Scientists replaced 80 percent of a ‘butterfly’ boy’s skin

Combination of stem cells and gene therapy essentially cures a genetic skin disease


SKIN REPAIR A 7-year-old with a rare genetic condition lost most of the top layer of his skin, the epidermis. Scientists used a combination of stem cells and gene therapy to repair the damage.  

Andrey Prokhorov/iStockphoto

In a last-ditch effort to save a dying 7-year-old boy, scientists have used stem cells and gene therapy to replace about 80 percent of his skin.

This procedure’s success demonstrates that the combination therapy may be effective against some rare genetic skin disorders. The study also sheds light on how the skin replenishes itself, researchers report November 8 in Nature.

In 2015, a boy with a rare genetic skin condition, called junctional epidermolysis bullosa, had lost most of his skin and was close to death. Children with the condition have mutations in one of three genesLAMA3, LAMB3 or LAMC2. Those genes produce parts of the laminin 332 protein, which helps attach the top layer of skin, the epidermis, to deeper layers.

MISSING PIECES A boy with a genetic disease called junctional epidermolysis bullosa lost the upper layer of his skin from most of his back and legs from an infection. Red shows where skin was missing. Green indicates blistered areas. People with this condition are called “butterfly children” because their skin is as fragile as the insect’s wings. T. Hirsch et al/Nature 2017

People with the condition are sometimes called “butterfly children” because their skin is as fragile as the insect’s wings. Even mild friction or bumps can cause severe blistering. The blistering can also affect mucus membranes inside the body, making breathing, swallowing and digesting food difficult. About 1 in every 20,000 babies in the United States are born with the condition, so roughly 200 children each year. More than 40 percent die before adolescence.

Doctors thought the boy would also perish, says Tobias Hirsch, a plastic surgeon at Ruhr University Bochum in Germany who helped care for him. Surgeons in a burn unit tried giving the boy a skin graft from his father, but the child’s body rejected the transplant. “We didn’t have any options to treat this child,” says Hirsch.

For help, Hirsch’s team turned to stem cell researcher Michele De Luca of the University of Modena and Reggio Emilia in Italy. De Luca and colleagues had pioneered techniques correcting the same genetic defect. In clinical trials, De Luca’s team had grown small patches of gene-repaired skin for children with the same condition.

Together, those cases had replaced 0.06 square meters of tissues, about the size of a piece of paper. But the boy, who has a mutation in the LAMB3 gene, had lost nearly all the skin on his back and legs and had blistering in other areas. The researchers needed to replace about 0.85 square meters of skin — 14 times more.  

In September 2015, the team took a 4-square-centimeter patch of unblistered skin from the boy’s groin and grew skin stem cells in the lab from that sample. Then De Luca and colleagues used a retrovirus to insert a healthy copy of the LAMB3 gene into DNA in the lab-grown skin stem cells.

Those genetically corrected skin cells grew into sheets that surgeons grafted onto the boy’s body in two surgeries in October and November 2015. After one more surgery to replace small patches of skin, he was released from the hospital in February 2016.

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“The kid is now back to school. He plays soccer,” says Hirsch. His new skin is fully functional. He still has some blistering in untreated areas, and his doctors are considering replacing more skin. Meanwhile, some of the corrected stem cells may be making their way into the boy’s untreated epidermis, and may eventually replace all of his skin. But researchers can’t take many samples of his skin to find out. “He’s a patient,” says De Luca. “He’s not a mouse.”

The case is a landmark in stem cell therapy, says stem cell researcher Elaine Fuchs of Rockefeller University in New York City. “It makes considerable headway in resolving a brewing controversy in the epidermal stem cell field” over exactly how the skin regenerates, she says.

One possibility is that a large number of stem cells populate the skin. Each stem cell can then either copy itself or morph into a variety of different types of mature skin cells. The other possibility is that only a small number of long-lived stem cells — known as holoclones — give rise to short-lived progenitor cells that are forerunners to mature skin cells.

When researchers inserted the LAMB3 gene, it landed in different places in each lab-grown stem cell. De Luca and colleagues used the different insertions like little bar codes to track the boy’s holoclones and other skin cells. At first, his skin was a patchwork of skin cells, with about 91 percent of progenitor cells having different insertions than the holoclones. After four months, only 37 percent of the progenitor cells were different from the holoclones. That indicates that most of the progenitor cells had died and were replaced by offspring of the long-lived holoclones. The data indicate that a small number of stem cells replenish the skin.

While progenitor cells live for just months, the researchers found, holoclones last a person’s lifetime. Those findings suggest that researchers need to be careful to nurture holoclones when growing skin in the lab, De Luca says.

Editor’s note: This story was updated November 15, 2017, to correct the date the study was published.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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