Combination of stem cells and gene therapy essentially cures a genetic skin disease
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 genes — LAMA3, 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.
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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Skin gene therapy
To save the life a young boy who lost most of his skin (left, red), researchers took a small bit of his remaining skin (gray) and grew skin stem cells in the lab. Researchers then used a retrovirus to insert a healthy copy of the LAMB3 gene, needed to help keep skin layers attached, into the stem cells’ DNA. Several types of progenitor stem cells (purple, yellow) were present in the lab-grown skin cells, along with long-lived holoclones (pink). Sheets of lab-grown cells were transplanted to the boy. As the skin replenished itself, the holoclones gradually took over, suggesting a small number of stem cells are responsible for growing all the skin.
“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.
Under the surface
Microscope images show that in normal skin (left) the top layer, called the epidermis (purple in bottom images), is fused to the dermis by laminin 332 (green, in top images) and other proteins. When a 7-year-old boy was admitted to the hospital, he’d lost most of his skin (bottom middle, arrows show where the epidermis is peeling away from the dermis). Mutations in the LAMB3 gene prevented the boy from making laminin 332 protein (top middle, white dashed line indicates where the protein should be), which helps fuse skin layers together. Gene therapy (right panels show the boy’s skin 21 months after therapy) restored laminin 332 (top, green) and his skin stopped blistering (bottom).
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.
T. Hirsch et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature. Published online November 8, 2017. doi: 10.1038/nature24487.
Science News Staff. FDA approves gene therapy to treat a rare cancer. Science News Online, August 30, 2017.
T.H. Saey. Gene therapy for blindness dims a bit. Science News Online, May 3, 2015.
T.H. Saey. Gene therapy treats children with rare diseases. Science News. Vol. 184, August 10, 2013, p. 19.
C. Ezzell. Skin genes underlie blistering disorder. Science News. Vol. 140, September 28, 1991, p. 197.