UNIVERSITY OF MINNESOTA UPDATE/h3>

Article, “Bone Marrow Transplantation for Recessive Dystrophic Epidermolysis Bullosa” from the University of Minnesota will be released in the August 12, 2010 issue of the New England Journal of Medicine.

Over the last three years the faculty of the University of Minnesota Division of Pediatric Blood and Marrow Transplantation have made substantive progress in the use of stem cells in the treatment of individuals with recessive dystrophic epidermolysis bullosa (RDEB).

Research began in 2007 using a mouse model of RDEB. Many different types of cells were tested and their impact on EB examined. The unexpected result of this research was that the mice could be partially treated with a rare subpopulation of bone marrow stem cells rather than skin specific or multipotent stem cells. The principal findings in the mouse model were that donor cells migrate to the skin lesions observed in RDEB, collagen type VII increases rapidly with subsequent development of anchoring fibrils, skin integrity is improved with relative resistance to blister formation in response to trauma, and survival is extended. These discoveries were reported in the journal Blood in 2008.

As a result of this finding in the animal model, a ‘first-in-human' clinical trial was initiated using unfiltered marrow stem cells in the treatment of children with RDEB. The primary goals were to determine the safety of the treatment and demonstrate enhanced skin and mucosal integrity and resistance to blister formation over time. Between 2007 and 2010, 7 patients with RDEB were enrolled and 6 received a stem cell infusion. The results of this first study in RDEB mimicked the results in the animal model in that donor cells migrated to the skin and mucosa, collagen type VII increased and skin integrity improved in varying degrees over time with increasing resistance to blister formation in response to negative pressure in those that have been studied. Because of the novelty of the study and current outcomes, the results of the clinical trial will be published in the New England Journal of Medicine on August 12, 2010. To the best of our knowledge, this is the first treatment strategy with the potential to reach all injured sites in the skin and mucosa of children with RDEB.

Already the investigators at the University of Minnesota have moved to a second trial, evaluating the potential added benefit of co-infusing mesenchymal stromal cells along with the marrow stem cells. The first patient was enrolled in February 2010. To date, 5 patients (4 with RDEB and 1 with JEB) have been treated with a sixth (RDEB) and seventh (JEB) in the queue. This is the first US trial with an active FDA IND file.

Tolar and Wagner are now attempting to identify the exact stem cell population that can home to and repair the damaged skin in RDEB. Once identified, strategies to isolate and expand these stem cells will be developed with the idea that such a strategy would be used in the future for treating patients. This work is funded by the Epidermolysis Bullosa Medical Research Foundation (EBMRF). EBMRF is proud to sponsor this work that may one day improve the safety and effectiveness of stem cells in the treatment of the more severe forms of EB.

Stanford Research Update: January 2010

Beginning in 1988, Dr Eugene Bauer headed the Stanford Department of Dermatology and led the way for EB research at Stanford. He recruited top scientists in disciplines related to EB. Today, Stanford University is continuing Dr. Bauer's work under the direction of Dr. Alfred Lane, Professor and Chair, Department of Dermatology. He, along with his team including Drs. Peter Marinkovich, Paul Khavari, Anthony Oro, Marius Wernig and Zurab Siprashvili, are making exciting progress toward clinical trials in gene therapy, collagen therapy, and stem cell therapy.

Gene Transfer becoming Gene Therapy

Gene transfer is the process of placing a new gene into a cell. For patients with recessive dystrophic epidermolysis bullosa (RDEB), we plan to place the correct type VII collagen gene into cells of RDEB patients who do not make effective type VII collagen. By attaching the correct type VII collagen gene to a virus (called a viral vector); we are able to use the virus as a tractor which pulls the correct gene into the defective EB skin cells. This process allows the defective cells to make the correct type VII collagen. We have done years of experiments documenting that we can do this and that the cells which receive the correct type VII collagen can multiply and generate skin that does not have EB. When this gene transfer process works on humans, then it will be considered gene therapy. The process of using a virus to carry the correct gene into a cell is considered a new drug by the Food and Drug Administration (FDA). Our goal is to develop effective gene therapy for all forms of EB, as well as other genetic diseases.

