Cell Transplants Help Hemophiliacs
Genes Engineered to Produce Blood-Clotting Factor Have Limited Success
By Rick Weiss
Washington Post Staff Writer
Thursday, June 7, 2001; Page A03
Human cells genetically engineered to produce a blood-clotting factor can be transplanted safely into people with severe hemophilia and can reduce the number of bleeding episodes in those patients, researchers reported yesterday.
In all six patients, the new genes stopped helping within 10 months, indicating that the technique will have to be improved if it is ever to become a practical treatment for the hereditary disorder.
Nonetheless doctors said they were buoyed by the results, which are the first to show that gene therapy can boost levels of the key clotting factor. If human studies bring improvements like those recently achieved in hemophiliac dogs, scientists said, gene therapy could become an important treatment in the next decade for many of the approximately 17,000 Americans with hemophilia.
"This is truly exciting news for the bleeding disorder community," said Mark Skinner, president of the National
Hemophilia Foundation in New York. "We believe a cure will come incrementally, it won't occur overnight. But to see an announcement like this encourages us that the field is commencing, there's a commitment to the research and it does hold promise for the future."
The study, led by doctors at Beth Israel Deaconess Medical Center in Boston and Transkaryotic Therapies Inc., a biotechnology company in Cambridge, Mass., comes at difficult time for people with hemophilia -- a disease that comes in many forms depending on which one of several clotting genes is faulty from birth.
Thousands died after receiving infusions of blood products contaminated with the AIDS virus in the early 1980s. Now, because of production problems, there is a major shortage of recombinant factor VIII, a manufactured form of the clotting factor that is absent or dangerously low in people with hemophilia A, the most common form of the disease. The new work also comes at a crucial time for gene therapy, an experimental approach that aims to cure diseases by replacing people's faulty genes. A decade of efforts in thousands of patients with many different diseases has yet to provide a documented cure. And the September 1999 death of a teenager in a gene experiment in Philadelphia that was later found to be in violation of several research rules cast a cloud over the entire field.
Researchers this week said that, given that record, they were reluctant to enthuse about the new result. But several noted that hemophilia is more likely than most diseases to respond to gene therapy. In part that's because even a small increase in clotting factor levels can make a big difference in a patient's health. In the new work, led by Beth Israel hematologist David Roth and described in today's issue of the New England Journal of Medicine, doctors removed a small patch of skin from each patient's arm and cultivated some of those skin cells in laboratory dishes. Then, using an electrical shock, the researchers blasted tiny holes in the cells' outer walls, through which they infused new copies of the factor VIII gene the cells had lacked.
Those genes turned the cells into tiny factor VIII factories. Doctors used a surgical instrument inserted through the skin just below the navel to inject a few hundred million of the cells deep into the patients' abdomens. The hour-long surgery was one of the major risks of the procedure for the bleeding-prone patients. Each received extra injections of clotting factors in advance and for a week afterward to prevent complications. Apparently the cells settled down and survived, because factor VIII levels rose in four of six patients -- albeit very modestly, with levels rarely exceeding 1 percent or 2 percent of normal. Initially those levels had been less than 1 percent in all patients.
Scientists are not sure how high concentrations must get to prevent abnormal bleeding, but as little as 5 percent is probably enough, experts said. Even at the 1 percent to 2 percent levels achieved in the experiment, bleeding episodes decreased for two of the three patients who kept careful logs before and after treatment. One who had spontaneous bleeding almost weekly before treatment had no such bleeding for 10 months after treatment.
Roth said the team has now treated six more patients with a modification that he hopes will lead to even higher levels of factor VIII. "Even if we achieve a long-lasting durable effect at a lower level, that would be a humble first step and it will evolve over time," she said.
Katherine High of Children's Hospital of Pennsylvania who is developing gene treatments for hemophilia B, said recent improvements in gene therapy techniques have raised clotting factor levels to about 10 percent of normal in hemophiliac dogs. "We are reasonably confident that you can get that level in people with some combination of techniques," she said. |
