Philadelphia, Pa. — Researchers led by physicians at The Children’s Hospital of Philadelphia reported encouraging early results in patients for a novel gene therapy designed to improve the clinical course of the bleeding disorder hemophilia B. Of three adult patients who received low doses of a beneficial gene, all showed evidence that the gene was transferred into muscle, and none of the patients showed signs of side effects. "This exciting new treatment offers the possibility of converting severe hemophilia B to a milder form of the disease through a relatively non-invasive procedure," said Katherine A. High, M.D., director of hematology research at The Children’s Hospital of Philadelphia, and the senior author of the study. Researchers from Children’s Hospital and Stanford University Medical Center reported their initial results in the March issue of Nature Genetics.

Three adult patients were injected with low doses of adeno-associated virus (AAV), a harmless human virus modified to carry genetic instructions to manufacture the blood clotting protein, called factor IX. It was the first time an AAV vector (a gene delivery vehicle) was inserted into patients’ skeletal muscle, in this case the thigh. Because a genetic defect makes them unable to produce enough of their own clotting factor, patients with severe hemophilia usually require frequent infusions of externally produced factor to protect them from painful joint damage and life-threatening internal bleeds. Over the first 100 days following the gene therapy, two of the three patients required significantly less of the infused clotting factor to treat hemophilia symptoms. No adverse side effects were experienced by any of the patients treated, according to Catherine S. Manno, M.D., a hematologist at The Children’s Hospital of Philadelphia and principal investigator of the clinical trial at that hospital.

Hemophilia is classified as severe if a patient is unable to produce at least one percent of the normal level of clotting factor. Even a very low dose of the vector resulted in factor IX levels above one percent in one patient, which was a surprise to the researchers. "This is better than we predicted based on our animal studies, and it may suggest that this gene therapy is more efficient in humans than in other species," said Dr. High. "We are in the beginning stage of using gene therapy in humans, but our results strengthen the possibility that this approach may help patients with other genetic diseases."

Hemophilia B is an inherited bleeding disorder that affects approximately 1 in 30,000 males worldwide. A defect in a single gene leads to a deficiency in a clotting protein, factor IX, which may give rise to spontaneous bleeding episodes which are sometimes life-threatening. The two major forms of the disease are hemophilia A and hemophilia B, caused by a lack of blood clotting factor VIII and IX, respectively. Hemophilia B, the target of the current research, is about one-fourth as common as hemophilia A, and occurs in an estimated 5,000 men and boys in the United States. Both forms of the disease are treated by infusing clotting proteins, either recombinant or derived from transfusions. However, the infusions are expensive, frequent (once a week or more), and sometimes stimulate the immune system to produce inhibiting antibodies, which may neutralize the benefits of treatment.

The human gene therapy, being conducted both at The Children’s Hospital of Philadelphia and at Stanford University Medical Center, builds on the researchers’ earlier pioneering investigations in mice and dogs. In January 1999, Dr. High’s group published a study in Nature Medicine showing that gene therapy achieved long-term improvement of naturally occurring hemophilia B in dogs. This was the first case in which gene therapy produced sustained correction of a genetic defect in a large animal. The gene therapy produced levels of clotting factor in the dogs that would be therapeutic if found in humans; those beneficial results continue nearly three years after the single treatment. Mark Kay, M.D., Ph.D., now Dr. High’s collaborator at Stanford University School of Medicine, and lead author of the current study, had published separate, but similar, results in dogs simultaneously with Dr. High in the same issue of Nature Medicine. The principal investigator of the current clinical trial at Stanford is Bert Glader, M.D., Ph.D.; Dr. Kay is co-principal investigator at Stanford.

As with any gene therapy, a crucial role is played by the vector, the agent that delivers the therapeutic genes into a site in the patient’s body. The vector used here was adeno-associated virus (AAV) vector, engineered from a human virus that most people are exposed to during childhood and which is not known to cause any disease. It was produced by Avigen, Inc. a biotechnology company whose scientists collaborated in the study.

Because other vectors used in human gene therapy have been known to stimulate unwanted immune reactions in patients, researchers monitored patients in this clinical trial closely for possible side effects, and found no toxicity after gene therapy was administered. Two other safety issues are being examined in the current study: whether material from the AAV vector inadvertently travels into germline cells (sperm cells, which transmit genetic material to offspring at the time of conception) and whether antibodies are formed that inhibit the action of the clotting protein. "With these initial patients, our gene therapy approach appears safe in all three areas," said Dr. Manno.

Two patients in an intermediate-dose group have since received injections of the vector. As the clinical trial continues, a third patient will be added to that cohort, along with three patients in a high-dose group. Safety will continue to be closely monitored, along with the effectiveness of higher doses. "Our goal is to identify a dose in which all the patients produce levels of factor IX above one percent," said Dr. Manno. "This could change their hemophilia to a milder form, and make a real difference in their lives."

The Children’s Hospital of Philadelphia, the nation’s first children’s hospital, is a leader in patient care, education and research. This 373-bed multispecialty hospital provides comprehensive pediatric services, including home care, to children from before birth through age 19. The hospital is second in the United States among all children’s hospitals in total research funding from the National Institutes of Health.

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