Mark A Kay, C S Manno, M V Ragni, P J Larson, L B Couto, A McClelland, B Glader, A J Chew, S J Tai, R W Herzog, V Arruda, F Johnson, C Scallan, E Skarsgard, A W Flake, and K A High, "Evidence for Gene Transfer and Expression of Factor IX in Hemophilia B Patients Treated with an AAV Vector," Nature Genetics , Vol. 24, No. 3, pp. 257-261 (March 2000).

Gene Experiment Helps Hemophiliacs
Joseph B. Verrengia,
AP Science Writer

5:00 PM EST; March 1, 2000; (AP) -- Amid controversy over the risks of gene therapy, scientists reported that an experimental gene-replacement procedure appears to improve blood clotting in hemophiliacs without triggering complications. Researchers at Children's Hospital of Philadelphia and Stanford University cautioned that their success in treating Hemophilia B, a relatively rare form of the illness, was encouraging but preliminary. Just three patients participated in the experiment, in which researchers injected patients with a healthy gene to stimulate production of a blood-clotting protein. An expanded trial with more patients and higher doses is under way.

If the method continues to work, it would be one of the few successful genetic treatments of any disease since the approach was introduced a decade ago. The new gene's effect is "modest, but measurable," said Stanford geneticist Mark A. Kay, who led the study. "It changes from severe disease to moderate, which really increases the quality of life for the individual." The hemophilia study appears in the March issue of Nature Genetics amid a public backlash against gene therapy.

The outcry was prompted by the death last September of a Phoenix teen-ager who had volunteered for a different gene experiment. Jesse Gelsinger, 18, was the first patient believed to die as a direct result of a gene therapy experiment. Researchers at the University of Pennsylvania had infused his liver with a gene aimed at reversing a rare metabolic disease of the liver. The procedure triggered an extreme immune-system reaction that caused multiple-organ failure in a very short time.

In recent weeks, several leading scientists -- including Caltech President and Nobel Laureate David Baltimore -- have questioned whether gene therapy is too risky. And the NIH, which funds gene therapy research, is evaluating 400 trials conducted with more than 4,000 patients. Other geneticists said the Hemophilia B study in Nature Genetics, while not conclusive, is a confidence-builder. "What I like is that it was a very low-risk study," said Baylor College of Medicine geneticist Arthur Beaudet. "There is a lot of uncertainty in the field now. It's reassuring to see some positive studies."

About 5,000 Americans suffer from hemophilia B. They produce insufficient levels of a clotting protein known as Factor IX. As a result, blood leaks into their joints. Many patients are disabled by age 30. Researchers believe hemophilia B is suitable for gene therapy because the Factor IX gene is small and a healthy copy can be easily substituted. Also, levels of Factor IX as low as one percent of normal can improve blood clotting, so the new gene does not have to work perfectly to be effective. Researchers injected a healthy Factor IX gene into the patients' thigh muscles. The gene had been incorporated into a low dose of a simple virus that has never been associated with human disease. As the virus spread, it copied the healthy gene into the patients' cells.

The healthy gene was producing effective levels of Factor IX in two patients within 12 weeks. Their reliance on clotting medication was reduced 50 percent 80 percent. (For whatever idiosyncratic reasons, the third patient showed no improvement.) In Gelsinger's death, Penn researchers used a different vector -- a virus that was known to stimulate a more vigorous response from the immune system. Another difference was that they injected a higher dose directly into the youth's bloodstream.