We have successfully reached a major milestone in our research. We have been assigned an investigational new drug number (IND) from the FDA, allowing us to move forward on development of our gene transfer program. This means the FDA has examined what we have created and stated that it is now safe to apply this process to humans in a special research situation. The FDA requires that the first RDEB patients tested are over the age of 18 years in order to be able to give an informed consent. If the process works well on several adults, then we will request permission from the FDA to begin to test children. Our plan is the remove a small piece of skin from a patient with RDEB, grow the skin in culture, put the correct type VII collagen gene into the cells, and then place the cells which contain the type VII gene back onto the research patient. We do this by growing the skin cells into a small sheet of cells that look like a thin piece of plastic wrap. The cells are placed over an area of wounded skin just like a skin graft. We expect the grafted cells to produce normal type VII collagen and the corrected cells will attach to the wound and repair the injured area. The corrected cells will have the same characteristics as the person's own skin cells and should not be rejected if grafted back onto the person. If this process is successful, then we would hope to eventually graft large wounds and possibly graft areas without wounds in order to prevent wounds.

Before we can begin this process in humans, we need to have the viral vector made by a special viral vector laboratory using Good Manufacturing Practice (GMP). That laboratory is currently in the final stages of production. Once they have the completed vector and we have confirmed that it works as well as the material we make in our laboratory, we can then complete several additional regulatory processes which are required before we begin experiments on adults with RDEB. We are currently looking for adults with RDEB who may be interested in being considered for future trials. We are examining them for the characteristics of their RDEB. Further details will be available at our website http://dermatology.stanford.edu/research/research.html

Protein Therapy for EB

While gene therapy holds promise as a long term therapy, current evidence suggests that type VII collagen protein therapy may prove to be an effective, easier and relatively non-invasive treatment for RDEB. After leaving the research group that discovered type VII collagen, Dr. Marinkovich brought to Stanford a strong interest in the biology of this protein. Development of a commercial production process and purification of type VII collagen is taking place here at Stanford, along with the assistance of industry advisors who specialize in GMP collagen manufacturing. Using cells and reagents which are pharmaceutical industry standards, we are completing experiments needed for FDA approval. These clinical trials for protein therapy will initially consist of the treatment and evaluation of localized areas of skin on a limited number of adult RDEB patients. As in the gene therapy trials, once efficacy and lack of toxicity can be established, we plan to expand type VII collagen protein therapy trials to RDEB children.

Stem Cell Therapy for EB

We have recently received a large Disease Team Research Award from the California Institute of Regenerative Medicine (CIRM) to develop induced pluripotent stem (iPS) cells from patients with dominant dystrophic EB (DDEB). The processes that we are developing will allow us to remove cells from a patient with EB and convert some of the cells to iPS cells, which can constantly renew themselves in culture. We hope to correct the genetic mutation in the iPS cells and then re-form them back as normal skin. The corrected cells will have the same characteristics as the person's own skin cells and should not be rejected if grafted back onto the person. The only difference from the person's original cells will be that the grafted cells will not cause EB. We will prepare these techniques in the manner that the FDA requires so that we can develop an additional FDA-approved method besides gene transfer to help EB patients.

Currently we are looking for adults and children with DDEB. Individuals who are interested in volunteering can obtain more information at our website http://dermatology.stanford.edu/research/research.html

In summary, science has developed methods of therapy for genetic diseases that were only dreams in the past. We are aggressively trying to move the dreams to reality.

USC Research Update: January 2009

The  EBMRF announced that David T. Woodley, M.D. and Mei Chen, PhD of  the Department of Dermatology at The Keck School of Medicine at the University of Southern California are recipients of a $150,000 Grant for their current research of Epidermolysis Bullosa.

The EBMRF awarded the grant to further expand Dr. Woodley and Dr. Chen's cutting-edge research into protein replacement therapy for treatment of patients with recessive dystrophic Epidermolysis Bullosa (RDEB).  Dr. Woodley's project proposes a clinical trial to treat RDEB patients with recombinant type VII collagen as well as a strategy for bringing this novel protein to market.

Dr. Mei Chen and Dr. David Woodley at the USC Laboratories for Investigative Dermatology have proposed initially using “Protein Therapy” for patients with dystrophic epidermolysis bullosa (DEB) as a temporizing measure until “Gene Therapy” is fully developed and proven safe.  They can produce milligram quantities of full-length recombinant, human type VII collagen and they now wish to make their recombinant, human, type VII collagen by so-called “Good Manufacturing Practices” (GMP) so that it is suitable for administration to human beings. “We believe that Protein Therapy is something that will work right now and can help patients with DEB because it worked so well in the DEB mouse model.” said Dr. Chen. 

