Hope For E.B. Kids: Stem Cells Fight Fatal Skin Disease - NewsChannel5.com | Nashville News, Weather & Sports

Hope For E.B. Kids: Stem Cells Fight Fatal Skin Disease

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MINNEAPOLIS, MN (Ivanhoe Newswire) - It's the worst disease you have never heard of. That's what parents call a deadly condition targeting children. It causes them to blister and develop open wounds with the slightest touch. Now, a new but risky treatment is giving families hope.

Bright-red blistered skin, excruciating open wounds outside and inside their bodies--they're not burn victims. These kids are born victims of E.B., epidermolysis bullosa.

"This is one of the most powerful diseases I've ever seen," Jakub Tolar, M.D., Ph.D., an associate professor and director of stem cell and gene therapies at the Blood and Marrow Transplantation Program at the University of Minnesota, told Ivanhoe.

"Any type of sheer force or little trauma could cause these huge blisters to form," Krista Boyd, whose son has E.B., said.

Krista's son, Keric, was born with E.B. His body lacked normal collagen type-7, a protein that holds the top and bottom layers of skin together. That fragile skin usually means a short, very painful life.

"If you don't have it, you have nothing to hold two layers together and that's why their skin sloughs off," Dr. Tolar said.

Keric's first few years were spent wrapped in bandages. Today, he's a different kid thanks to a risky stem cell treatment. The bone marrow transplant procedure has helped some kids, but others have died because of it.

"We know this is dangerous, but living with E.B. is very dangerous. It's very unsafe to have E.B. because you know you're going to die of it," Dr. Tolar said.

First, doctors at the University of Minnesota use high-dose chemo-therapy to wipe out the immune system. Then, donor stem cells are injected. The cells make their way to the skin and secrete collagen type-7. If the treatment works it makes the skin more resistant to blistering and can encourage healing.

"This is the first time they have an option of actually living close to normal lives," Dr. Tolar said.

Dr. Tolar said he wants to give kids a fighting chance against E.B.

"Diminishing human suffering is high on my list," Dr. Tolar said.

Today, Keric is more concerned with his dance moves than his condition and his mom is thrilled.

"We thought our life was just going to be a slow progression of Keric getting worse and more medical problems and more worries, but we never imagined it could be so good," Krista said.

Right now, the University of Minnesota has the only program in the world that's using bone marrow and cord blood stem cells to treat E.B. No child has been 100 percent cured with the treatment, but many like Keric are living near-normal lives with just a few lingering wounds to care for.

RESEARCH SUMMARY

BACKGROUND: Epidermolysis Bullosa (EB) is a rare genetic disorder that makes the skin so fragile that the slightest friction causes blisters and skin tears due to lack of collagen in the skin. EB is usually noticeable shortly after birth or detected early on in a child's life. If children with EB do not die of infection early on in life, many with the disease do not live beyond their 20s or 30s. EB can lead to an aggressive form of skin cancer. It is estimated that up to 12,000 people in the United States have some form of EB. The eyes, mouth, throat, and other internal organs are also affected by this disease. EB is not limited to any ethnic group or gender. In some countries, even euthanasia has been considered for newborns with the severest forms. While children will live long term, the severest forms of EB are generally lethal. Until recently there was no treatment and no chance for cure. (SOURCES: www.sciencedaily.com, www.debra.org,www.niams.nih.gov)

SYMPTOMS: The major sign of all forms of EB is fragile skin that blisters. Other symptoms are loss of fingernails and toenails, excessive sweating, difficulty swallowing, and redness of the skin. The skin blistering and tearing can lead to serious complications. Skin cancers can eventually form from the blistering and tearing. EB also occurs internally and can lead to nutritional problems and many other complications.(SOURCE: www.mayoclinic.com)

CAUSES: Most people with EB have inherited the condition through faulty genes they received from one or both parents. Genes are located in the body's cells and determine inherited traits passed from parent to child. They also govern every body function, such as the formation of proteins in the skin. More than 10 genes are known to cause the different forms of EB. It's also possible to develop Epidermolysis Bullosa as a result of a random mutation in a gene that occurred during the formation of an egg or sperm cell. (SOURCE: www.mayoclinic.com)

