Business Wire - Monday January 4, 1999

The researchers found that a single infusion of an engineered DNA delivery vehicle containing a human or canine clotting factor gene led to long-term production of the missing protein in the liver of hemophiliac animals. Hemophilia is a genetic disease that leaves 1 in 5,000 males at risk of spontaneous and life-threatening bleeds.

"This is something that we've worked out in the lab that has a high potential of working in people," said Mark Kay, MD, PhD, associate professor of pediatrics and genetics, director of Stanford's program in human gene therapy and senior author of the multi-center study.

Unlike the blood of healthy people, which quickly gels when it spills from blood vessels, the blood of hemophilia patients lacks sufficient amounts of clotting factor VIII (hemophilia A) or factor IX (hemophilia B). In these patients, minor injury can cause profuse bleeding, forcing them to be immediately transfused with the appropriate clotting factors -- factors that are usually prepared from human blood products.

To avoid risk from infection with blood-borne agents such as HIV and hepatitis viruses, and to alleviate the demand on human blood supplies, scientists are developing genetically engineered clotting factors. Some are already in clinical use, but they still require regular transfusion to staunch or prevent onset of bleeding.

Gene therapy would obviate the need to externally administer the missing clotting factor. A functional copy of the clotting factor gene could be inserted into the patient's cells to replace the defective gene and produce life-long protection from hemophiliac bleeds.

In the study, researchers infused the human gene for factor IX into the liver of hemophilia B mice, leading to production of factor IX and correction of the bleeding disorder. These mice are still alive more than a year after treatment compared to untreated mice which usually fall victim to spontaneous fatal hemorrhage at two to three months of age. Furthermore, the treated mice experienced no adverse side effects.

"The thing that is really important is that it's safe," said Kay. "There's no reason why it can not be developed for human trials."

Because a large animal model was needed to confirm the results before human clinical trials could be considered, the research team tested the technique in dogs suffering from this genetic disease. Timothy Nichols, MD, associate professor of medicine, and colleagues at the University of North Carolina, Chapel Hill, infused two hemophiliac dogs with a small dose of the factor IX gene, resulting in production of the clotting factor at a level of one percent of the normal amount found in healthy dogs' blood.

Physicians already know that even this tiny amount makes a big difference in clinical symptoms. "At one percent clotting factor, it changes from severe disease to moderate, which really increases quality of life of the individual," said Kay.

In the eight months following treatment, both dogs' blood clotted more quickly, and only a single spontaneous bleed was recorded in one of the dogs compared to an average of five bleeds per year in untreated hemophilia B dogs. Kay and his team are very enthusiastic about the results. "This is a one-time treatment that we predict will be enough to treat the individual life-long," said Kay.

Continuing research is now focusing on treating more animals, adjusting dosages for maximum benefit and adapting the protocol for Hemophilia A -- the more common form of the disease. Human studies may begin in 1999.

The collaborative research team includes investigators at the University of Washington, Seattle; the University of North Carolina, Chapel Hill; and Cell Genesys Inc [Nasdaq:CEGE - news].

Funding for this research was provided by grants from the National Institutes of Health.

Contact: Stanford University Medical Center Kristin Weidenbach, 650/723-0272 or 650/723-6911 http://www-med.stanford.edu/center/communications
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