Systemic Therapy for a Genetic Skin Disease

Leena Bruckner-Tuderman, M.D.
N Engl J Med 2010; 363:680-682August 12, 2010

Article
With an area of almost 2 m2, the human skin forms a large physical barrier between the organism and the environment. Diseases of the skin can have a severely negative effect on the quality and length of life of the persons affected.
Although effective treatments have been devised for common skin diseases, curative therapies do not exist for genetic skin disorders, of which there are nearly 400. There are too few patients within each group to provide an incentive for the pharmaceutical industry to develop drugs. Scientists, however, have recognized the value of monogenic diseases as models for the investigation of therapeutic approaches. Preclinical testing of therapies involving genes, small interfering RNA (siRNA), proteins, and cells,1 both in animal models2 and in pilot trials with individual patients,3-5 has fueled enthusiasm for evidence-based treatments of genetic skin diseases.
The systemic therapy for a genetic skin disease described by Wagner and colleagues in this issue of the Journal 6 represents a leap forward. These investigators describe a phase 1–2 clinical trial of allogeneic bone marrow transplantation or umbilical-cord blood transplantation to treat epidermolysis bullosa.
Epidermolysis bullosa is a heterogeneous group of disorders characterized by chronic epithelial fragility7; the key symptom in all forms is trauma-induced skin blistering. It is caused by the mutation of 1 of at least 14 genes encoding proteins of the dermal–epidermal junction — a specialized basement-membrane zone that attaches the epidermis to the dermis.1,7 Patients have large, painful skin lesions, physical impairment, and a permanent need for assistance. For a patient with generalized epidermolysis bullosa, the estimated cost of symptomatic treatment of the skin alone exceeds $30,000 each year.
One of the most severe of the epidermolysis bullosa subtypes is generalized recessive dystrophic epidermolysis bullosa,8 which is caused by mutations in the gene encoding collagen VII (C7) and is characterized by a lack of this collagen and its polymers — the anchoring fibrils — in the skin and mucosa. In recessive dystrophic epidermolysis bullosa, trauma-induced blistering and chronic, nonhealing wounds are associated with scarring. Joint contractures, mutilating deformities of the hands and feet, malnutrition, and growth retardation are secondary symptoms requiring continuous multidisciplinary management. A feared complication of this disorder is the development of squamous-cell carcinomas early in life. These cancers are aggressive, with a high propensity for metastasis.
Wagner and colleagues initiated their study after obtaining positive results on preclinical tests.9 Seven children with recessive dystrophic epidermolysis bullosa (between 15 months and 14.5 years of age) were treated with immunomyeloablative chemotherapy and subsequent bone marrow transplantation, umbilical-cord blood transplantation, or both. Before treatment, all the children had extensive blistering, with varying degrees of involvement of other organs. Five of the seven graft recipients were alive between 130 and 799 days after transplantation and had a substantial proportion of donor cells in the skin (median, 20%). In five of the six children who could be evaluated, the authors observed an increase of C7 at the dermal–epidermal junction. They did not, however, observe distinct anchoring fibrils. The children's parents reported improved wound healing and less blistering within the first 100 days. Presumably, the healthy hematopoietic donor cells in the skin synthesized and secreted C7, which was then incorporated into the dermal–epidermal junction.
These data are consistent with studies in mice indicating that 30 to 40% of physiologic C7 levels is sufficient for clinically significant skin integrity.10,11 Inducing normal levels of C7 at the dermal–epidermal junction does not seem to be required for a clinical benefit in children with recessive dystrophic epidermolysis bullosa, although the extent to which the level of C7 is increased generally correlates with the extent of improvement.6,11
The assessment of clinical symptoms was quite subjective in this trial and was based partly on parents' reports or reductions in bandage use. Because recessive dystrophic epidermolysis bullosa has a naturally undulating course, it is difficult to determine how much of the clinical improvement in the children was due to transplantation and how much was due to a long period of careful medical attention, protection from trauma, and standardized wound care. Future trials must use more objective methods to assess the frequency of blistering, the stability of the dermal–epidermal junction, and the extent of wound areas.
Larger patient cohorts will be pivotal in determining the long-term success of transplantation of bone marrow or umbilical-cord blood as a therapy for recessive dystrophic epidermolysis bullosa. Future trials must focus on the extent and duration of the therapeutic effects and the adverse effects associated with transplantation. Longer follow-up periods are required to show whether higher C7 levels in the skin and improved resistance to mechanical stress can be sustained. In a previous investigation of bone marrow transplantation in the treatment of osteogenesis imperfecta, another disease caused by a mutation in a collagen gene, the clinical benefits tapered off 1 to 2 years after transplantation.12
Bone marrow transplantation is a standard treatment for malignant disorders of the hematopoietic and immune systems, and Wagner et al. have shown that some patients with mucocutaneous fragility can tolerate the procedures required for such treatment. Nevertheless, bone marrow transplantation has potentially life-threatening adverse effects that must be carefully weighed against the symptoms of recessive dystrophic epidermolysis bullosa and its associated risks. In the present trial, one of the seven patients died during conditioning and another, as a result of infections, after about 6 months.
This brings up the question of age relative to bone marrow transplantation. The general condition of the patient is an important consideration — that is, optimal clinical benefits may not be achieved if symptoms are too advanced. Children with recessive dystrophic epidermolysis bullosa have blistering at birth, but the severe secondary symptoms develop progressively during childhood. It would seem reasonable to perform transplantation as early as possible, with the aim of preventing severe scarring, deformities, and also, ultimately, squamous-cell carcinoma. However, it seems plausible that parents would find it difficult to subject their young children — not yet severely affected — to a therapeutic regimen that could pose the risk of life-threatening toxicity.
Many questions about cellular mechanisms also remain to be answered. Which specific bone marrow–derived cells are critical for therapeutic efficacy? How do they home to the skin? Does their state of differentiation, longevity, or location affect the extent to which they improve skin integrity?
Despite the many unresolved clinical and scientific issues, the study by Wagner and colleagues gives cautious hope that effective therapy of recessive dystrophic epidermolysis bullosa and other genetic skin diseases may one day be available.
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SOURCE INFORMATION
From the Department of Dermatology, University Medical Center Freiburg, and Freiburg Institute for Advanced Studies, School of Life Sciences–Lifenet, University of Freiburg, Freiburg, Germany.