PREVENTING BLISTERS: In most forms of EB, blisters will form with the slightest pressure or friction. You can help to avoid blistering by keeping rooms at a cool temperature. It is important to apply lubricants to the skin to reduce friction and keep the skin moist. Use soft clothing that requires minimal handling when dressing a child. Avoid carrying a child with EB, especially from under the armpits. Using sheepskin on car seats and other hard surfaces will provide softness for the skin. To help prevent scratching a child can wear mittens at bedtime. (SOURCE: www.mayoclinic.com, www.niams.nih.gov)

NEW TREATMENT: At one time, research on EB was limited to describing the disease and understanding what happens in the layers of skin. Today, research focuses on finding gene mutations and their effect on the tissues, copying genes, reproducing gene mutations for research to correct them, inserting healthy genes to replace missing or mutated genes, and screening those who may have a gene mutation causing EB.

University of Minnesota Physician-researchers John E. Wagner, M.D., and Jakub Tolar, M.D., Ph.D., have for the first time used stem cells from bone marrow to repair the skin of patients with a fatal skin disease with EB. "What we have found is that stem cells contained in bone marrow can travel to sites of injured skin, leading to increased production of collagen which is deficient in patients with EB." Tolar was quoted as saying. SOURCE: www.niams.nih.gov, www.sciencedaily.com, www.health.umn.edu)

INTERVIEW

Dr. Jakub Tolar, M.D, PH.D, Bone Marrow Transplant Doctor at the University of Minnesota Medical School Pediatrics Center talks about his experience with children who have Epidermolysis Bullosa.

Tell me what this disease is and how it affects people?

Dr. Tolar: Epidermolysis bullosa is one of the most awful diseases I've ever seen, and I take care of children with cancer and know what tragedy is. The child is born without the majority of his or her skin and this defect never heals. They live the rest of their days in constant pain and suffering. The challenges they endure are beyond almost everything I've ever seen. Most of us would give up. They live like walking burn victims, bandaged from neck to toe. Gradually their fingers and toes fuse together. They end up in a wheel chair; they cannot even hold a pencil. They cannot eat, they cannot swallow. They have to be fed by a stomach tube and they never really relax. They cannot sleep well because they are in pain. After this cruel life, they develop a form of skin cancer that will take their lives in in their teens or young adulthood.

Is this something you are born with? So the skin doesn't develop correctly in the womb, is this what happens?

Dr. Tolar: The reason why the skin sloughs off is genetic; they are missing collagen, which is like glue. Collagen attaches the top layer of skin to the bottom. If you don't have it, the layers of skin come apart. It is a genetic disease. The collagen gene is mutated and faulted. The manifestation of the gene is only obvious after the child is born.

So you know within days of birth?

Dr. Tolar: You do, in the delivery room, obviously he or she is missing skin, typically from the waist down and on the face and arms. It's obvious immediately that something is very wrong. Some of my colleagues are not used to seeing this disorder. It takes some time to diagnose, but you know right away this is not right.

This just seems impossible to try and survive at all.

Dr. Tolar: It is impossible. In the past these children would have died of infections within days. Because this is an open sore, think of this as a burn, like being scalding from the waist down. This disease is a chronic problem only because of the advances in medicine and the support of antibiotics. It requires very complicated bandages and changing of the bandages, a specialized way of taking care of the wounds, and also supplemental nutrition, They cannot eat and grow normally. You feed them in an artificial way, any other way they would die.

So the treatments are just to maintain and try and keep the infections away?

Dr. Tolar: There are many compassionate physicians who have been taking care of these kids. This is not dissimilar to other diseases that happen in childhood. There are brain diseases, internal diseases that are not treatable; all you can offer is support. This has been done by very smart people for decades, even before we knew what epidermolysis bullosa was, we were trying, but in my opinion it went nowhere. It's basically futile; you do this because of the kids you are responsible for—your patients—and their families. Outside of these supportive measures, the methods developed in the past decade have been very creative but only focused on individual wounds. The problem with these measures is that they're not going to last. You cannot possibly cover all the wounds in the body. The skin can blister anywhere and everywhere; it's difficult to heal the wounds in the esophagus and food pipe. Current therapies focus on keeping them alive and treating the individual wounds.

