Children with this rare metabolic disease die by the age of 6 because they are missing an important enzyme, alpha-L-iduronidase, which leads to progressive damage in the brain, heart, bones, cartilage, liver and corneas. Stem cells from cord blood provide the needed enzyme in the brain and the rest of the body, thus halting the disease and aiding repair in these organs and tissues, the Duke study showed.
In fact, survival was higher and complications lower among the Duke children who received cord blood than among children previously described in the medical literature who had received adult bone marrow, said Duke's Susan Staba, M.D., lead author of the study. Results of the study in 20 children with Hurler's Syndrome are published in the May 6, 2004, issue of the New England Journal of Medicine. The research was partially funded by the National Heart, Lung, and Blood Institute.
Bone marrow from adult donors can save some Hurler's patients, but an exact match cannot be found in time for more than 50 percent of children, and time is critical in treating these children, said the researchers. Moreover, adult bone marrow fails to engraft in 28 to 37 percent of Hurler's patients, meaning the donor bone marrow does not take hold and begin to grow in the patient.
As an alternative treatment, Duke physician Joanne Kurtzberg, M.D., director of the Pediatric Blood and Marrow Transplant Program at Duke and senior author of the paper, tested the ability of cord blood stem cells to provide the missing enzyme and thereby halt the progressive organ deterioration in these children. Stem cells in cord blood are less mature than adult bone marrow cells and thus do not need to perfectly match the patient's immune-related blood proteins called antigens, said Kurtzberg. Moreover, cord blood stem cells appear to repair more of the damage caused by Hurler's syndrome than does adult bone marrow.
In the Duke study, 85 percent of children who received cord blood survived for two to seven years -- the longest period of time they have been followed. Survival among Hurler's children who receive bone marrow is between 63 and 72 percent.
"Cord blood stem cells appear to correct the organ damage better than adult bone marrow does," said Kurtzberg. "The children's cognitive skills continued to improve after transplant to such a degree that they actually gain mental skills faster than age-matched control children and cross over into the normal range at three to four years post transplant."
Such cognitive gains might be related, in part, to transplanting the children at a slightly younger age, before their disease has progressed beyond repair, said Kurtzberg. Yet stem cells in cord blood have many traits that create a more favorable environment for recovery, she added. Because they are immature, they can more readily turn into other cell types and thus have a better chance of repairing existing damage, she said.
Moreover, said Kurtzberg, stem cells' immaturity significantly reduces their ability to recognize the patient as foreign and attack his or her tissues, a life-threatening condition called graft-versus-host disease. Graft-versus-host disease occurred in 30 to 50 percent of Hurler's syndrome patients receiving adult bone marrow. This condition contributes to up to half of the deaths among children who receive adult bone marrow transplants.
Kurtzberg's team has also utilized the benefits of cord blood to avoid giving children radiation prior to transplant, a neurologically toxic regimen that is often necessary to make bone marrow transplants -- but not cord blood transplants -- successful.
"We have created a chemotherapy regimen that facilitates engraftment without giving the child radiation," said Kurtzberg. "We're able avoid radiation in large part because the properties of cord blood enable us to achieve engraftment more readily and with less manipulation of cells than is possible with adult bone marrow."
The findings are yet another example of the promising capabilities of stem cells derived from umbilical cord blood, she said. Kurtzberg pioneered the use of unrelated umbilical cord blood transplants to cure children with resistant cancers and rare metabolic diseases. She and her colleagues have transplanted more children using cord blood than any other group in the world -- 460 to date -- and proved just this year that stem cells from cord blood actually infiltrate the brain and damaged heart muscle to repair the damage.
Kurtzberg's team has also treated more children with Hurler's syndrome than any center in the world. The current study reported the first 20 children who were treated with cord blood transplants between December 1995 and October 2002. After transplantation, children were followed and evaluated by Maria Escolar, M.D., at the University of North Carolina Center for Child Development to chart their physical growth and cognitive skills. All children had either stable or improved brain function after transplantation, the study showed. Growth velocity also returned to normal in the majority of children within one year of transplant. Kurtzberg also assessed their organ function and found improvements in each deficit area following transplant.
"Cord blood presents an excellent source of stem cells, and it is readily available to nearly every child who needs it," said Kurtzberg. "It provides an important therapeutic option for young patients with severe Hurler's syndrome who lack a perfectly matched and related adult bone marrow donor."
Patients with a milder form of the disease, with no brain involvement, can receive enzyme therapy alone. However, because enzymes do not cross the blood-brain barrier, they cannot repair the brain damage that occurs in more severe forms of the disease, said Kurtzberg. For these children, transplantation is essential.
Journal
New England Journal of Medicine