For the first time, an international team of medical researchers has successfully treated patients with a fatal and rare skin disease called recessive dystrophic epidermolysis bullosa (RDEB) using bone marrow stem cells: so far 10 children with an aggressive form of the disease have been treated successfully although two have since died from related complications.

Drs John E. Wagner and and Jakub Tolar from the University of Minnesota Medical School in the US and colleagues from Portland, Oregon, also in the US as well as colleagues in the UK and Japan, wrote about their research in a paper published in the New England Journal of Medicine on 12 August.

Epidermolysis bullosa (EB), is a rare, genetic skin disease where even the slightest friction causes the skin to blister and scrape off. As well as affecting skin, EB also affects the lining of the mouth and the esophagus.

EB varies widely in severity and forms, the most severe of which are generally lethal. Patients with more severe forms are very fragile, living in constant pain and scarring, which can leave them disfigured and disabled, and they often die young.

The website EB Info World describes the condition as one where the skin has no anchors to hold its layers together. For instance, people with RDEB have no collagen 7, the protein responsible for keeping layers of skin “glued” to one another and to the body.

The National Epidermolysis Bullosa Registry estimates that EB occurs in 20 newborns per 1 million live births in the United States. While the exact number of people with EB is unclear, estimates suggest there are around 25,000 – 50,000 Americans living with EB, most of which have the simplex form, which is mild and for which they may not even seek medical help. But a minority of people with EB have severe forms like Recessive Dystrophic EB, requiring hours of daily intense care, because any activity that rubs or causes pressure produces a painful sore akin to a second-degree burn.

A child born with a severe form EB has an extremely difficult life ahead; it will scream with pain when bathed, it will never run and jump and play like other kids, as even the act of crawling as an infant will cause its knees to bleed. Parents and carers of babies with severe EB painstakingly wrap each of their little fingers with Vaseline gauze and then more gauze to try and prevent their hands from scarring, webbing and contracting.

Despite this, many teenagers with severe EB have stumps for hands because their fingers have scarred and healed together. Of those who go on to live to their 20s and 30s, most develop an aggressive form of skin cancer. Some countries have even considered euthanasia for newborns with the severest forms of EB.

That is because until now there has been no treatment and no chance of a cure.

This study is the first to show that bone marrow stem cells can home to the skin and upper gastrointestinal tract and change the natural course of the disease.

Wagner, who is University of Minnesota Medical School’s director of pediatric blood and marrow transplantation and clinical director of the Stem Cell Institute, told the press that:

“Whether stem cells from marrow could repair tissues other than itself has been quite controversial.”

“But in 2007 we found a rare subpopulation of marrow stem cells that could repair the skin in laboratory models. This astounding finding compelled us to test these stem cells in humans. This has never been done before,” he added.

Tolar, an associate professor of pediatric transplantation at the Medical School said they found that:

“Stem cells contained in bone marrow can travel to sites of injured skin, leading to increased production of collagen which is deficient in patients with RDEB.”

Tolar went on to explain that bone marrow trasplants are one of the riskiest yet also one of the most successful procedures in medicine.

“Patients who otherwise would have died from their disease can often now be cured. It’s a serious treatment for a serious disease,” he added.

Wagner, Tolar and colleagues started working on the study in 2007. Since then 10 children with the most aggressive forms of EB have received bone marrow transplants at the University of Minnesota Amplatz Children’s Hospital, with some responding better than others.

Wagner said you have to look at these results in context: “you have to understand how horrible this disease actually is,” he urged, in order to understand the achievement.

“From the moment of birth, these children develop blisters from the slightest trauma which eventually scar. They live lives of chronic pain, preventing any chance for a normal life. My hope is to do something that might change the natural history of this disease and enhance the quality of life of these kids,” said Wagner.

In their paper, Wagner, Tolar and colleagues describe how they treated seven children with RDEB between October 2007 and August 2009 with “immunomyeloablative chemotherapy and allogeneic stem-cell transplantation”.

The aim was to increase the amount of C7 expression which they assessed “by means of immunofluorescence staining” and use of “transmission electron microscopy to visualize anchoring fibrils”. They also kept a photographic record of blister formation and wound healing.

In their results they reported that one patient died of “cardiomyopathy before transplantation”, and of the remaining six, one had “severe regimen-related cutaneous toxicity”, while all had improved wound healing and reduced blister formation between 30 and 130 days after receiving the new bone marrow.

One further patient died at 183 days after transplant “as a consequence of graft rejection and infection”. The other five were alive 799 days after transplantation.

The researchers concluded that:

“Increased C7 deposition and a sustained presence of donor cells were found in the skin of children with recessive dystrophic epidermolysis bullosa after allogeneic bone marrow transplantation.”

They said further studies should now be done to “assess the long-term risks and benefits of such therapy in patients with this disorder”.

Wagner and Tolar are continuing to assess the progress of the children. They are checking their overall health and the strength of their skin, and also using lab tests to see how well the donor cells are integrating into their skin, as well as measuring levels of collagen 7.

“What we now know is that after this treatment, healthy donor cells reside in the skin, collagen 7 consistently increases over time and the skin gradually becomes more resistant to blister formation,” said Wagner.

“This discovery expands the scope of marrow transplantation and serves as an example of the power of stem cells in the treatment of disease,” he added.

“While the treatment offers a chance for a better life, it comes with significant risk,” said Tolar. “Two children have died from complications related to the treatment, so refinements are needed.”

“Bone Marrow Transplantation for Recessive Dystrophic Epidermolysis Bullosa.”
John E. Wagner, Akemi Ishida-Yamamoto, John A. McGrath, Maria Hordinsky, Douglas R. Keene, Megan J. Riddle, Mark J. Osborn, Troy Lund, Michelle Dolan, Bruce R. Blazar, and Jakub Tolar.
N Engl J Med 2010; 363:629-639; August 12, 2010
DOI: 10.1056/NEJMoa0910501

Sources: University of Minnesota, EB Info World, Stanford School of Medicine.

Written by: Catharine Paddock, PhD