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    Blocking gene may aid marrow transplants

    Turning off the gene in mice vastly broadens the pool of marrow donors. Next question: Will it work in people?

    By WES ALLISON, Times Staff Writer
    © St. Petersburg Times
    published March 15, 2002


    TAMPA -- Considering that less than a third of people who need a bone marrow transplant find a suitable match, new groundbreaking research on mice offers the potential to save the lives of thousands of people each year.

    In today's issue of the journal Science, researchers at the H. Lee Moffitt Cancer Center report that mice deprived of a specific gene overwhelmingly survived bone marrow transplants from unsuitably matched donor mice.

    The gene, called SHIP, helps govern the proliferation of certain killer immune cells in the blood. When it's blocked, the mice's immune systems were less likely to attack the donated bone marrow. And, more important, immune cells in the donated bone marrow were less likely to attack their new host, a common condition called graft-versus-host disease.

    If the same holds true in people, patients with leukemia and other blood diseases would benefit from a much larger pool of potential donors, making lifesaving transplants far more likely than they are today.

    "The overwhelming majority of patients go untransplanted because they can't find a donor," said Dr. William G. Kerr, the lead author of the study and an associate professor of oncology and biochemistry at Moffitt and the University of South Florida.

    The SHIP gene "tells us what the target is, so we can now translate this to the clinic and develop pharmaceutical approaches so we can transplant more people," he said.

    Researchers hope the finding leads to a drug that could temporarily block the SHIP gene in people. It could be taken before, during and shortly after the transplant, then discontinued after the donor cells become established.

    Marrow is a spongy tissue inside the bone that produces blood and immune cells. Giving bone marrow cells from one person to another -- called an allogeneic transplant -- can successfully treat cancers of the blood, such as leukemia and myeloma, or replace marrow destroyed during the treatment of other cancers.

    Transplants also work on some genetic and immune disorders.

    However, the chance of finding a suitable match from an unrelated donor is about one in 20,000. With a parent or sibling, the odds improve to about one in three. And the risk of graft-versus-host disease makes it extremely dangerous for people over 55.

    At any given time, some 3,000 Americans are searching for a bone marrow match, the National Marrow Donor Program says, which is what made the Science study so exciting.

    In their experiment, Kerr and his colleagues engineered mice to be born without the SHIP gene. The mice then were given bone marrow cells taken from mice that normally would have been terrible matches.

    But, without the SHIP gene, 85 percent of them survived.

    By contrast, less than one-third of mice with the SHIP gene lived.

    Dr. Alan Kinniburgh, vice president of research for the Leukemia & Lymphoma Society of America, said many of the 61,000 Americans who die of blood-related cancers each year could be treated if the findings translate into help for people.

    "If this works out, it will offer a much less toxic and more effective procedure for the transplant," he said. "The further you can go with mismatches, the better off you are."

    Currently, donors are chosen by a process called HLA typing. HLAs are proteins found in every tissue of the body, and they serve to alert natural killer immune cells that something is amiss.

    Everyone has six types of HLAs, but the types vary from person to person. A suitable donor must have at least four of the same HLAs as the patient, preferably five.

    Graft-versus-host disease occurs when the donor's immune cells don't recognize the patient's HLAs, so they start attacking healthy tissues. Less commonly, the patient's immune cells attack the donor cells, a condition called rejection. Immunosuppressant drugs can control both, but the treatment leaves the patient vulnerable to infection.

    "It's just a very significant problem, and anything we can do to overcome that is important," said Dr. Karen Fields, chief of the medicine service and a transplant physician at Moffitt, which does more bone marrow transplants than any cancer center in the Southeast.

    Kerr's team found that disabling the SHIP gene allowed other, less predatory killer cells to crowd out those that would have attacked the mismatched HLA. It also prevented rejection.

    "They are blind to the fact that this is a mouse cell from another mouse," Kerr explained.

    In people, the donor's cells should become established in the bone marrow and begin producing their own blood and immune cells, ending the risk of graft-versus-host disease, he said. Theoretically, the SHIP gene could then be enabled again.

    But there's a big difference between a mouse and a human, and disabling the SHIP gene in people -- even temporarily -- may have unforeseen consequences.

    Clinical trials in people are likely several years away. The next step is testing the concept in larger animals, as well as to begin work on a drug to inhibit SHIP. Kerr plans to meet with pharmaceutical companies about sponsoring that research.

    "This is a long way from humans, yes," said Fields, who was not involved in the study. "But the concept is an excellent concept, because it ... gives us a drug that would be specific."

    To learn more about marrow transplants?

    National Marrow Donor Program or (800) 526-7809

    National Cancer Institute

    Leukemia & Lymphoma Society of America

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