Dr. Woodley added: “Doctors have great experience injecting type I collagen into the upper dermis of patients for photo aged skin.  The collagen persists for about 6 months. Therefore, we do not see any technical hurdles to administering intradermal injections of our recombinant human type VII collagen into DEB patients.”  In addition, the injection into patients of a purified protein will not involve cells or viruses which are both large safety issues with the Federal Drug Administration.  “We believe the FDA will more likely approve Protein Therapy relatively quickly compared with cell or gene therapy, and protein therapy will answer many essential questions that are essential for gene therapy.  In the first Phase I study with “Protein Therapy”, the investigators plan on injecting 100 micrograms of the protein into four quadrants of a 6 cm by 6 cm test site.  This will be compared with a similarly sized control site that will not be injected.  The investigators will examine new blister formation and open wounds in the two sites.  They will also take biopsies from the sites and examine the amount of type VII collagen and the number of anchoring fibrils at the junction between the epidermis and dermis.  If human DEB patients are similar to the DEB mouse model, one would expect a cessation of new blister formation, less open wounds, and the expression of type VII collagen and anchoring fibrils in the injected site.  Drs. Chen and Woodley were quick to point out that one of the main goals of a Phase I trial is patient safety.  Therefore, DEB patients who enroll in the study will be monitored in many ways during and after administration of the collagen. “Of course, in addition to proving safety, Dr. Chen and I are very hopeful that Protein Therapy will also prove to be efficacious and improve the skin blistering and skin fragility in the patient's test sites.” said Dr. Woodley.

The EBMRF is grateful to DebRA of America for their support and resources in awarding this grant.

Stanford Research Update: May 2008

Beginning in 1988, Dr Eugene Bauer, headed the Stanford Department of Dermatology and led the way for EB research, enlisting the top scientists in disciplines related to EB research and recruiting them to Stanford. Today, Stanford University is continuing Dr. Bauer's work under the direction of Dr. Alfred Lane, Professor and Chair, Department of Dermatology. He, along with his team including Dr. Peter Marinkovich and Dr. Paul Khavari are making exciting progress toward clinical trials in gene therapy and collagen treatments. See below for the latest findings.

We are currently looking for subjects to participate in a preliminary screening for a possible gene transfer trial for recessive dystrophic epidermolysis bullosa (RDEB).

We are looking for subjects who meet the following criteria:

1- Have a clinical diagnosis of RDEB by a local dermatologist
2- Are 18 years of age or more and are willing to give consent. Estimated to have at least 100 to 200 cm2 areas of open erosions on the trunk or extremities
3- Are able to undergo adequate anesthesia to allow grafting procedures to take place
4- Both parents alive, do not have EB, and are willing to give consent for genetic testing
5- Medically stable to travel to Stanford University Medical Center
6- No medical illnesses expected to complicate participation
7- Currently this study is limited to residents in the USA

If you meet the above criteria, you may be eligible to come to Stanford University and participate in the screening phase of our trial. The screening will involve skin biopsies, blood tests, and genetic testing. We will pay the travel expenses related to this trial.

If you would like more information, or have any questions regarding our study and/or our eligibility criteria, please contact our Clinical Trial Coordinator, Emily Gorell, at (650) 725-4302 or at egorell@stanford.edu. Emily can send you a copy of the informed consent and other documents related to this trial.

RESEARCH REPORT EPIDERMOLYSIS BULLOSA 2007
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. Stanford University School of Medicine's Department of Dermatology has focused on EB research for the past 19 years. Our research is funded by the National Institutes of Health, the Epidermolysis Bullosa Medical Research Foundation (EBMRF) and the Nu Skin Force for Good Foundation. We have focused on 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 and regulatory challenges remain to be surmounted prior to bringing these efforts forward to initial clinical trials in human patients. For preliminary information about our research in EB see our Stanford EB Research Update: February 2005.

