Study points to possible gene therapy cure for hemophilia

June 09, 1999

CHAPEL HILL, N.C. - New results from gene therapy studies at the University of North Carolina at Chapel Hill may lead to an effective long-term treatment, if not a cure, for hemophilia A, the most common form of this inherited blood disease.

Studies in mice involved attaching a cloned gene responsible for human clotting factor VIII - a protein severely deficient in people with hemophilia A - to a genetically engineered virus called AAV. A single injection of the virus led to a gradual increase in blood levels of factor VIII, which have remained stable for 11 months.

"This is the first result in animals demonstrating the efficacy of this approach to hemophilia A," says Dr. Christopher E. Walsh, assistant professor of medicine at UNC-CH School of Medicine and clinical director of the university's Gene Therapy Center. "The goal is one dose -- that essentially one dose delivered by gene therapy would be all that's needed to be physiologically cured of future bleeds."

On June 9, in Washington, D.C., Walsh and his colleague, Dr. Hengjun Chao, a postdoctoral researcher at the center, will present the new findings to the American Society of Gene Therapy.

The UNC-CH researchers point out that earlier gene transfer attempts in mice using other virus systems resulted in higher blood levels of factor VIII. These, however, proved short-lived, lasting from just a few days to a few months. Moreover, those treatments proved highly toxic to the liver, which is the source of the clotting factor.

"Compared with other viral vectors - retrovirus and adenovirus - AAV has its advantages: it is nonpathogenic, non-toxic, and provides very long-term expression of the factor VIII protein," Chao says.

The UNC-CH researchers were able to achieve factor VIII levels up to 20 percent of normal in a strain of healthy mice and factor VIII "knockout mice," a strain genetically bred without the gene for the clotting protein.

"Although the [blood] levels of factor VIII are not at 100 percnet using AAV gene transfer, they would be clinically beneficial to patients with hemophilia A," Walsh says. He notes that people with severe hemophilia typically have factor VIII blood levels less than 1 percent of normal. "Those patients start spontaneous bleeding into joints and muscle and need frequent transfusion. And those are the bulk of hemophilia patients with inadequate factor VIII levels."

Thus, the results in mice translated into humans would mean that the sustained factor VIII levels obtained through AAV gene therapy would dramatically reduce spontaneous bleeding and its manifestations.

"So for most of the patients, if you can get their factor VIII levels to greater than 5 percent constantly, they wouldn't have joint disease, the chronic arthritis, the deformities, and other problems hemophilia patients go through by the time they're in their twenties and thirties," says Walsh.

The researchers will soon test AAV factor VIII gene transfer in dogs using a cloned canine factor VIII gene. This will reduce the likelihood that the animal's immune system will mount an attack on the protein, which sees it as "foreign."

"We can probably get levels much higher because presumably the immune response to that protein would be limited," Walsh says.

Of the roughly 30,000 people with hemophilia in the United States, about 80 percent have hemophilia A. Now that genes for the major clotting factors have been cloned, the proteins are made in cell lines, and purified products can be manufactured in vast quantities -- without the HIV and hepatitis risk that were associated with the earlier clotting proteins made from blood products. Still, treatment is costly. An average hemophilia A patient uses about $3,000 to $4,000 a dose, which lasts about 12 hours.

"And many times, even with that, they'll have bleeding that will not stop and the factor must be given frequently," Walsh says. "That's why our goal is one dose only."
Note to media: Dr. Walsh can be contacted at 919-966-9116 or 919-966-9117 or email UNC-CH School of Medicine

media contact is Lynn Wooten, 919-960-8263 or email

University of North Carolina Health Care

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