Nonviral Gene Therapy for Hemophilia Safe and Beneficial

Release Embargoed Until: June 6, 2001 5:00 p.m. EDT

Contact: Bill Schaller(617) 632-8062[email protected]

Study Finds Nonviral Gene Therapy for Severe Hemophilia A is Safe with Early Signs of Benefit

BOSTON--A phase I study led by researchers at Beth Israel Deaconess Medical Center has demonstrated that a factor VIII gene therapy-based treatment for severe hemophilia A is safe and well-tolerated. The results of this first human investigation of hemophilia A gene therapy also showed that the treatment, which was derived from patients' own cells, may be effective in reducing the occurrence of spontaneous bleeding, a frequent and potentially lethal symptom of the severe form of the disorder. The findings are published in the June 7 issue of the New England Journal of Medicine.

The study, which utilized a nonviral gene therapy system developed by Transkaryotic Therapies (TKT) of Cambridge, Mass., involved six patients with severe hemophilia A, a deficiency of the blood clotting protein called factor VIII. Each patient was treated with his own cells after the cells were genetically modified in a laboratory to express factor VIII. While the study was conducted to determine whether the treatment was safe, the researchers found that four of the six patients had elevated plasma levels of factor VIII activity after receiving the genetically modified cells. This increase coincided with a decrease in bleeding and/or a reduction in the amount of factor VIII needed to treat bleeding. In addition, two of these patients experienced no episodes of spontaneous bleeding during a 10 month period following treatment.

"It is greatly encouraging to see that this treatment is safe, that no immune responses to factor VIII developed in any patient, and that no patient developed side effects from the genetically modified cells," says David A. Roth, M.D., director of hemophilia clinical research at Beth Israel Deaconess and the study's principal investigator and lead author. "There is still a lot of work that needs to be done on these and other patients before we can move on to future studies to formally evaluate efficacy, but we are optimistic based on the clinical responses we observed, especially in light of the modest increases in factor VIII activity achieved at this early stage."

Roth and his colleagues utilized a nonviral, ex vivo technique to transfer the factor VIII gene into cells derived from the patient. The process involves isolating a patient's fibroblast cells from a small skin biopsy specimen. The factor VIII gene expression plasmid is introduced into these cells using electroporation, a brief electrical pulse. A clonal population of cells that expresses factor VIII is isolated, characterized and then injected into the fatty tissue in the patient's abdomen using a laparoscopic procedure. The risks associated with viral vector gene therapy are essentially obviated by the nonviral method used here to introduce the factor VIII gene into the cells, by modifying the cells outside the patient's body, and by administering a clonal population of characterized cells with a single genetic modification. The risks that were minimized by the nonviral approach used in this study include unintended immune reactions, infections, genetic mutations and gene transfer to reproductive tissues.

Hemophilia A is an X chromosome-linked hereditary bleeding disorder due to a defect in the blood coagulation factor VIII gene. The disorder has an incidence of 1 in 5000 male births and affects approximately 15,000 men in the United States. Patients experience recurrent bleeding throughout their lives, and depend on intravenous injections of replacement factor VIII to control bleeding. Despite replacement therapy, patients are at risk for developing progressive joint destruction, transfusion-associated infections and even death from bleeding into vital organs. The costs of factor VIII replacement therapy typically exceed $100,000 annually for patients with severe hemophilia A.

The severity of hemophilia is determined by the level of factor VIII activity in a patient's plasma. People with less than 1 percent of normal factor VIII activity have severe hemophilia. People with 1 to 5 percent of normal levels have moderate hemophilia, and those with greater than 5 percent of normal levels have mild hemophilia. Approximately 60 percent of patients have severe hemophilia and experience frequent spontaneous bleeding into joints and soft tissues. In contrast, those with mild hemophilia typically bleed only after injuries or surgery. Gene therapy represents a new strategic approach to the treatment of hemophilia, which if ultimately successful, could transform the care of such patients.

"Hemophilia A is an attractive candidate disease for gene therapy because factor VIII production is not regulated in response to bleeding, and the delivery of factor VIII into the bloodstream does not require expression of the gene by a specific organ," says Roth, who also is an assistant professor of medicine at Harvard Medical School. "Even a small rise in the circulating levels of factor VIII, for example from 1 percent to 5 percent of normal, would make a profound difference to the patient by transforming his disease from a severe to a moderate or mild form."

The paper's other authors are Nicholas E. Tawa, Jr., M.D., Ph.D., and Joanne M. O'Brien, R.N., from Beth Israel Deaconess, and Douglas A. Treco, Ph.D., and Richard F Selden, M.D., Ph.D., from TKT. The study was funded by TKT. The study's authors from Beth Israel Deaconess have no financial interest in TKT. Treco and Selden hold TKT stock.

Beth Israel Deaconess Medical Center is a major patient care, research and teaching affiliate of Harvard Medical School and a founding member of CareGroup Healthcare System. Beth Israel Deaconess is the third largest recipient of National Institutes of Health research funding among independent U.S. teaching hospitals.

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