9-Year old Raises Money for Friend With 'Butterfly' Disease

Any of the treatments being developed for EB could help patients with other skin diseases caused by a single mutated gene, such as epidermolytic ichthyosis, which causes reddening, scaling, and severe blistering of the skin, Marinkovich noted.

There are also many different experimental approaches to skin grafts, including methods that break down a patient’s skin sample into a liquid, growing a slurry of new cells, and spraying them over a burned area or a wound.

Treating burns or deep injuries can be far more complicated than merely replacing the top layer of skin, the epidermis, Atala noted. Human skin has several layers and is itself a complex organ. Atala’s lab is working on ways to regenerate and replace the multiple layers of skin lost in a serious burn or injury.