Hemophiliac Study Raises New Hopes
That Genetic Therapy May Yet Work
By LAURA JOHANNES
Staff Reporter of THE WALL STREET JOURNAL
June 7, 2001
An unusual new type of gene therapy boosted levels of clotting factor in the blood of a small number of hemophiliacs, allowing two severely ill patients to live 10 months without spontaneous bleeding, Harvard University researchers found.
The study results, published in Thursday's New England Journal of Medicine, are far from the kind of proof needed to take the therapy to market. In particular, it isn't clear if the salutory effect lasts long enough to make the procedure practical. But the finding feeds the reviving hopes that gene therapy, written off by many scientists as a miserable failure, may yet work.
In gene therapy, healthy copies of genes are inserted into the body to correct problems caused by defective or missing genes. Alarm over the procedure's safety rose after the death of an 18-year-old patient at the University of Pennsylvania in 1999. But since then, preliminary successes have been seen in treating children with a rare immune-system disorder, and in some forms of cancer.
The hemophilia research team, which includes Boston's Beth Israel Deaconess Medical Center and Transkaryotic Therapies Inc. of Cambridge, Mass., is the second group of scientists in recent months to offer hope that the nation's 17,000 hemophiliacs may one day live normal lives.
"There's no doubt in my mind that gene therapy is going to cure hemophilia. It's just a question of when," says Mark A. Kay, who heads the gene-therapy program at Stanford University. Dr. Kay, part of a team that recently used a different gene-therapy method to get promising early results in hemophilia B, an unusual form of the disease, adds, "It's not clear which approach will ultimately prove best."
Hemophilia is widely believed to be one of the easiest targets for gene therapy, and at least a dozen U.S. teams are working on it. The disease, while devastating, has a very simple cause: Due to a genetic defect, its victims lack one or more of the blood components that aid clotting. As a result, they face danger from relatively small cuts and are plagued with continual bleeding, which often occurs in the joints even without injury.
Since the 1970s, the availability of injectible clotting factors has dramatically improved the lives of hemophiliacs. But the medications have been no panacea. Many hemophiliacs contracted the AIDS virus from the injections, which were made from human blood. Even today, with safer products available, high cost limits their use primarily to stanching heavy bleeding after it occurs, rather than preventing it. A single shot to counter bleeding from a banged elbow could cost $2,000.
Recently, a shortage of medication, caused in part by bacterial contamination at a major U.S. plant, has forced patients to forgo shots for minor bleeds. "What little I have in my refrigerator I am saving for major events," says Mark Skinner, president of the National Hemophilia Foundation, a nonprofit advocacy group.
The Boston research, begun in 1998, was the first that attempted to use genes to treat hemophilia A, which affects 80% of hemophiliacs. The research also uses an unusual new approach, which scientists hope will resolve longstanding problems with traditional gene therapy.
Typically, a therapeutic gene is inserted into a virus, such as one that causes colds, and the virus is injected into the patient. The hope is that the virus -- which has been stripped of its disease-causing components -- will infect cells, and thus transmit the healthy gene to them. However, many experiments failed when patients' bodies mounted a defense against the virus.
"It's a vexing circumstance," says Francis Collins, head of the U.S. National Institutes of Health's genome program. "How do you get efficient gene delivery in the face of an immune system that is basically designed to prevent intruders?"
In the approach devised by Transkaryotic, which funded the study, scientists seek to disarm these defenses by using the patients' own cells as a sort of Trojan horse to deliver the genes. A small clump of skin cells are removed from the patients' arms with a scalpel. Then, using a patented method, the company inserts the desired gene into the cells. The altered cells are then implanted, in a one-hour operation, through a small incision into the fat of the patients' abdomen. Once there, they serve as a tiny manufacturing plant for Factor Eight, the clotting protein missing in patients with hemophilia A.
The New England Journal study was primarily designed to test the safety of the procedure, and researchers, out of caution, inserted cells making only small amounts of the clotting protein. Still, the outcome, in addition to demonstrating the procedure's safety, included a surprising amount of therapeutic effect: Four of the six patients saw significant increases in their levels of clotting factors for several months.
Two who kept detailed diaries reported that they were able to go weeks or months without drugs, and 10 months without spontaneous bleeding. The most visible effect was seen in one of these two patients, who received the cells producing the highest level of clotting protein. In the year before the treatment, he had experienced spontaneous bleeding once or twice a week.
Unfortunately, this patient's spontaneous bleedings resumed after that, leaving him back where he started. "This could be a major technical obstacle, since the procedure is so cumbersome it's not something you can do every four to six months," says Stanford's Dr. Kay. A more traditional virus-delivery method used in his study, a team effort with Children's Hospital in Philadelphia, had very modest effects, but one patient appears to be making some clotting factor two years after treatment.
The Boston study's lead author, David A. Roth, an assistant professor of medicine at Harvard and head of hemophilia research at Beth Israel Deaconess, says scientists can probably produce a longer-term effect by engineering the cells to produce greater quantities of the clotting factor, and by implanting more cells into the body.
Transkaryotic hopes its technology, if it proves its mettle in hemophilia, will have wide applications, from giving diabetics a steady supply of insulin to correcting high-blood cholesterol. "There are a large number of other diseases that will follow," says Transkaryotic founder and Chief Executive Richard Selden. "But it's important to make sure we are cautious. In gene therapy, if you move too quickly, you can hit roadblocks."
Write to Laura Johannes at laura.johannes@wsj.com |
