Genetically altered cells ease hemophilia.

People with severe hemophilia live in fear of cuts and bruises, which bleed profusely and require prompt injections of expensive medication. Worse yet, these people often experience spontaneous bleeding inside their joints, even without apparent injury.

Scientists now report that a new form of gene therapy provides some protection against bleeding. The gains are modest, not all patients improved, and the benefits don't appear to last. But the treatment reduced the use of clotting medicine in some patients and didn't cause any serious side effects.

If any disease seems susceptible to gene therapy, it's hemophilia. A lone mutation can leave a person bereft of one of the proteins essential for proper blood clotting. Thus, replacing a single faulty gene would seem enough to reverse the disease. However, delivering genes has proved difficult (SN: 5/13/00, p. 309). Now, people with hemophilia typically treat themselves with injections of purified clotting protein.

In the recent study, scientists removed a piece of skin from the arms of six people with severe hemophilia A. In this condition, a person produces inadequate amounts of a clotting protein called factor VIII.

The scientists impregnated some of the excised cells with plasmids--rings of bacterial DNA--that they had altered to carry a gene encoding factor VIII. The researchers then reproduced the cells that had taken up the desired gene and that, unlike natural skin cells, made factor VIII.

Study participants received injections of these genetically engineered copies of their own cells into midsection fatty tissue. Three participants each received 100 million such cells, and three others each received 400 million, says study coauthor Richard F Selden, a geneticist who heads Transkaryotic Therapies in Cambridge, Mass. He collaborated with researchers at Harvard Medical School in Boston. The team's report appears in the June 7 NEW ENGLAND JOURNAL OF MEDICINE.

Periodic blood tests over the next year revealed that all three patients in the high-dose group and one in the low-dose group sometimes had factor VIII concentrations that the researchers interpreted as higher than those shown at the start of the study. At some visits, the reimplanted cells were producing as much as 2 to 4 percent of normal factor VIII amounts.

"You don't need a lot [of factor VIII] to make a big difference in a person's everyday life," says hematologist Carol K. Kasper of the University of Southern California in Los Angeles.

People lacking the protein face up to 30 bouts a year of spontaneous bleeding into their joints, as indicated by swelling. The two patients in whom the therapy had the strongest effect reported no need to treat themselves for spontaneous bleeding for roughly 10 months beginning shortly after treatment. Then, however, the effect seemed to wear off.

Still, Selden admits to being "thrilled" with the results since this is the first gene therapy for hemophilia A in people.

"I think these results are exciting," says Katherine A. High, a hematologist at Children's Hospital in Philadelphia. "They confirm [that] even low levels of circulating clotting factor can have an ameliorating effect on this disease."

Not everyone agrees that the study was informative, however. Christopher E. Walsh, a hematologist at the University of North Carolina in Chapel Hill, points out that the increases in factor VIII were small. "They are really at the limits of detection," he says. Also, there was no placebo group in the study. Participants might have expected to feel better and been less likely to treat themselves for internal bleeding, Walsh says.