Genetically Corrected Skin Grafts Lead to Long-term Benefits in JEB Case
Transplanting a patient’s own genetically corrected skin grafts safely and effectively treated skin loss and ulcers affecting 80% of the body in a boy with a life-threatening form of generalized junctional epidermolysis bullosa (JEB), a study shows.
Notably, these benefits were sustained for at least five years, highlighting that this type of cell-and-gene therapy approach may be effective in other types of epidermolysis bullosa (EB), the researchers noted.
“This study confirms that [such treatment] can restore large areas of epidermis affected by junctional epidermolysis bullosa over the long term,” they wrote, adding that their results “pave the way for a combined cell-and-gene-therapy platform” for other EB forms.
The case study, “Transgenic Epidermal Cultures for Junctional Epidermolysis Bullosa — 5-Year Outcomes,” was published in The New England Journal of Medicine.
Epidermolysis bullosa refers to a group of rare skin disorders that make the skin extremely fragile and prone to blistering.
Generalized JEB is characterized by recurrent and widespread blistering that also affects the mucosal lining of the mouth and digestive tract, subsequently impairing patients’ ability to eat and digest food. Blisters occur within a layer between the epidermis — the top skin layer — and the dermis, which is immediately below the epidermis.
The chronic wounds that result from JEB contribute to significant pain, and also are common sites for the development of infections and skin cancer. There currently is no cure for JEB and more than 40% of patients die before adolescence.
Some previous studies have suggested that skin transplants may be an effective approach for treating skin blisters in people with epidermolysis bullosa.
The child in this study, then age 7, who had life-threatening JEB with widespread skin damage, was treated with two transplants, the first done in October 2015 and the second the next month. A medical team from Germany and Italy transplanted the boy with his own genetically modified skin. The researchers reported on the successful case in 2017.
Now, the same team of researchers described the long-term outcomes of this approach, at five years post-transplant.
Since birth, the boy, who carried a JEB-causing mutation in the LAMB3 gene, had developed blisters all over his body, particularly on his limbs, back, and flanks. He had already lost 60% of his epidermis when he was first admitted in 2015 to the Ruhr-University’s Children’s Hospital, in Germany.
After all subsequent available treatment options failed, the hospital’s medical team asked for the parents’ and health authorities’ permission to conduct a transplant of genetically engineered lab-grown skin derived from the patient.
In collaboration with researchers in Italy, the medical team isolated the boy’s keratinocytes — the main cell type in the epidermis — from a small sample of a non-blistering skin region.
They then used a modified and harmless retrovirus to insert a working copy of the LAMB3 gene into these cells. This way, when keratinocytes renewed, or divided into equal cells, their “daughter cells” would still carry the healthy version of the gene.
Keratinocytes were next grown into epidermal sheets, which were subsequently transplanted into 80% of the boy’s body — the amount of skin showing epidermal loss at the time — over two surgeries later that year. All limbs, flanks, and the entire back were treated with these skin grafts.
After five years and five months, the boy “had recovered well and was engaged in age-appropriate social activities,” the researchers wrote.
His transplanted skin, from the grafts, had grown into a functional, stable, and robust skin that was not prone to blistering, even when exposed to friction. No adverse events (side effects) were observed on the transplanted areas, and mucosal involvement was minimal.
Further analyses confirmed that the regenerated epidermis consisted only of genetically modified keratinocytes, which showed normal levels and localization of laminin 332-beta3, the protein subunit coded by the LAMB3 gene. That means the new skin was comprised only of the genetically modified skin from the grafts.
The sensory function of the boy’s skin “was greatly — although not completely — restored at the 5-year follow-up,” the researchers wrote. Specifically, the boy detected thermal stimuli and pain at the normal range, but showed abnormal mechanical detection thresholds.
To minimize blister formation in untransplanted skin, those areas were treated with appropriate medication that was applied weekly by professional nurses. However, this treatment was stopped for 18 months due to COVID-19 restrictions, resulting in massive blisters that developed on his untransplanted skin. Notably, no blistering occurred on the transplanted areas.
This raises the question of whether such a therapeutic approach should be applied only on blistering areas or also in areas most likely to develop blisters.
While it is possible that the random insertion of a gene into a cell’s DNA results in genetic changes leading to uncontrolled growth of the cell and tumor formation, there were no signs of such event in this case, the team noted. No such events have been recorded in more 30 years of research in human epidermal cells as well, they said.
In fact, early treatment with this approach may ultimately reduce the risk of skin cancer in EB patients, as this is probably caused by skin defects, sustained wound-healing stimuli, and chronic inflammation, “all of which would be restored by regeneration of a functional transgenic epidermis,” the researchers wrote.
Early and progressive transplants also may “improve functional outcomes of the dermal compartment and may also prevent disease exacerbation,” they added.
These long-term findings highlight the safety and efficacy of such a cell-and-gene-therapy approach and suggest that it “could be used to tackle other devastating forms of epidermolysis bullosa,” they concluded.