“As skin diseases go, recessive dystrophic epidermolysis bullosa is about as severe as it gets,” says Angela M. Christiano, Ph.D, the Richard and Mildred Rhodebeck Professor of Dermatology. Unfortunately, there are thousands of kids and families in the U.S. who know this all too well.
An inherited skin disorder, epidermolysis bullosa (EB) usually begins in infancy, sometimes in utero. In the most severe form of the disease, recessive dystrophic EB, painful, disfiguring blisters, much like third-degree burns, form all over the skin in response to the slightest trauma. Epithelial tissue that lines the mouth, esophagus, lungs, and other structures can also be affected. “There’s no curative therapy, just wound care and medical management at the moment,” says Dr. Christiano, who is also Director of the Department’s Basic Science Research Group.
But there’s a glimmer of hope. A team of researchers at Columbia, including Dr. Christiano, is testing a promising new approach to EB: a modified bone-marrow stem cell transplant.
The idea behind the treatment is to give EB patients a long-lasting supply of type VII collagen, an adhesive protein that anchors the outer layer of skin, known as the epidermis, to the layer below, the dermis. Patients with recessive dystrophic EB have two defective type VII collagen genes (one inherited from each parent), which leads to an abnormal form or even complete absence of the protein.
Initially, researchers had high hopes that EB could be corrected with gene therapy. In this approach, skin cells are harvested from a patient, grown in culture, and infected with a virus carrying sufficient, normal type VII collagen genes to replace the missing protein. After the skin cells incorporate the genes, they are grafted back onto the patient. For various reasons, the treatment has proven much more challenging than originally thought. First, the new skin cells don’t persist in the skin after grafting. “Also, you can cover only a small patch of skin,” says Dr. Christiano. “To cover the entire outer surface of a child would be cumbersome, if not impossible. And this doesn’t address the epithelial tissues lining the inside of the body.”
A few years ago, Dr. Christiano began looking at a different way to deliver type VII collagen to affected tissue. “When patients have a bone-marrow transplant, stem cells in the donated marrow repopulate the marrow in the recipient, but they also wind up in a lot of places, including the skin,” she explains. This observation led her to reason that if an EB patient were given a bone-marrow transplant harvested from an unrelated person with normal type VII collagen genes, the stem cells would eventually find their way to the patient’s skin and other affected tissues and begin producing normal collagen. She and several other groups have since tested the concept on a special breed of mice that lack the type VII collagen gene. “It wasn’t a home run, but there was marked improvement,” says the researcher.
Dr. Christiano then turned to Mitchell Cairo, M.D., Chief and Bone marrow Transplantation and Professor of Pediatric Medicine and pathology at NewYork-Presbyterian Hospital at Columbia University. Dr. Cairo had developed a process called ‘reduced-intensity conditioning’ before bone marrow transplantation for use in non-malignant diseases like EB. This method, which destroys only a portion of the patient’s marrow yet allows permanent stem cell engraftment, comes with a much reduced risk profile that makes it feasible to think about attempting stem cell therapy in EB. Together, Drs. Cairo and Christiano had the workings a potential EB breakthrough.
Clinical trials of the new treatment, using unrelated umbilical cord blood as the source of the stem cells, are slated to begin this July. EB children, and their parents, will be eagerly watching and waiting.