What is the average life span, of these patients?

Dr. Tolar: If you look the whole group of epidermolysis bullosa patients, there are about 20 different diseases, some are not severe, and some are very severe. We specialize only in the very severe ones. To even consider bone marrow transplant, patients have to have a fatal disease and no other options. Only two out of the twenty types of EB are severe enough to go to bone marrow transplantation. One is called dystrophic EB and the other is called junctional EB.

Now the difference is that the children with severe junctional EB will die, no matter what you do, within a one-year range. The children with recessive dystrophic EB will be able to live to their late childhood, even early adulthood, until they succumb to cancer of the skin. There are milder forms of both of these conditions, and the people who have the milder forms can live to be 50. I know a woman in Canada who is in her 60s but that is not the severe form.

Tell me about what your research is?

What we are doing here in this lab has been looking at how to help these kids. Five years ago the mother of two boys with this condition asked Dr. Wagner for help. He came back and talked to us about the condition, and basically I decided to take it to a lab and do something about it. It would be not only dishonest but also questionable scientifically to go to a clinical trial in patients without any data. We'd basically be aiming at the stars. That is why we did what is logical and proper, and we went to the lab to see if there was even a potential for our ideas to work. We got mice that are also missing collagen type 7, so we can model the human EB. We used the mice as a surrogate for humans, and then we applied the stem cell technology to the mice. We basically have taken the mice and given them the stem cells of different kinds, ones from the skin, from bone marrow, ones that make blood or don't make blood. And after many, many months and many, many failures, we arrived at a population of stem cells in the bone marrow that rescued about 15% of these animals. This was the first time that we had any indication that there is a possibility that you can take stem cells and at least partially alleviate the problems these children have.

So now we have seen in their skin that the mice are actually making the collagen type 7, a significant change because genetically these mice cannot make any. And we have seen that their blisters healed. Then, and only after that, we opened the clinical trial. The clinical trial is a bone marrow transplantation trial and what that means is that a few cells from a healthy person are transferred to the person with a disease. How we do it, is we take a sample of the bone marrow from a donor's hip bone in the operating room and take this in a bag to the child with the disease, but before this can happen successfully we have to treat the child with chemotherapy. Because if you do not, the healthy cells of the donor will be rejected by the immune system of the child.

So you wipe out the immune system with chemotherapy before you start?

Dr. Tolar: Yes we do. There are three medications we have used for decades and we know how they behave: we know how toxic they are, and how helpful they are, and we give them in combination during a seven-day period before the transplant. The patients get the chemotherapy first, then on what we call day zero, they get the infusion of the bone marrow or cord blood stem cells, and then we wait about three weeks before we see the donor cells growing to a high enough percentage in the blood that we can count them. And hopefully the cells are that of the donor, and if they are, then potentially it will heal their skin.

How are the stem cells given; is it an IV drip?

Dr. Tolar: We put an intravenous catheter into the chest of these kids; it is the only way to safely deliver the high doses of chemotherapy.

So it goes into the heart? So the stem cells go into the heart? Are the stem cells manipulated, so they know to become collagen 7?

Dr. Tolar: I think that what you have are these cells from the bone marrow and there are some of them, maybe less than 1%, that don't produce collagen type 7 immediately, but what they do is they hold to the skin and when they get instructions from the environment in the skin they then make collagen type 7.

Tell what you were thinking when you saw these results in the first patient.

Dr. Tolar: It is a combination of desire to help that kid and enormous responsibility for that kid and it doesn't change whether it is the first or seventh or 14th it is always that way. Just last night, I learned that the last of our patient has been engrafted with donor cells and that was an enormous relief to me and it doesn't go away with the numbers on the list, you remain anxious, but anxious in a positive way. You have, with the permission of the parents, selected for them a life-saving measure. And yes, both parties know, professionals and lay, the parents, us, we all know that this is dangerous, but living with EB is very dangerous and unsafe because you know they are going to die from it. That's why such an aggressive approach is taken to counteract this enormous destructive power of EB.

How many children have you treated?

Dr. Tolar: We have treated more than a dozen at this time. Unfortunately, several have died.

