Gene therapy ameliorates clotting disorder.

Generations of humans, from plebeians to royalty, have suffered from the blood-clotting disorder known as hemophilia. This week, a scientific team reports using gene therapy to treat dogs with a canine version of hemophilia B, an inherited bleeding disease that afflicts one of every 30,000 persons.

If genetic engineers can perfect the technique in dogs, they may be able to offer relief to humans, says Savio L.C. Woo of the Bay for College of Medicine in Houston.

"This is the first step," adds Kenneth M. Brinkhous of the University of North Carolina School of Medicine at Chapel Hill. "It has tremendous potential." Brinkhous and Woo led the multicenter research team reporting the advance in the Oct. 1 SCIENCE.

Hemophilia B occurs mostly in males. Those with the disease are deficient in the blood-clotting protein factor IX. The inadequate or inactive supply of clotting factor results in periodic internal bleeding. Although hemophiliacs can ward off such episodes by injecting a concentrated form of factor IX, the treatment falls far short of a cure, and the annual cost runs from $60,000 to $100,000 per patient.

Many researchers believe that a gene therapy solution to blood-clotting disorders would provide patients with longer-lasting, cheaper protection from bleeding episodes. To test whether such an approach would work, Brinkhous, Woo, and their colleagues turned to a canine model - that is, dogs that produced no detectable amounts of factor IX and therefore suffered from hemophilia B.

The team began by injecting three of the dogs with a crippled virus carrying the canine factor IX gene. These viral vectors, which cannot replicate, traveled through the bloodstream and entered the liver cells of each dog. In each cell, the gene coding for factor IX inserted itself into the DNA and turned on, instructing the cellular machinery to crank out the crucial clotting protein.

After therapy, the dogs began producing factor IX, although these levels were about 1,000 times less than normal. Yet even that modest amount appeared to transform the disease from severe to moderate, an improvement that has lasted up to nine months.

In addition, blood from the treated dogs showed a "really dramatic" decline in the amount of time it took to clot in the test tube.

Woo says they injected just one genetically engineered virus for every 10 liver cells. He believes that the amount of factor IX produced would rise if the team could deliver more of the viral vectors to the dog liver cells.

If they succeed with such animal experiments, researchers could begin human trials of gene therapy for hemophilia B. If gene therapy can coax human livers to produce even modest amounts of clotting factor, people with hemophilia could cut down on or even eliminate their routine injections of clotting factor, Brinkhous notes. Eventually, the team hopes to extend their work to hemophilia A, the more common form of the disease.