Battling ''EB''
Gene Therapy Holds Hope for Rare, Devastating Skin Disease

BY MARK SHWARTZ

WINTER 2007 -- For most kids, running, skating, and other physical activities are just a normal part of growing up. But for the Chavez brothers--José, age 17, Abraham, 12, and Marlon, 9--even the simplest act, such as riding a bicycle or hugging their dog, can have painful consequences. All three brothers were born with a severe form of epidermolysis bullosa, or EB, an inherited skin disease in which even the slightest physical contact can cause blisters that turn into agonizing sores, which are slow to heal. 

Anna L. Bruckner, MD, examines EB patient Abraham Chavez.

''Sometimes I don’t want to go out, because everybody stares at me,'' says Abraham, an eighth grader, whose young body is riddled with scars and lesions from the disease. 

''Some forms of EB are fairly mild, but Abraham and his brothers have a rare, severe type called recessive dystrophic EB, or RDEB,'' says Anna L. Bruckner, MD, assistant professor of dermatology and of pediatrics at Stanford University. ''Their skin is incredibly fragile, so they need frequent bandaging--a painful ordeal that can take several hours a day.'' 

As director of pediatric dermatology at Packard Children’s Hospital, Bruckner heads the only clinic in the western United States that specializes in treating children with EB. ''We regularly see about 35 patients with severe RDEB a year,'' she says. ''They come from all over--California, Nevada, Washington, even overseas. We provide them a full suite of clinical services, including a pediatric pain specialist, physical and occupational therapists, a nurse specialist, a social worker, and a nutritionist.''

The Chavez family has been coming to Packard for 11 years--a 200-mile round-trip drive from their home in Stockton, Calif. ''My wife and I are constantly changing their bandages,'' says Fernando Chavez, the boys’ father. ''It’s a full-time job taking care of these guys.'' 

During one recent clinic visit, Bruckner examined the bandaged wounds on the boys’ legs, hands, and torsos for signs of infection. 

''Basically, these kids are wrapped like mummies, because any trauma will tear their skin off,'' says Alfred T. Lane, MD, professor of dermatology and of pediatrics at Stanford. ''Bandages may cost as much as $40,000 a year, and insurance won’t cover it. So if you’re not poor when you have the disease, you’re poor when you treat the child.'' 

Diet and nutrition is another major challenge for EB patients and their families. ''Blistering can occur in the mouth and esophagus, which makes it hard for them to eat,'' Bruckner explains. ''As a result, they become very undernourished. Their food has to be liquefied and supplemented with vitamins and other nutrients.''

Some children, like 9-year-old Isaias Zarate, require surgery to keep their esophagus open. Isaias also has severe scarring that has caused his fingers and joints to contract, making it difficult for him to hold a fork or dress himself. This year, he and his mother, Eliut Dominguez, made two trips from their home in Los Angeles to Packard Children’s, where Stanford surgeon James Chang, MD, performed hand surgery to separate the boy's fingers. 

Paul A. Khavari, MD, PhD, and Isaias Zarate (inset)

''These patients and their families are truly heroic, because they are living with a disease that causes suffering virtually every moment of every day,'' says Paul A. Khavari, MD, PhD, the Carl J. Herzog Professor in Dermatology at Stanford. ''There is almost nothing I’ve experienced in medicine that is so heartbreaking as seeing a young child who can’t play or run normally and is covered with bandages, wounds, and bleeding sores.''

Because no standard medications are available to treat this traumatic blistering, Khavari has turned to a promising experimental technique known as gene therapy. RDEB is caused by a defect in a gene that produces collagen VII, a protein that helps glue the epidermis, or top layer of skin, to the dermis, the deeper layer below. Without collagen VII, the skin is unable to withstand normal stress, and blisters easily. 

The idea behind gene therapy is to insert normal copies of the defective gene into the patient’s skin cells in a laboratory Petri dish, then graft those cells back onto the patient’s wounds. ''If it works, the new skin cells will produce the missing collagen VII glue, which will restore normal adhesion between the epidermis and the dermis,'' Khavari says. 

He and his co-workers successfully demonstrated the technique in a recent experiment using human skin cells grafted onto immune-deficient mice. Now, Khavari, Lane, and Stanford colleagues M. Peter Marinkovich, MD, and Zurab Siprashvili, PhD, are seeking approval from the Food and Drug Administration to conduct similar trials on RDEB patients who are 18 or older. 

''We hope that gene therapy will stop the blistering for more than a year,'' says Marinkovich, associate professor of dermatology at Stanford. ''If it proves successful on adults, then perhaps we can begin testing it on children.'' 

In the past, kids with severe RDEB often died before adulthood. Today, with advances in nutrition and basic care, many survive into their 20s and 30s, only to succumb to a lethal form of skin cancer. ''The lessons we learn from gene therapy and EB may enhance our understanding of that kind of cancer, as well as the more than 175 genetic diseases that affect the skin,'' Khavari says. ''Stanford and Packard have become world leaders in this kind of research.'' 

For Fernando Chavez and his three sons, help cannot come too soon. ''The boys have good times and bad times, but I tell them not to give up,'' he says. ''Right now, the number one priority for all of us is to find a cure.''