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| Dermatology |
Epidermolysis Bullosa (EB) is a rare, inherited blistering skin disease that affects all ethnic and racial groups. There are several forms of EB, ranging in severity from mild to lethal. Research at Stanford University School of Medicine's Department of Dermatology, funded by the National Institutes of Health, the Epidermolysis Bullosa Medical Research Foundation (EBMRF) and the Nu Skin Force for Good Foundation, is directed at identifying new strategies for the treatment of EB. These strategies have displayed promise at the pre-clinical levels in experimental models, however, key scientific challenges remain to be surmounted prior to bringing these efforts forward to the U.S.F.D.A. for initial pilot clinical trials in human patients. There are no current or imminent clinical trials at this time. Should current research efforts progress to a new molecular therapy trial for EB at Stanford, it is planned that trial information will be posted on this web site and on those of the Epidermolysis Bullosa Medical Research Foundation (EBMRF) and the Nu Skin Force for Good Foundation.
Research Progress Update
Following the discovery of the genes and proteins involved in EB by a number of groups, pre-clinical efforts at Stanford and other institutions have pursued efforts at building the scientific and technical capabilities to support molecular therapy for EB. Molecular therapy efforts for EB are presently focused on both gene and protein-based therapies because both types of molecules ( genes and proteins ) show potential promise. Stanford investigators have been directing their research toward the two lethal forms of EB, Junctional EB (JEB) and Recessive Dystrophic EB (RDEB). These EB types are caused by mutations in specific laminin and collagen genes. To date, all efforts have been pre-clinical studies in the laboratory and no EB patient has yet been treated with a new molecular therapy for EB here at Stanford.
The initial phase of effort involved building human tissue-based laboratory models of EB. These laboratory models were successfully developed and have permitted the assessment of potential therapeutic approaches. The first major therapeutic strategy involved using viruses to correct EB tissue. Using a type of virus known as a retrovirus, it has been possible to insert a normal copy of a laminin gene to correct JEB cells and tissue in the laboratory. This approach was also used successfully at another institution with a collagen gene to correct RDEB cells and tissues. The emergence of concerns over problems observed with the use of viruses in therapy of blood and liver disease at other institutions, however, has slowed the progress of efforts to use viruses to treat EB.
To develop a virus-free approach to correction of EB, more recent studies have used circular DNA pieces that contain laminin and collagen genes. This so-called “naked” DNA approach has permitted correction of both JEB and RDEB cells in the laboratory in a similar manner to that achieved with viruses. The cells targeted by this approach are keratinocytes , or the cells that line the surface of the skin. Getting DNA into these cells requires growing them in sterile lab dishes. Applying this approach to patients therefore would require the following steps, once the clinical and molecular diagnosis of EB had been made: a) removing skin by a biopsy b) growing keratinocytes in the lab in sterile dishes c) inserting the corrective DNA into the cells in the lab d) grafting the cells in a surface sheet back onto a wound on the patient. The need for skin grafting onto a wound bed and the difficulty of growing large numbers of healthy keratinocytes capable of covering the body surface has stimulated efforts to develop a simpler strategy.
One possible way to simplify molecular therapy for EB was identified in the form of fibroblast injection . Fibroblasts are cells that live under the keratinocyte surface lining in the skin. They secrete molecules involved in EB, including laminins and collagens. Fibroblasts can be grown with greater ease than surface keratinocytes and can be injected into skin with a needle, rather than grafted. An approach to fibroblast gene transfer was established that would involve: a) removing skin by a biopsy b) growing fibroblasts in the lab in sterile dishes c) inserting the corrective DNA into the cells in the lab d) injecting the cells back into the skin of the patient. Current efforts with fibroblast injection are directed at increasing the efficiency of the process and comparing it to other approaches developed at other institutions, including injection of corrective collagen protein, which has recently also shown promise in laboratory models of RDEB.
In parallel to development of corrective strategies for EB have been studies directed at understanding some of the problems that plague EB patients, including skin cancer , which occurs with greatly increased frequency in RDEB. RDEB patients suffer from a form of skin cancer that arises from keratinocytes and is called Squamous Cell Carcinoma (SCC) . While not all RDEB patients will have SCC in their lifetime, those that do tend to be diagnosed at a younger age and with more abundant and aggressive tumors than non-RDEB patients. Recent work has explored potential mechanisms for increased SCC in RDEB. Cells from RDEB patients that retain a fragment of the specific collagen affected in RDEB, collagen VII, have been shown to form experimental tumors in the laboratory at similar rates to cells from normal patients. In contrast, RDEB patient cells entirely lacking any pieces collagen VII protein do not form tumors in the experiments performed so far but they can regain tumor-forming ability if given collagen VII fragments. This suggests the presence of collagen VII protein pieces may permit cancer formation but that it does not itself cause cancer. Further studies are necessary to define the role of collagens in cancer and to see if collagen abnormalities combine with the chronic wounding seen in RDEB to increase the risk of cancer in RDEB patients.
