Earlier this month, Donald N. Miller rolled up his sleeve in a Pittsburgh hospital and became the first person to receive a new, experimental gene therapy treatment aimed at curing the most common kind of hemophilia.
An inherited bleeding disorder, hemophilia affects about 20,000 male Americans. Three different types of gene therapy for the disorder are now being tested in humans, and researchers predict that hemophilia may soon become the first inherited disease to be successfully treated by giving patients replacement genes that would function for long periods of time.
The experimental hemophilia treatments represent a new wave of gene therapy approaches being developed for a number of diseases, said James M. Wilson, professor of medicine at the University of Pennsylvania School of Medicine and president of the American Society of Gene Therapy, which met in Washington this month. Researchers are applying lessons learned from pioneering, largely unsuccessful gene therapy trials that took place earlier in this decade.
Most of those early tests used engineered viruses called "vectors," often versions of the common cold virus, to put new genes into patients. But the body's immune system viewed the viruses as invaders and mounted a reaction that tended to inactivate the inserted genes. Since then, however, researchers have developed new vectors that are less vulnerable to attack by the immune system. Tests in animals suggest that gene therapy using the newer vectors may be able to successfully treat hemophilia as well as some kinds of inherited high cholesterol, eye disorders such as macular degeneration and retinitis pigmentosa, and a number of other conditions.
"I really believe that . . . we're sitting on vector technology that's going to cure disease," Wilson said. "It's just going to take us a while to prove it."
Hemophilia is a perfect test case for the new approaches, researchers say, because if an inserted gene functions even a little, it may be enough to correct the blood clotting disorder.
People with hemophilia suffer spontaneous, often crippling bleeding into their joints and are at risk for life-threatening hemorrhages in the brain, digestive tract and other sites. Hemophilia A, which accounts for 80 percent of cases, occurs in people who have a defective gene for Factor VIII, a protein needed for the chemical reaction that makes blood clot. Hemophilia B, the other form of the disease, is caused by a defective gene for Factor IX, another clotting protein.
Both proteins are normally made by the liver, and the symptoms of the two types of hemophilia are virtually identical. People with severe hemophilia make almost none of the clotting protein produced by the affected gene, said Katherine High, a professor of pediatrics at the University of Pennsylvania Medical School. High is leading a gene therapy trial for hemophilia B.
At the first sign of hemorrhage into a joint, hemophilia patients must take an intravenous injection of the protein they lack, usually about once a week. Treatment costs between $50,000 and $100,000 per year, and even with weekly injections, many people still develop disabling joint problems.
If gene therapy can raise levels of the missing clotting protein to as little as 2 percent of the amount found in a healthy person, it will prevent patients from suffering spontaneous hemorrhages into the joints, brain or other organs, said Margaret V. Ragni, a professor of medicine at the University of Pittsburgh who is leading a gene therapy study for hemophilia A.
The gene therapy products now being tested by High and Ragni have succeeded in preventing such hemorrhages in hemophilic dogs, with the effect of a single treatment lasting at least two years.
"Let's suppose this gene therapy works," said Ragni. "The goal would be, you take a young child. . . . You would just give a dose and avoid all of this morbidity, all of these chronic joint problems and, lo and behold, you'd have a much better quality of life."
Miller, 50 years old, was the first hemophilia A patient treated in Ragni's trial, which is testing the safety of a treatment manufactured by Chiron Corp. of Emeryville, Calif. Miller said he suffered life-threatening bleeding in his throat and intestines as a child.
"Several times I was given hours to live," he said. During one protracted hospitalization, he recalled, "I got 157 pints of blood in five weeks."
Since better preparations of the clotting protein have been developed, Miller said, he has had fewer hemorrhages, but he still suffers from chronic joint problems. Miller and his wife live on a sheep farm in Mt. Pleasant, Pa. He publishes large-print books and works as a computer consultant.
He said he didn't hesitate to volunteer for the study. "Somebody had to be the first one to do it," he said. If it works, "it means I won't have to be sticking myself with needles."
The Chiron product contains a nearly complete gene for Factor VIII that is transported into cells by a vector made from a mouse retrovirus. Retroviruses are a large family of viruses that includes the AIDS virus.
The engineered vector has had all of its functional viral genes removed, said Ragni. "The only thing left is its ability to gain entrance into the cell," she said.
Researchers believe the virus inserts the gene primarily into cells of the liver and spleen, but it has also shown up in other organs, including the bone marrow and the gonads. However, there is no evidence that it gets into "germ-line" cells such as sperm or eggs, said Margaret Liu, vice president for vaccines and gene therapy research at Chiron.
Miller received the gene therapy starting June 1, in brief intravenous injections every day for three days. Since then, he has been home working on his sheep farm. Although the pilot study is not designed to test the product's effectiveness, researchers hope to see some effect on his blood's ability to clot within the next few weeks.
Miller is optimistic. One day last week, he said, he had a nosebleed and continued working outside instead of lying down for half an hour as he ordinarily would. "It quit real fast," he said.
High's study, which also began this month, is testing the safety of gene therapy for hemophilia B, using a Factor IX gene carried by a vector called adeno-associated virus (AAV). She injects the product, made by Avigen Inc. of Alameda, Calif., into a thigh muscle. It is taken up by muscle cells, which then begin to make the clotting protein.
Another company, Transkaryotic Therapies Inc., of Cambridge, Mass., is testing an outside-the-body form of gene therapy for hemophilia A at Beth Israel Deaconess Medical Center in Boston. Each patient undergoes a skin biopsy to obtain cells called fibroblasts, which are grown in the laboratory. Researchers insert a Factor VIII gene into the cells, using a technique that doesn't require a viral vector, then inject them back into the patient. Additional companies are also developing products for hemophilia.
Chiron's Liu said her company is working on a "stable" of vector viruses that could be used to deliver genes for different purposes. The field's future, she predicted, lies with the development of a variety of carefully engineered viruses for ferrying genes into the body. "It's not just going to be that you have one vector and this is the solution for gene therapy."
CAPTION: Nurse Valerie Bond applies ice to the arm of Donald L. Miller, who is receiving an experimental treatment for hemophilia.