How gene therapy saved a little boy's life



When a rare genetic condition destroyed nearly 80 percent of a 7-year-old's skin, doctors were sure he would die. But the stars aligned and an experimental gene therapy treatment saved his life.

Modern medicine is amazing. We can transplant hearts and even faces, as well as treat countless diseases. However, when it comes to genetic conditions, we have yet to arrive in the 21st century.

Epidermolysis bullosa (EB) — which is sometimes referred to as butterfly disease — is one such genetic condition. It is caused by several different mutations in proteins that hold the two layers of the skin, the epidermis and dermis, together.

Junctional EB (JEB) affects around 5 percent of individuals with EB and is caused by mutations in proteins that sit at the junction between the skin layers.

Dr. Leena Bruckner-Tuderman — from the Department of Dermatology in the University Medical Center at the University of Freiburg and the EB Center Freiburg, both in Germany — explained to me that people with JEB are in constant pain, and that "[...] minor mechanical stress or friction can cause the [skin] layers to separate and to form blisters and wounds."

"Frequent medical treatments and hospital visits are necessary," she added, "but no cure exists for JEB."

This is the story of how an experimental gene therapy saved a little boy's life, giving hope to the hundreds of thousands of families affected by EB worldwide.

'We were sure that he would die' Dr. Tobias Rothoeft — who works in the Department of Neonatology and Pediatric Intensive Care of University Children's Hospital at Ruhr University Bochum in Germany — explained in a press briefing how he came to care for the young boy.

He is a co-lead author of the study, which describes the treatment and which is published today in the journal Nature.

"We got this kid transferred in summer 2015 from another tertiary care hospital [...]," explained Dr. Rothoeft. "He was admitted there because he had developed an infection in which he rapidly lost nearly two thirds of his body surface area. When he was admitted to our burns center, he was in a septic state [...] so we had a lot of trouble in the first days keeping this kid alive."

After trying several different treatments — including a skin graft from the boy's father — the medical team were left with few options.

"After nearly 2 months, we were absolutely sure that we could [do] nothing for this kid and that he would die." Dr. Tobias Rothoeft But the boy's parents asked if anything else could be done.

"We studied the literature again and approached Dr. De Luca and his team and he promised us he could give us enough skin to heal this kid," Dr. Rothoeft explained.

This was to be the pivotal moment.



Growing skin

Dr. Michele De Luca — a professor of biochemistry and director of the Centre for Regenerative Medicine "Stefano Ferrari" at the University of Modena and Reggio Emilia in Italy — has spent a lifetime developing therapies for skin and eye conditions.

While Dr. Rothoeft and his colleagues were doing their best to keep the boy alive, Dr. De Luca and his team were busy preparing the cells in their laboratories in Modena.

Growing keratinocytes, or cells from the epithelium, is relatively straightforward. This is based on a technique that was developed in the 1970s and still in use today for the treatment of severe burn injuries.

The big difference in this case was that the team had to correct the genetic mutation that causes JEB. Dr. De Luca has been working on a technique to achieve this feat for nearly 20 years. To fix the genetic defect, the researchers used a virus to insert a normal copy of the faulty gene into the cells.

In fact, they treated two people with JEB with genetically modified keratinocytes — and the results were published in 2006 and 2016.

This case was to be their biggest challenge yet; never before had they attempted to repair such a large area of skin.

Three operations later... By the time the boy went into his first operation, he had lost nearly 80 percent of his skin. The surgical team applied genetically modified skin grafts to his arms and legs.

Afterward, he was kept in an artificial coma for 12 days in order to keep the grafts immobile and allow the cells to attach.

The procedure was a success and the patient showed the first signs of improvement.

For co-lead study author Dr. Tobias Hirsch — from the Department of Plastic Surgery in the Burn Centre of BG University Hospital Bergmannsheil at Ruhr Bochum University — the seemingly infinite supply of cells that Dr. De Luca was able to grow was a clear advantage.

"So you can have double the whole body surface or even more. So that's a fantastic option for me as a surgeon to treat this child, because we can get as [many] cells as we need to cover all open areas on the child." Dr. Tobias Hirsch

A second and third operation followed to cover his back, buttocks, and parts of his shoulders, hands, and chest in genetically modified grafts.

Finally, the team could stop his pain medication. After spending nearly 8 months in the intensive care unit, the little boy was allowed to go home.



Playing soccer

Fast-forward 21 months, and "the kid is doing quite well," according to Dr. Rothoeft. "The skin is of good quality, [...] it's perfectly smooth and it's quite stable. If he gets any bruises like small kids [...] have, they just heal as normal skin heals."

"He still has some blisters in non-transplanted areas," Dr. Rothoeft added. "He never had any blisters where we transplanted him."

Children with EB often can't take part in activities that put them at risk of harming their skin. But not our young patient; he's happily playing soccer with his siblings and friends.

Dr. Rothoeft explained that because the little boy can take part in activities that other children with EB would never do, he does get some blisters. But he did say that "the problem with the blisters is restricted on 2 or 3 percent of his body surface area now in areas which we did not transplant."

Overall, however, the patient's quality of life has improved tremendously, Drs. Hirsch and Rothoeft agreed.

"The change is from being on morphine the whole day to no drugs at all at the moment." Dr. Tobias Rothoeft

A breakthrough for gene therapy

For the field of gene therapy, this is clearly a success story. What the team was also able to show with this work is that it only takes a small number of stem cells to regrow skin.

Dr. De Luca speculates that based on their data, these stem cells exist in the skin for our entire lifetime, which is a topic that scientists have been arguing about for years.

"From a biological point of view, [...] we think this epidermis will stay forever. [...] The big message is that once you've regenerated the epidermis with stem cells, [the cells] behave as they are supposed to." Dr. Michele De Luca

However, the significance of this finding goes beyond the basic science of how our skin works; it also gives researchers such as Dr. De Luca the necessary information to grow just the right mix of cells in the laboratory for a stem cell therapy.

So, what does this breakthrough mean for others with EB? "Here," urges Dr. De Luca, "we should be very, very cautious."



Clinical trials ongoing

The mutations that cause other forms of EB may be more difficult to fix. "We might have problems that we did not encounter in JEB," Dr. De Luca explained. "But this is only going to be discovered after the phase I/II clinical trials, which we are doing right now."

The results of a clinical trial involving four people living with dystrophic EB highlight this issue. The mutation in question here affects type VII collagen, which is a protein essential to the structural integrity of the skin.

Although the team saw an initial improvement in wound healing, the effect started to taper off after 1 year. The study authors speculate that this may due to limited numbers of stem cells available from these people, as their skin is very damaged due to the disease.

In an editorial published in the journal Molecular Therapy, Prof. Bruckner-Tuderman comments that the study "underscores the challenges of designing effective molecular therapies for genetic diseases."

But the results published in Nature today leave Prof. Bruckner-Tuderman, who was not involved in the study, hopeful.

"The development of experimental therapies like [this] one [...] gives hope that evidence-based curative treatments will at some point become possible and clinical reality for many patients with JEB and other forms of EB." Prof. Leena Bruckner-Tuderman

This treatment is a significant breakthrough not only for JEB, but for skin science, gene therapy, and regenerative medicine alike. But most importantly, it saved a life.