Hemophilia : The AIDS Disaster, Genetic Engineering

by Food and Drug Administration (FDA)

(Page 2 of 3)

The AIDS Disaster

For some time, scientists had known that hemophiliacs were at high risk of hepatitis, a group of viral diseases that can be transmitted by contaminated blood and blood products. Though not usually fatal, hepatitis is serious. The forms known as B and C are sometimes serious enough to be life- threatening, and hepatitis B sometimes leads to liver cancer. In 1982, FDA licensed a vaccine to protect against hepatitis B.

But for AIDS, there is no cure and no vaccine. The first cases of AIDS in persons with hemophilia were reported in 1981. In the early years of the AIDS epidemic, doctors understood that hemophilia patients treated with plasma concentrates prepared from pooled plasma were at enormously high risk of HIV (human immunodeficiency virus) infection, because there was then no way to screen plasma or plasma donors for HIV, the virus that causes AIDS.

In the early and mid-1980s, as many as two-thirds of all Americans with hemophilia became infected with HIV. The National Hemophilia Foundation reports that by June of 1992, 2,248 cases of AIDS had been confirmed among persons with hemophilia and an estimated 1,500 people with hemophilia had died from the disease. Ironically, use of the plasma concentrates that had ushered in hemophilia's "golden age" had become one of the most perilous risk factors for the disease.

But if that was the tragically bad news, the good news is that scientists quickly exploited new techniques and discoveries to develop clotting factor products that carried minimal risk of AIDS infection. Heat treatment was first used in 1983 to destroy viruses in plasma-derived products, and within a few years more advanced virus-inactivation methods were developed that virtually eliminated the risk of HIV transmission from antihemophilic agents. During this same period, highly sophisticated techniques for separating factors VIII and IX from plasma, as well as tests to screen for HIV in blood and blood donors, further increased the safety of plasma-derived products for hemophilia therapy.

Genetic Engineering Offers Hope

The gene for factor VIII was isolated in 1984. It was then possible to extract that gene from human cells and insert it into cultures of hamster cells growing in the laboratory. The hamster cells could then be made to produce large quantities of factor VIII, which is then recovered from the cell culture, purified by techniques similar to those used with plasma- derived factor VIII, and formulated into a product for treating human hemophilia. The recombinant factor VIII produced by this technique is indistinguishable from factor VIII obtained from blood plasma. Two recombinant factor VIII products were recently licensed by FDA. Recombinate, produced under a shared manufacturing agreement between Genetics Institute, Inc., Cambridge, Mass., and Baxter Healthcare Corporation of Glendale, Calif., was approved in December 1992. Kogenate, manufactured by Miles Inc., Elkhart, Ind., was approved in February 1993.

While there is a theoretical risk of virus infection from the biological materials used in both plasma-derived or recombinant clotting factor (which uses albumin), the actual risk is zero, according to William Fricke, M.D., who heads FDA's Laboratory of Hemostasis. Fricke also says that recombinant factor VIII products appear to be no more likely than plasma-derived products to cause an immune response in hemophilia patients.

Somewhere between 10 and 50 percent of people treated with clotting factor develop antibodies to it, which destroys the factor. About half of them get no benefit from clotting factor and must rely on other measures to prevent and control bleeding.

Does genetic engineering hold the key to a cure for hemophilia? Experts think it may, but that victory isn't right around the corner. The technology that allows scientists to isolate clotting factor genes and use them to produce synthetic factors in tissue culture can theoretically make it possible to replace a hemophilia patient's defective gene with a normal one. The drive to figure out how to do that is in high gear, but the solution may not come easily. The factor VIII gene is one of the largest, and therefore most complex, human genes yet described. It is five times larger than the factor IX gene and 116 times larger than the gene responsible for sickle cell disease, for which gene therapy has not been perfected.

Despite the obstacles, people in the hemophilia community are optimistic about the promise of gene therapy. Frederick R. Rickles, M.D., chief of the division of hematology and oncology and professor of medicine at the University of Connecticut School of Medicine, points out that the replacement gene would not have to work perfectly to be beneficial.

"If you convert someone from less than 1 percent clotting factor, which defines severe hemophilia, to 5 percent, which is mild hemophilia . . . you've taken someone from severe spontaneous bleeding to a point where he . . . requires extra clotting factor only under special circumstances, such as surgery. Successful [gene] therapy does not require full normal clotting factor production. A little would be enough," says Rickles, who is also vice president for medical and scientific affairs of the National Hemophilia Foundation. Gene therapy for hemophilia has yet to be tried in humans. Studies in the laboratory and in experimental animals involving factor VIII and IX genes seem to show that the technique works, but it's too soon to tell for sure. Still, there are grounds for hope that hemophilia is headed for a second golden age — this time a lasting one.

About the Author

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FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.