June 23, 2008 Researchers and clinicians have paved the way toward a cure for a young boy’s genetic and fatal skin disease, recessive dystrophic epidermolysis bullosa (RDEB), by using a cord blood and bone marrow transplant. Nate Liao, 25 months old from Clarksburg, N.J., underwent the experimental therapy in October 2007, as the result of a research and clinical collaboration between researchers at Columbia University Medical Center in New York and Thomas Jefferson University in Philadelphia and physicians at the University of Minnesota and University of Minnesota Children’s Hospital, Fairview.
Children with RDEB have skin that is exquisitely delicate because of a genetic defect that results in the absence of a critical protein called collagen type VII, which anchors the skin and lining of the gastrointestinal (GI) system to the body. Without collagen type VII, the skin of people with RDEB is extraordinarily fragile; tearing and blistering occur with minimal friction.
RDEB is associated with painful wounds, mutilating scaring, malnutrition due to the erosion of the esophagus, and frequent infections, so to minimize the risk of tears and blistering those affected must have their entire body continuously wrapped in bandages. Up until now, there have been no successful treatments for children with RDEB and it is always fatal due to malnutrition, infection or eventually an aggressive skin cancer.
In this trial, through the infusion of marrow stem cells obtained from a healthy donor, transplanted stem cells produce collagen type VII and correct the underlying genetic defect.
“We have established a new standard of care for these EB patients, beginning with Nate,” said John Wagner, M.D., the lead University of Minnesota Medical School physician who developed the clinical trial. “Nate’s quality of life is forever changed.”
The concept of using circulating stem cells to treat a skin disease like RDEB was introduced by Angela M. Christiano, Ph.D., professor of dermatology and genetics and development at Columbia University Medical Center, who has been involved in the study of the genetics of RDEB for more than 15 years. Her laboratory performed the first genetic studies on the Liao family and determined the exact molecular basis for their individual case of RDEB. She has studied several gene therapy approaches for RDEB in the past before turning her attention to circulating stem cells.
“This is the first time physicians have approached the treatment of RDEB or any similar skin disease, from a systemic perspective, using marrow-derived stem cells as a means to replace the missing protein, collagen type VII, throughout the body,” said Dr. Christiano.
The groundbreaking research leading up to the clinical trial required that the investigators first showed evidence of a benefit of stem cell therapy in a mouse model of RDEB. Collaborating with Christiano, University of Minnesota researchers Jakub Tolar, M.D., Ph.D., and Bruce Blazar, M.D., discovered that certain stem cells found in bone marrow could correct the biochemical defect in RDEB. The mouse model of RDEB was generated specifically for the purpose of testing novel RDEB therapies, by the laboratory of Jouni Uitto, M.D., Ph.D., professor and chair, Department of Dermatology and Cutaneous Biology, at Thomas Jefferson University in Philadelphia. Analysis also was performed at Asahikawa Medical College in Asahikawa, Japan.
Using the RDEB mouse, Drs. Tolar and Blazar showed that delivering marrow-derived stem cells in the bloodstream greatly lengthened the life expectancy of the mice, and also healed existing blisters. Using the positive results from the RDEB animal model, Dr. Wagner’s team at UMN then designed a clinical trial to test stem cell therapy for RDEB for the first time in patients suffering from the disease; Nate being the first in the trial.
Drs. Christiano and Uitto are experts in the genetic basis of different forms of EB, and their work together has included identification of the human and mouse type VII collagen genes, establishing type VII collagen gene mutations as the molecular basis for dystrophic forms of EB, leading to the development of DNA-based diagnostic tests for EB and eventually to pre-clinical animal models, through research supported from Dystrophic Epidermolysis Bullosa Research Association of America (DebRA of America) and the National Institutes of Health. Dr. Christiano’s ongoing work on stem cell therapy for RDEB and other disorders is supported by the New York State Foundation for Science, Technology and Innovation (NYSTAR).
“The work announced today is the culmination of several years of preclinical work supported in part by the DebRA of America, specifically, the development of a mouse model that recapitulates the features of RDEB, including severe skin blistering at birth,” said Mary Sprague, executive director of DebRA. “DebRA of America is pleased that its support to fundamental basic research in EB has facilitated this major achievement towards treatment, and eventually a cure, for RDEB.”
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