Our relentless effort has been the development of successful gene transfer for recessive dystrophic epidermolysis bullosa (RDEB) patients which eventually will lead to a clinical trial. Children with RDEB are born lacking normal type VII collagen. Children with RDEB develop a relentless, scarring EB subtype, which produces painful blisters and wounds on skin and mucous membranes. The incidence of RDEB is estimated to be about 1 to 2 per 1,000,000 people. Current therapy for RDEB consists of only palliative wound care and there are no therapies available that alter the course or severity of this disease. We have demonstrated in our research laboratories that genetically corrected RDEB keratinocytes (skin cells from the top layer of skin) engineered to express type VII collagen can correct human RDEB skin tissue grafted onto immune deficient mice, providing proof of concept for corrective molecular therapy for RDEB. We now hope to eventually extend this approach to RDEB subjects by grafting the patient's own genetically corrected RDEB keratinocytes back on to their wounds as is described below. This technique is called gene transfer. If it works successfully it would be called "gene therapy".
The process of developing a gene transfer trial in the United States of America is extremely complicated. Our major focus must be to minimize any risks that patients with RDEB would suffer in a trial. We are doing everything that we can to make this trial as safe as possible. The first required step is approval from the Recombinant DNA Advisory Committee (RAC). The RAC is a Federal Committee that considers the current state of knowledge regarding recombinant DNA. Since gene transfer involves use of recombinant DNA, the RAC review and approval is the very first step necessary for any human gene transfer trial in the USA. The RAC considers hypothetical hazards and methods for monitoring and minimizing risks. We received approval from the RAC on March 14, 2007. The webcast of that meeting is available here. Our presentation starts about 4 hours and 38 minutes into the meeting.

We have several more major steps to complete before a clinical trial can commence. These steps require close collaboration between our research group and several regulatory agencies including the Federal Drug Administration (FDA), the Stanford Human Research Protection Program (IRB), and the Stanford Administrative Panel on Biosafety. Each of these steps involve continuous examination that our plans will minimize the risks that an RDEB patient, who enters such a trial, would face. We are working to develop a Phase 1 clinical trial. Phase 1 studies are designed to determine the metabolic and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. The current trial design involves 1) biopsy of the skin of the subject with RDEB, 2) growth of their keratinocytes in culture, 3) insertion of the correct COL7A1 gene into these cells, and 4) grafting of genetically corrected keratinocytes onto the RDEB subject's wounds. We have preliminary data that transplantation of an RDEB patient's own genetically engineered keratinocytes to the patient's own wounds will restore normal type VII collagen expression in the skin of the RDEB subjects. The objective of this study is to achieve proof-of-concept for this general approach to cell-based gene therapy in humans and to set the stage for further therapeutic extension in RDEB. The initial trial will involve small areas of skin on adults 18 years old or older with RDEB. In the USA 18 years of age or older is considered the age when a person can make their own decisions about health care, and they can decide if they do or do not want to enter this type of trial.

Questions About What Will Happen Next

When will this trial begin?
We are unsure about when we will be able to start this trial. We are working diligently to move this research forward as fast as possible. We are sharing this information now not to give false hopes but to inform you of our plans and current success. If we are able to start the trial, we will announce that information on this web page, and we will also send information to physicians interested in caring for patients with EB.

Who will be the first subjects in the trial?
We hope to start to screen subjects for this trial in the near future. Those subjects will need to be 18 years old or older, have RDEB, and be healthy enough to come to Stanford University for evaluation. We need to obtain regulatory approval before we can begin screening. There will be specific requirements that subjects must meet in order to make this trial as safe as possible for the potential candidates. All of the requirements are not yet decided but will be considered by the regulatory agencies.

Are there any risks with a gene transfer trial?
We are concerned about many risks. In one gene transfer trial for children with a lethal blood disease, several of the children developed leukemia. In a previous trial for a metabolic disease, one child died. In some of the trials for cancer some of the subjects have shown benefit and some have not benefited at all. It is important to realize that a Phase 1 trial is designed to protect the subject while looking for any risks or illnesses that may develop.

What will happen next?
First will be the process of screening potential subjects 18 year old and older. When that process starts we will put that information on this web page.

RDEB affects infants and children. When can we try to help them?
Gene transfer trials of this type usually need to demonstrate benefit in adults before children can be tested. If we are able to show benefit in adults with small risks, we will begin to test children as soon as possible. We understand the pain and suffering that the children with RDEB feel. We want to help as quickly. We also do not want to do any experiments that may make the pain and suffering worse for children or adults.

Are we working on any other EB treatments?
Yes, we are still examining the potential of protein therapy for EB. In addition we continue to examine the relationship between RDEB and squamous cell carcinoma. That information is in our Stanford EB Research Update: February 2005.

Is there someone I can speak to in order to understand more about EB, gene transfer, 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 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. Also your dermatologist who cares for you or your relative may be able to explain the details of this information to you.