June 15, 2001 Researchers at Johns Hopkins Children's Center report success in treating sickle cell disease in mice with a modified bone marrow transplant. The finding adds further support to human trials now under way at the Children's Center.
A group led by pediatric hematologists Robert Iannone, M.D., and James Casella, M.D., and oncologist Ephraim Fuchs, M.D., found that a "mini-transplant" of just 40 percent normal bone marrow was enough to reduce anemia and organ damage in mice with sickle cell anemia (SCA). Their study, which appears in this month's Blood, is the first to thoroughly examine the effects of transplanting a limited amount of normal bone marrow to treat sickle cell disease.
The report's lead author, Robert Iannone, identified the ratio of normal to sickle cell-making marrow necessary to treat SCA in mice. Once doctors know the threshold level of normal bone marrow required to prevent complications from SCA, Iannone says it will be possible to tailor a mini-transplant to humans that could sufficiently treat a patient's SCA while drastically reducing the danger of donor tissue rejection often associated with bone marrow transplants.
After destroying each genetically normal mouse's bone marrow, the research team transplanted in different amounts of normal and sickle cell-making marrow, waited four months to let the grafts settle, and examined the qualities of the rodents' blood cells.
Mice with 25 percent normal donor marrow had 90 percent or greater normal red blood cells in their bloodstreams. The remaining deformed red blood cells were too few to cause severe oxygen deficiency and tissue damage. "Even a small amount of normal marrow can result in drastic reductions in abnormal red cell counts," Iannone says.
The research team also found that 15 percent sickle cells in the blood stream appears to represent a threshold level in mice, above which SCA's most damaging symptoms return. Reducing the amount of sickle cells below this threshold was achieved with a transplant of less than 25 percent normal marrow.
"Sickle cell anemia can be highly morbid," Iannone says. "In addition to extreme pain, children can have severe complications, including stroke."
Encouraged by the results of the mouse model study, Iannone's group initiated clinical trials of mini-transplants to treat sickle cell disease in humans. Two patients have already completed the trial and are doing well, Iannone says. While definitive results are not yet available, Iannone says he remains hopeful that the trials will offer children with SCA an alternative to other therapies.
Sickle cell anemia affects approximately 72,000 Americans, primarily African-Americans. It is an inherited blood disorder caused by a single mutation. Smooth and flexible oxygen-poor red blood cells turn rigid and crescent-shaped, or "sickled." The deformed cells are dangerous because they tend to bunch up in capillaries and veins, cutting off oxygen flow and causing extreme pain and organ damage. Blockages of small blood vessels can also cause damage to tissues and vital organs, leading to other serious medical problems.
Co-authors of the study include Johns Hopkins School of Medicine researchers Leo Luznik, Ph.D., Laura Engstrom, Anita Hawkins, M.S., Constance Griffin, M.D., Lori Noffsinger, and Frederic Askin, M.D. Sickle cell transgenic mice were provided by E.M. Rubin of Lawrence Livermore Laboratories in Berkeley, Calif. The study was funded by an institutional pilot project grant from Fujisawa Healthcare Incorporated, Dearfield, Ill.
If you or your child would like to participate in the mini-transplant clinical trial, contact the pediatric Division of Hematology at 410-955-6132.
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