Gene therapy helps counter hemophilia B

Enabling cells to make a clotting compound allows some patients to quit medication

A gene therapy based on a cargo-toting virus that gravitates to liver cells might provide hemophilia B patients with long-lasting protection against bleeding, an international team of scientists reports online December 10 in the New England Journal of Medicine.

Hemophilia B is the second-most common form of hemophilia, a hereditary disorder in which blood fails to clot properly. Patients must receive preventive injections of a clotting compound called factor IX to prevent bleeding from cuts, scratches or bruises. In the new study, four of six hemophilia B patients given the gene therapy no longer need the clotting compound.

The work “is truly a landmark study, since it is the first to achieve long-term expression of a blood protein at therapeutically relevant levels,” physician Katherine Ponder of Washington University in St. Louis, who wasn’t part of the study team, wrote in the same issue of the journal. The findings were also presented December 11 in San Diego at a meeting of the American Society of Hematology.

British researchers treated six men ages 27 to 64 with the gene therapy, an innocuous virus coupled with components that induce liver cells to make factor IX. Before the study, the men had been getting intravenous infusions of factor IX two to three times a week, says study coauthor Andrew Davidoff, a surgeon at St. Jude Children’s Research Hospital in Memphis, Tenn., where the gene therapy was designed.

Each patient received a single infusion of the therapy, called serotype-8-pseudotyped, self-complementary adenovirus-associated virus vector. Scientists have now monitored the men for nine to 20 months.

Four patients who received medium or high doses of the therapy have made enough factor IX themselves to cease getting the preventive infusions of it. Two patients who were given low doses of the gene therapy are making less. While they still need factor IX infusions, they have cut back to one every 10 to 14 days, Davidoff says.

The virus used as the delivery vehicle, known as AAV-8, was chosen in part because it is unlikely that many people receiving it would have been exposed to it and already made antibodies against it, Davidoff says. The virus also targets liver cells, which naturally make factor IX. And although AAV-8 enters a cell it doesn’t integrate with material in the nucleus, greatly reducing the risk that the therapy would interfere with normal cell function.

Because of these attributes, “there’s a modest level of excitement” about this approach, says hematologist W. Keith Hoots of the National Heart, Lung, and Blood Institute in Bethesda, Md., which funded the study in part. The treatment cannot be repeated in a patient, however, because the immune system would recognize AAV-8 the second time around. Even so, the approach has promise because there are dozens of other AAVs that are still untapped, Hoots says.

Two of the patients were given a brief course of steroid drugs when they showed signs of liver inflammation, but no other side effects emerged. Earlier tests in large animals had shown that this therapy could last 10 years or longer. Further testing in people is planned, Davidoff says.

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