Gene Therapy Offers Hope for Hemophilia B

Dec. 12, 2011— -- SAN DIEGO -- This may be a very Merry Christmas for people with hemophilia B.

For the first time, researchers have demonstrated that gene therapy can overcome the blood protein deficiency, originally named Christmas disease after the first reported sufferer.

In a small study, six hemophilia B patients were treated with a viral vector that expressed factor IX (FIX), according to Amit Nathwani of University College London and colleagues.

Four of the six have stopped FIX prophylaxis and the other two have been able to extend the period between doses, Nathwani and colleagues reported online in the New England Journal of Medicine and here at the annual meeting of the American Society of Hematology.

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Aside from transient elevations in liver enzymes in two patients, the procedure does not appear to have any acute or long-lasting toxicity, the researchers reported.

The gene therapy approach "has the potential to convert the severe bleeding phenotype into a mild form of the disease or to reverse it entirely," Nathwani and colleagues concluded, although they said more work is needed to define the risks and benefits.

The report is "truly remarkable," according to Dr. Katherine Ponder of Washington University School of Medicine in St. Louis.

In an accompanying editorial, Ponder said the trial is "truly a landmark study, since it is the first to achieve long-term expression of a blood protein at therapeutically relevant levels."

But she cautioned that the procedure still needs study in more patients to ensure it is safe.

Previous studies with a similar approach -- using an adenovirus-associated virus (AAV) vector -- had shown only a transient expression of FIX, possible because of a T-cell-mediated immune response, Nathwani and colleagues noted.

To avoid that issue, they used a different vector – a modified adenovirus-associated virus serotype 8 – that is less commonly seen in humans than the earlier vector.

The AAV8 vector also has the benefit that it is liver-tropic, meaning it can be simply and safely administered through the peripheral vein, the researchers noted.

The six patients were given escalating doses of the vector, and the results were roughly dose-dependent, the researchers reported.

Patients in the low-dose group, the first to be treated, currently have stable FIX levels of about 2 percent of normal, and one has been able to stop regular FIX prophylaxis, while the other has extended the time between doses.

The two in the medium-dose group have FIX levels of up to 3 percent of normal; one has had long periods without prophylaxis, while the other has stopped treatment, although he continues to play cricket and soccer.

In the high-dose group, one patient had FIX levels that peaked at 7 percent of normal before dropping to about 3 percent after an elevation of liver enzymes that was about five times the upper limit of normal. The event was treated with prednisone and the enzymes returned to normal levels.

That patient was free of prophylaxis for six months after the transfer, but needed bolus shots of protein concentrate after trauma incurred during a field trip.

Gene Therapy Helps Hemophilia B Patients

The most recent patient achieved FIX levels of between 8 and 12 percent of normal during the eight weeks after gene transfer and did not have protein prophylaxis even though he was training for a marathon, the researchers reported. He also had transient elevation of liver enzymes, although they did not reach the upper limit of normal.

Hemophilia has been known through history, but the first case of hemophilia owing to FIX deficiency was reported in 1952 and was dubbed Christmas disease after the patient, 10 year-old Stephen Christmas.

The study is "important for both a subtle and obvious reason," according to Dr. Thomas DeLoughery of the Oregon Health & Science University in Portland, Ore. The subtle reason is that the study shows that factor levels of only a few percent of normal can prevent spontaneous bleeding, he wrote in an email to ABC News and MedPage Today.

"This therapy will greatly improve the lives of patients with hemophilia by reducing the numbers of bleeds and need for therapy," he said, although there will still be a need for the protein in cases of trauma or surgery. More obvious is that hemophilia therapy is very expensive, and this may reduce costs. "Some patients will need up to a million dollars' worth of factor to prevent bleeding, so this reduction in factor use should translate into cost savings," DeLoughery said. "This is a game changer."