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Gene Transfer Study for RDEB

Investigators: Dr. Jean Tang, MD, PhD and Dr. Pete Marinkovich, MD 


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Update – June 2015

We have grafted four patients and are looking for our fifth and final patient

We are currently looking for subjects with Recessive Dystrophic Epidermolysis Bullosa (RDEB) to participate in a gene transfer study.  Entrance into the gene transfer study is a two-step process.  We will select subjects who have first participated in our study of the characteristics of patients with dystrophic EB.  The Characteristics study will involve a trip to Stanford, in which we will perform blood tests, skin biopsies, and possibly genetic testing.  We will pay for the laboratory expenses and reasonable travel expenses related to this visit to Stanford University. More information on the Characteristic study is listed on a separate webpage. Please contact our research coordinator, Kylie Loutit at (650) 721-7166 for information on this gene transfer study or the Characteristics study or if you have any questions.

Once we have evaluated your characteristics, subjects may be invited to enter the gene transfer study, depending on the results of the Characteristics study.  The results of the testing that we will do in the Characteristics study will let us know if you meet the criteria listed below for the gene transfer study.  Depending on the results of the Characteristics study we may invite you to participate in the gene transfer study.  If you are invited to participate in the gene transfer study, we may need to perform additional tests on you, but we will also need to do genetic testing of your parents.

For the gene transfer study, we are looking for subjects who meet the following criteria:

For information about your rights as a research participant, please contact, please contact the Stanford Institutional Review Board (IRB) at (650) 723-5244, or toll-free at 1-(866) 680-2906.

Information about Epidermolysis Bullosa (EB)

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. Children with recessive dystrophic epidermolysis bullosa (RDEB) are born lacking normal type VII collagen.  RDEB patients 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.

Stanford University School of Medicine's Department of Dermatology has focused on EB research for the past 25 years.  Our research is funded by the National Institutes of Health and the California Institute of Regenerative Medicine as well as a number of non-profit organizations focused on EB including:

Current approved 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 focused on identifying new strategies for the treatment of EB.  

Information about Gene Transfer/Gene Therapy:

We are working to develop a successful gene transfer for RDEB patients. 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 plan to extend this approach to RDEB subjects by grafting the patient’s own genetically corrected RDEB skin cells 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 would suffer in a trial.  We are doing everything that we can to make this trial as safe as possible. 

We have undergone numerous regulatory review processes. 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. 

We have had close collaboration between our research group and several regulatory agencies including the Food and Drug Administration (FDA), the Stanford Institutional Review Board (IRB), and the Stanford Administrative Panel on Biosafety.  Each of these steps involved continuous examination that our plans will minimize the risks that an RDEB patient, who enters such a trial, would face.

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 (skin cells) in culture in a special clean room
3) Insertion of the correct COL7A1 gene into these cells
4) Grafting of genetically corrected cells onto the RDEB subject’s wounds. 
We have preliminary data that transplantation of an RDEB patient’s own genetically engineered skin cells to the patient’s own wounds will restore normal type VII collagen expression in their skin. 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 want to enter this type of trial.

Questions About What Will Happen Next

When will this trial begin?

This trial has started! We have grafted our first subject and are looking for additional subjects. 
There is a two-step process required to enter the gene transfer trial.  We will first need to see if you meet the criteria for the study, described above.  We do this by having you participate in our “Characteristics” study. 

The Characteristics study will involve a trip to Stanford, in which we will perform blood tests, skin biopsies, and genetic testing.  We will pay for the laboratory expenses and reasonable travel expenses related to this visit. You can contact our research coordinator to find out more about study enrollment.  Kylie Loutit may be reached at (650) 721-7166 or kloutit@stanford.edu.

Who will be the first subjects in the trial?

The first subjects will need to be 18 years old or older, have RDEB, and be healthy enough to come to Stanford University for evaluation.  We have additional requirements, which we will find out from results of the Characteristics study. A list of criteria for the gene transfer trial can be found at the top of this page.

After a subject is invited to enroll in the gene transfer study, we will need to perform additional tests, including genetic testing of both parents.  This is to confirm genetic mutations associated with RDEB.

As we move forward, we hope to be able to enroll subjects under the age of 18, starting with older age groups first. 

If any other enrollment criteria change, we will update this website. 

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 of gene therapy for cancer some of the subjects have shown benefit and some have not benefited at all. 

We also want to make sure that grafted subjects do not have an immune reaction. Our enrollment criteria has been designed to minimize this risk.

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.

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 five adults with small risks, we hope to enroll children as soon thereafter. 

We understand the pain and suffering that the children with RDEB feel.  However children do not have the legal and mental ability to commit to this type of a research study unless we can show benefit in adults.  We want to help as quickly as possible.  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?  

We recently completed an online survey of itch in EB patients.  We hope to follow this study up with an interventional study examining various treatments for itch in EB patients.

We are participating as a site in Scioderm’s study of SD-101 cream. (http://www.sderm.com/)

We are still examining the potential of protein therapy for EB.  Protein therapy involves introducing type VII collagen directly to a participant’s skin.

In addition we continue to examine the relationship between RDEB and squamous cell carcinoma.
 
We are also still investigating the use of stem cells for EB. http://med.stanford.edu/ism/2009/october/cirm.html

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 related to the research effort ongoing at Stanford University.  This website 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.

 

 

 

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