Genetic Engineering Achieves ‘Major Step’ Toward Hemophilia Cure

Implants of genetically engineered skin cells in dogs with hemophilia B, a rare bleeding disorder in which the blood does not clot properly, can bring the symptoms under control for short periods, according to researchers from the Salk Institute in La Jolla.

Although the researchers have many technical obstacles to overcome before the new approach can produce a cure in the animals, their research, reported Monday in the prestigious Proceedings of the National Academy of Sciences, represents a bold new approach to this genetic disorder, which is presently treated with an expensive protein isolated from concentrated blood plasma.

“This is a major step forward toward a cure for hemophilia,” said hematologist Frederick Rickles of the University of Connecticut School of Medicine. “I think it’s just terribly exciting.”

Hemophilia afflicts as many as 20,000 males in the United States. Women can carry the gene for the disorder, but generally do not develop it.

It is caused by a defective gene that would normally serve as a blueprint for a protein that plays a crucial role in the clotting process that prevents people from bleeding to death after being cut or wounded. It exists in two main forms, called A and B.

Hemophilia A, the more common form and the type which is associated with European royalty, is caused by a defect in a protein called Factor VIII. Hemophilia B, also known as Christmas disease after the surname of the first two people diagnosed with it, is caused by a defect in a protein called Factor IX.

Currently, the only treatment for either type is injections of either Factor VIII or Factor IX isolated from the blood of healthy individuals. Because the proteins are present in blood in only very small quantities, large volumes of blood must be pooled for the isolation procedure, greatly increasing the risk that the material will be contaminated with the viruses that cause hepatitis or AIDS.

An estimated 90% to 95% of the nation’s 7,000 to 9,000 hemophiliacs with the most severe cases of the disease are thought to be infected with the AIDS virus. Among moderate hemophiliacs, who require fewer injections, the infection rate is thought to be between 40% and 50%.

Researchers have developed techniques to cleanse blood products of viruses, but the isolated protein is very expensive. A year’s treatment may cost as much as $50,000.

As an alternative to collecting Factor VIII from blood, researchers have produced it in the laboratory using genetic engineering techniques. This product has been successfully tested in humans, but the U.S. Food and Drug Administration has not approved it for marketing. Genetically engineered Factor IX has not yet been tested in humans.

The new research reported Monday opens the door to a technique by which hemophiliacs would produce the protein in their own body.

The research was conducted using dogs which suffer from hemophilia B. They are maintained in a unique colony at the University of North Carolina in Chapel Hill by pathologists Marjorie S. Read and Kenneth M. Brinkhous. Called keagles, the animals arose from a cross between a cairn terrier and a beagle, and the colony has been maintained for 25 years.

Salk Institute molecular biologists Jonathan H. Axelrod and Inder M. Verma took skin cells from keagles and used a specially designed virus to introduce a healthy gene for Factor IX into them. Their paper reports that the cells produce and secrete Factor IX.

Axelrod and Verma have constructed mini-organs with the engineered cells and implanted them under the skin of the keagles. The implant produces Factor IX for at least a few weeks and the animals’ blood will clot normally, Axelrod said. But the clotting time gets longer and longer, indicating failure of the implant.

So far, he said, “we can’t pinpoint a specific problem.” It may be that the cells are dying or that they stop producing Factor IX. The researchers are trying to isolate and correct the problem.

“I’m not discouraged by that,” said Rickles, vice president of medical affairs for the National Hemophilia Foundation. “While it may take some time, we are on the right track.”