Frequently Asked Questions About Efforts Towards Therapy
How can I find out the genetic defect for a family member with EB?
The physician treating the patient or the referral medical center in your region should be able to assist with the steps needed to do this. Two websites for related diagnostic resources that are not affiliated with Stanford University are:
1) GeneTests - Funded by the National
Institutes of Health (NIH)
2) GeneDx - DNA Diagnostic Experts
How soon will the first EB trial start at Stanford?
There are no trials imminent at Stanford. The process of gaining approval to start a pilot clinical trial for EB and other human diseases is a lengthy process that involves coordination with specific offices of the U.S. Food and Drug Administration. When a clinical trial nears initiation, information will be posted on this site.
Will gene or protein therapy be used first to treat EB patients?
The nature of the first therapies to be used for specific treatment of EB patients at Stanford or other institutions is not yet clear. Current research is designed to identify therapeutic approaches with the best durability and safety profiles. For all approaches being developed, the ultimate timing and design of potential clinical trials is not yet known. For example, the number of required treatments and how long any treatment would last is not clear.
Is there someone I can speak to in order to get the latest information on progress in EB therapy?
This web site is maintained to provide the most current public information and was designed to both inform the community and to prevent staff from being diverted from research efforts to repeat answers to the similar questions arising from EB patient families around the world. In the event that a clinical trial nears initiation, contact information will be posted on this site.
What about other genetic skin diseases?
Although further work is needed, lessons from the approaches being developed for EB may be applicable to other life-threatening genetic skin disorders.
Frequently Asked Questions About RDEB and Cancer
Are RDEB patients that retain collagen fragments at higher risk for skin cancer?
The answer to this question is unknown. Studies to address this are being planned here at Stanford. An announcement will be posted on this web site when enrollment for studies on collagen retention in RDEB and skin cancer begins.
Does collagen cause cancer?
Collagens are a normal part of the body and have not been appreciated to play a primary role in causing cancer. Cells from RDEB patients that retain a portion of collagen VII were recently observed to form experimentally-induced tumors in the laboratory at similar rates to cells from normal patients. RDEB patient cells that entirely lack collagen VII protein do not form tumors in the experiments performed so far but they can regain tumor-forming ability if given collagen VII fragments. This suggests the presence of collagen VII protein pieces may permit cancer formation but that it does not itself cause cancer. Further studies are necessary to define the role of collagens in cancer and to see if collagen abnormalities combine with the chronic wounding seen in RDEB to increase the risk of cancer in RDEB patients.
How can I find out whether my RDEB family member retains a portion of collagen?
To our knowledge, this sort of test is not commercially available. The potential value of this test in predicting cancer formation in RDEB is unknown. Until further studies are done, the value of this test is also unclear. Because of the limited state of present knowledge, Stanford physicians that treat EB patients are not currently recommending this test be performed, even should it become commercially available.
Could collagen replacement in RDEB cause cancer?
The answer to this question is unknown. Any new therapy holds theoretical risks of a variety of side effects, including cancer. This possibility would be monitored in any EB molecular therapy trial.
Is there someone I can speak to in order to understand more about EB and cancer?
As in the case of therapy efforts, this web site is maintained to provide the most current public information on this subject and was designed to both inform the community and to prevent staff from being diverted from research efforts to repeat the same answers to the similar questions arising from EB patient families around the world. In the event that further information becomes available, this site will be updated to reflect this new information.
Support Genetic Skin Disease Research at Stanford
Individuals interested in supporting EB research at Stanford may send donations to either EBMRF or directly to the Stanford Department of Dermatology. Your support helps us to direct more resources into this effort so that we can accomplish our goals sooner. To give a donation, click the "Make a gift now!" button below. If you would like to mail a donation, the addresses are listed below.
Stanford Department of Dermatology
Attn: Alfred Lane, MD
900 Blake Wilbur Drive
Stanford, CA 94305-5334
More information about donating.
EB Medical Research Foundation
130 Sandringham Road
Piedmont, CA 94611
More information about the EBMRF.
Derm Intranet