Krabbe’s therapy shows promise

Posted: May 18, 2005
Watching her infant daughter die of Krabbe’s disease was horrifying.

At first, the baby cried all the time. Then, LeA Gartzke gagged on her milk – throwing up everything she consumed. Unable to eat, the Shorewood child rapidly began to lose weight, requiring doctors to insert a stomach tube.
Soon after, the seizures began, sending her body into spasms, stiffening her muscles, making it all but impossible for her or her parents to bend her arms and legs. And as more of her defective brain cells died, she became blind and unresponsive, said Micki Gartzke, LeA’s mother.
In 1998, at age 2, LeA died – the same age as the vast majority of babies with Krabbe’s.
However, an experimental treatment using transplanted umbilical cord blood has produced astonishing results for children like LeA. Indeed, another Wisconsin child is among the first who may have been cured by this novel therapy, reported today in the New England Journal of Medicine.
Although it’ll be years before doctors will know whether it actually is a cure, the research suggests that babies born with this genetic neurological defect not only can survive, but also can have a fairly normal quality of life if they are treated early.
“This can really be lifesaving and life-altering,” said Joanne Kurtzberg, senior author of study.
Kurtzberg, a professor of pediatrics and pathology at Duke University Medical Center, and other researchers reported that transfusing cord blood from unrelated donors into infants with the disease before symptoms appear resulted in 100% survival for the invariably fatal disorder.
Krabbe‘s disease is from the same family of genetic neurological disorders that includes the disease featured in the 1992 movie “Lorenzo’s Oil.”
About one in 100,000 babies are born with Krabbe’s, and about one in 7,000 are born with related nerve cell disorders.
More recently, Krabbe’s disease got national attention when former Buffalo Bills quarterback Jim Kelly established a foundation to create awareness and fund research after his son, Hunter, was born with the disease in 1997.
Hunter now is 8 years old. He is one of the oldest living children with the infantile form of the disorder, although he is severely disabled, according to Lisa Donato, a spokeswoman for the Hunter’s Hope Foundation, which provided partial funding for the study.
Lack of crucial enzyme
Babies with the disease lack an enzyme that is crucial to the production of myelin, a fatty substance that coats nerve cells. Without the coating, the brain cells can’t function properly.
The umbilical cord blood contains stem cells that have the gene for the enzyme. The researchers believe that when those cells get into the brain, normal myelination can take place.
Four-year-old Jeremy Thoms of Eau Claire was one of the first 11 infants who got the therapy at Duke.
In 1988, Jeremy’s parents, Randy and Tanys, lost another son, Alex, to the disease. As carriers of the defective gene, the Thomses knew there was a 25% chance that Jeremy had the disease, Randy Thoms said.
So Jeremy was tested right after he was born.
“When Jeremy was diagnosed, we didn’t know there was a treatment,” Tanys Thoms said. “We thought we were going to go through the same horror again.”
However, their pediatrician learned of the experimental treatment trial that was going on at Duke in Durham, N.C. They decided to try it even though they knew the treatment would involve a grueling regimen of chemotherapy for nine days before the umbilical cord blood transplant.
“You have to do it,” Randy Thoms said. “It was a chance at life.”
The chemotherapy was designed to destroy Jeremy’s bone marrow and immune system before he got a transfusion of about 1 billion cord blood cells. He spent the next four months recovering in Durham.
Today, “He’s doing great,” said co-author Kurtzberg, who also is Jeremy’s physician. “He’s one of the kids who walks, runs and climbs and does all the things normal kids do. He’s cognitively normal.”
In fact, Randy Thoms said, Jeremy has developed into a very smart boy, “a little stinker” who loves firetrucks, trains and Thomas the Tank Engine. Jeremy still has a little trouble pedaling a tricycle and walks upstairs slowly, but “I think he’ll be fine,” Randy Thoms said. “He’ll have a job. He’ll marry.”
Lifetime effect unknown
Doctors not associated with the study said the therapy was an important advance.
“It is clear they are surviving better and living longer,” said William Rhead, a professor of pediatrics and pathology at the Medical College of Wisconsin and medical director of genetics at Children’s Hospital of Wisconsin. “This is a glass that is way more than half full. This is wonderful.”
But more time will be needed to learn if the therapy has long-term, lifetime benefit, Rhead said.
The oldest child in the study is a girl who is now 6½.
“It is very striking that you can treat kids so early and get such a good result,” said Richard Jacobson, an associate professor of neurology and pediatrics at the Medical College.
Very few states test for the disease, said Jacobson, director of neurophysiology at Children’s Hospital, and Wisconsin is not one of those.
But the success of the treatment, which he described as a crude form of gene therapy, suggests that all babies should be tested for the disease early on.
The success of the treatment largely was limited to Jeremy and 10 other babies who received their transplants before symptoms appeared, all between 12 and 44 days after birth. All those babies survived and had improvements in development skills, although a few had mild to moderate delays in language and motor skills.
Also, all of them were alive far longer than siblings who died of the disease.
Fourteen other babies between the ages of 142 days and 352 days got transplants after symptoms appeared. Only 43% of those babies survived, and the ones who lived had minimal neurological improvement and were extremely disabled. Four died of Krabbe’s disease, and four died because of complications from the transplant, said lead author Maria Luisa Escolar.
“The timing is critical,” said Escolar, an assistant professor of pediatrics at the University of North Carolina at Chapel Hill. “It has to be done early in life.”
Indeed, the success of early treatment has prompted researchers to consider the treatment as a possible in-utero therapy. Although in-utero procedures have other risks, doing the transplants long before birth would eliminate the need for chemotherapy because immune system rejection likely would not occur, Escolar said.
In-utero transplants likely are a few years off, Escolar said.
The treatment now costs about $600,000.
The transplant, said David Margolis, director of the bone marrow transplant program at Children’s Hospital of Wisconsin and associate professor of pediatrics at the Medical College, is a very straightforward process and is something that could easily be done at his hospital.
But, he said, transplants are not slam-dunks – they are risky procedures.
“There is the sad, realistic possibility that someday soon, a child will die from a transplant-related complication.”
But the big question is how many will survive and how many years will the treatment last?
“Our hope is that it will be a permanent fix,” Kurtzberg said.
Tanys Thoms said that belief hit home when Jeremy returned to Duke for his first annual follow-up visit.
The visit involved a complete physical and an extensive battery of tests, including an MRI, a spinal tap, X-rays and an echocardiogram, she said.
Tanys Thoms asked how long the visits would have to continue.
When they told her he’d have to keep coming back until he was 50, she was shocked.
“But then I realized they expected him to live that long,” she said.

From the May 19, 2005, editions of the Milwaukee Journal Sentinel