It was a small number? I read two. Were there more children who did not make it during the procedure?

Dr. Tolar: Four altogether. One child died before the transplantation because of the side effects of the chemotherapy. Three others have died after the stem cell infusion. They died of infections, which is common unfortunately in the children with EB. Some of them had organ damage, which comes from the harshness of the BMT process. Of the remaining patients, all but one has been improved. What I mean by improvement is important to describe. The quality of life is better than before. This is not just me saying this; it is their parents. The essence of medicine, I think, is to decrease suffering and that is what we are seeing. Until the transplant, every moment of their lives has been overshadowed by this disease. There has not been a waking minute of their lives that they have not been chained by this disease. Now they can play. They can ride a bike, jump on a trampoline, eat potato chips, and they can play with other kids. This is very different, but having said that none of them are completely healed. What I mean by that, is there typically is a sore somewhere, either on an ankle or a hand, somewhere that is not completely healed. We have ideas about how to fix that. We think that with more time this will actually improve too.

Your whole bone marrow can be used to make these collagen-producing cells. There are waves of cells that contribute to the healing. Collagen builds up over time and helps make the skin stronger.

Is it something that can be done again if the parents really want to go through that?

Dr. Tolar: We are learning from every single patient. We will soon have a third version of the clinical trial. We do things differently than with we did with the first couple versions. We have learned a huge amount of information on what to do or not to do. We shift from the clinic to the lab with no problem of doing both, that's where the advance comes from. We are changing the field of doing this as we are doing this.

Do you theorize that this will last in these kids?

Dr. Tolar: That's a good point. It is unknown, but we can make an educated guess. The first-ever successful bone marrow transplant was done in the building next door by Dr. Robert Good and his team in 1968. We have done this for a long time, and we know that very early patients with leukemia are still producing good cells. The second part is that the first EB transplant patients are now more than three years out and continue to be better.

And the child who is three years out maintained what he started out with or gotten better at all?

Dr. Tolar: He got better, but he has at least two sites that need more work and these have not healed. But his overall status is very different from what you know would happen if he was not treated. We know how this disease behaves if you don't do anything, it gets progressively worse.

What is the age range of patients you've treated?

Dr. Tolar: Youngest 9 months, oldest 14.5 years.

This is not a common disease, how does someone contact you if they may be a contact?

Dr. Tolar: We do this carefully. Patients travel here because this is a place with special expertise; they don't come because of the weather. This is something different then what's in their backyards. If you have a kid with a lethal disease, the last thing you want to do is go away and live there for six months and be away from your family support. WE don't really encourage anyone to come here, people seek us out, and we don't seek people out. I have a deep respect for families who decide they don't want their child to go through this and what it takes to take care of their child the old way. These are questions of life. These questions are between the parents and the kids. Our role is to help them by telling them what's available.

As the study progresses and you continue to treat more and more children with repeatable results how is this changing the disease and the prognosis of this disease?

Dr. Tolar: Dramatically, this is the first time they have an option to live anything close to normal life. I am not saying there are no other possibilities out there. I think the most likely scenario is that we will make this safer using less chemo, using cells targeted towards the skin, and maybe we will end up with is a group of treatments one can select from.

Where does your passion from, what drives you?

Dr. Tolar: Doing something with my life, doing something that matters and has substance. Diminishing human suffering is high on my list.

What do you hear from parents after their kids have gotten better?

Dr. Tolar: They are grateful. They come and say we knew this was going to be ok, we knew that you said he or she can die from this. We are very honest about the severity of this disease—this is way too serious not to be—they know what they are going to go through. When they come out on the other end, no one comes out the same way they were before, it just doesn't happen that way. It's incredibly hard. They are grateful the child survived, they are grateful that the skin is healing. One of the boys just this Saturday went home and can wear shoes for the first time, and for the first time play how he wanted to do all along. It is game changing for the parents to see this, at the same time they are realistic, they know what complications to look for, they know how close their kid was to dying. Also, they know that there are things in their future that will still need attention and medical care.

FOR MORE INFORMATION, PLEASE CONTACT:

Jakub Tolar, MD, PhD
University of Minnesota
(612) 625-2912
E-tolar003@umn.edu

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