New Trick Improves Odds in Bone Marrow Transplants

Knocking out key enzyme helps healthy stem cells thrive

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HealthDay Reporter

THURSDAY, Aug. 12, 2004 (HealthDayNews) -- A new way to stretch already limited supplies of blood stem cells could make bone marrow transplants more effective in the future, researchers report.

The scientists tinkered with only one tiny but critical thing: They knocked out a key enzyme in those cells so they can implant and multiply more easily once they're in the patient's bone marrow.

These are not the type of stem cells around which the current political debate swirls; they come from such sources as volunteer donors or umbilical cords and they are an essential part of the treatment for leukemias, other cancers and some genetic blood disorders. The technique is to knock out the patient's faulty bone marrow with chemotherapy or radiation, and then replace diseased blood stem cells with healthy stem cells that settle in the marrow and multiply.

The problem is the donated stem cells often don't lodge and grow as well as hoped, said Hal E. Broxmeyer, a professor of microbiology and immunology at the Indiana University School of Medicine. He is lead author of a report on the growth-encouraging method in the Aug. 13 issue of Science.

"When you take these cells, put them in the body and try to get them to expand, the results have been unencouraging," Broxmeyer said. "Even cells from bone marrow do not work well."

The cells do grow enough to provide lifesaving help for many patients. But more people could be helped, Broxmeyer said. For example, stem cells from umbilical cords have been used in more than 3,000 patients, but most of them have been children, who don't weigh that much. The cord cells can't be used in adults because they just don't multiply enough to meet the needs of heavier bodies.

The Indiana researchers have found that one enzyme, designated CD26, plays a major role in stem cell growth. That enzyme knocks out a molecule that helps a stem cell find its proper home in the bone marrow and also stimulates multiplication of the cell when it becomes implanted.

"If you can block the enzyme's activity or get stem cells that don't make it, you can make homing more efficient," Broxmeyer said.

They have tried both methods in laboratory animals, first giving stem cells a dose of a peptide that knocks out CD26, then implanting those cells in mice.

"Homing improved by at least 50 percent in mice, and the repopulating ability of the cells is greater, so we get a twofold increase in the ability of cells to repopulate the body," Broxmeyer said.

And genetically engineered mice have produced marrow stem cells that lack CD26 and are even more efficient at reproduction than the cells treated to knock out the enzyme, he said.

But the knockout method is the leading candidate for possible human trials, Broxmeyer said. A first step has been taken with studies to see if the method used in the mouse trials are effective with human stem cells that are being implanted in mice.

"If that works well, we will try as quickly as we can to go to human clinical trials," Broxmeyer said. It's much too early to discuss when such trials might take place, but "if the data looks good, we will start talks with clinicians," he said.

The work looks very promising, said Dr. Qiang Tian, stem cell group leader at the Institute for Systems Biology, a nonprofit research organization in Seattle.

Noting that "enormous efforts have been exerted to improve the growth of hematopoietic stem cells," as they are formally known, Tian said the Indiana report is "very exciting."

"It will be interesting to investigate in the future what specific targets in the recipient bone marrow and responsible for interactions with CD26," he said.

More information

The basics of bone marrow transplants are explained by the National Marrow Donation Program.

SOURCES: Hal E. Broxmeyer, Ph.D., professor of microbiology and immunology, Indiana University School of Medicine, Indianapolis; Qiang Tian, M.D., Ph.D., stem cell group leader, Institute for Systems Biology, Seattle; Aug. 13, 2004, Science

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