Gene therapy study produces promising results for patients with hemophilia B

A fraction of patients with a common form of the bleeding disorder hemophilia develop an allergic reaction to the blood-clotting treatment they need to keep them alive. But using gene therapy, University of Florida researchers were able to reverse this reaction and provide long-lasting treatment for the disease in an animal model, according to findings published today in the journal EMBO Molecular Medicine.

If successful in humans, gene therapy could not only provide much-needed therapy for patients with hemophilia B, but also spare them from costly and difficult treatment regimens, said Roland Herzog, Ph.D., a professor of pediatrics in the UF College of Medicine and a senior author on the paper.

Patients with hemophilia B don’t make Factor IX, a protein that allows the blood to clot, so when a blood vessel is injured, the vessel is not sealed and blood continues to leak out.

“With the current therapy, protein replacement therapy, some patients’ immune systems reject it,” Herzog said. “There are ways to still treat the patient, but it is much more complicated. If someone has developed an antibody to Factor IX and won’t respond to the clotting factor, then doctors can still stop bleeding, but they have to give bypass agents. Those can be quite expensive, sometimes more than $100,000 just to stop the bleeding. There was a need to develop a superior alternative.”

Gene therapy techniques for treating hemophilia that were developed at UF are already in human clinical trials at other institutions and have been successful. During gene therapy, a harmless adeno-associated virus ferries a working gene into the body to replace a faulty one. In the case of hemophilia B, when gene therapy is successful, the body starts making its own Factor IX again, eliminating the need for protein replacement therapy, except in certain cases, such as during surgery or after a traumatic injury.

But researchers had not yet shown if gene therapy could work in patients who had developed an immune reaction to Factor IX.

“We worried that we would give gene therapy and once the body began to pump out Factor IX, we wouldn’t know if it would cause the same allergic reaction as protein replacement therapy,” Herzog said. “We did not observe any of that. It has turned out to be quite safe. Instead, the antibodies just disappeared. Then, we see correction of the bleeding disorder. The liver keeps making Factor IX and secretes it. We can also give Factor IX again and there is still no immune response. It is a long-lasting immune tolerance.”Because patients sometimes need additional treatments with the clotting protein, particularly if they have been in an accident, it’s important to know they can receive additional supplementation safely, said lead author David Markusic, Ph.D., a UF research assistant professor of pediatrics.

But researchers are moving forward with caution. Although these initial tests in an animal model were successful, additional studies are needed before human trials because dangerous side effects could occur if the gene therapy worked without curbing the immune response, Herzog said. For example, if the body started making its own Factor IX after gene therapy, but a patient still suffered an immune reaction, it could cause serious kidney damage.

Markusic has received an additional grant from the Bayer Hemophilia Awards Program to dig deeper into this immune reaction and pinpoint what is happening at the immune cell level after gene therapy.

The researchers also aim to test the technique in hemophilia A and other conditions, such as Pompe disease.

The National Institutes of Health and the Bayer Hemophilia Awards Program funded the study. In addition, the researchers, who are affiliated with both the UF Genetics Institute and the Powell Gene Therapy Center at UF, also received support from the Children’s Miracle Network.