The Associated Press

A revolutionary gene therapy treatment that cured 10 French boys of a deadly inherited disorder known as "bubble boy disease" gave two of them leukemia, scientists said Sunday.

Dr. Salima Hacien-Bey-Abina said genetic tests have confirmed that the treatment, the first time that gene therapy has cured a disease, triggered the cancer in the toddlers. The boys are responding well to anticancer therapies, she added.

Experts said it is now clear that the virus used to carry the needed gene into the children's bodies landed in a bad place. Scientists had always feared that cancer might occur if the virus used in the therapy lodged near certain genes that control cell growth and affected those too.

Addressing a conference of the European Society of Human Genetics, Hacien-Bey-Abina of the Necker Hospital for Sick Children in Paris said tests have shown that in the first toddler stricken with leukemia, the correcting gene landed inside a cancer-promoting gene called LMO-2. In the second toddler, the gene landed near the LMO-2 gene.

"Apart from the tragedy of those two kids, I think this has put an enormous skid under a great deal of gene therapy, on this whole business of using retrovirus vectors" to get the needed genes into the body, said Andrew Read, a professor of genetics at Manchester University and chair of the scientific committee for the conference.

"That is a perfectly general problem of retroviral vectors and not a problem of the particular virus they used or the particular disease they treated and I cannot see how in principle you can get rid of that risk," said Read, who was not involved in the research.

The boys were given the treatment starting in 1999 when they were babies, ranging in age from one month to 11 months.

The first toddler who developed leukemia appeared healthy until August last year 30 months after treatment when scientists found leukemia-like overproduction of white blood cells. After that finding, the United States suspended its three gene therapy studies for the disorder.

A second child then developed leukemia in December, 34 months after getting the therapy, Hacien-Bey-Abina said.

The boys were born with severe combined immunodeficiency, or SCID, a rare inherited disease that occurs in about 1 in 75,000 births. The best known victim was David, Houston's famous "bubble boy" who lived in a germ-proof plastic enclosure until his death at age 12 in 1984.

The French boys had X-linked SCID, a severe form that strikes only boys. It is the most common form of SCID, accounting for about half of cases.

The disease involves a genetic mutation that leaves them without certain proteins crucial to developing disease-fighting immune cells. Without treatment, sufferers die very young.

Many babies with the disorder are saved with bone marrow transplants, but they need monthly infusions of immune globulin, antibodies culled from donated blood, for the rest of their lives.

To reverse the defect, doctors at Necker Hospital drew bone marrow from the boys. They mixed specific stem cells from the marrow with a harmless virus in which a gene that makes the missing protein had been inserted.

They injected the reconstituted cells back into the boys, giving them a working immune system.

"All the patients except patient four and patient five are doing well. They are healthy and they are at home," Hacien-Bey-Abina said.

She said that one of the problems might have been the two boys who developed leukemia were the youngest in the group when they received the treatment. One was a month old, while the other was three months old. She theorized that their stem cells were possibly too immature.

Also, while the average number of reconstituted cells injected back into the boys was 9 million cells per kilogram of body weight, "the two patients who developed leukemia received a particularly high number of transduced cells, around 20 million," Hacien-Bey-Abina told the audience.

Hacien-Bey-Abina proposed that one possible way around the problem is to incorporate into the virus a so-called suicide gene, which would abort the treatment if things go wrong. Another way would be to build in a buffer zone around the virus to diminish its effect on nearby genes.

Even if such approaches don't work, Read said, it doesn't mean that the therapy should never be offered to children suffering from X-SCID.

"In a disease like SCID, where you know the kid is going to die if you can't give them a bone marrow transplant, then if we're really talking about a one in four risk of leukemia and the leukemia is treatable, maybe the risk is worth taking," Read said. "But it's certainly not worth thinking about for more trivial conditions."

On the Net:

European Society of Human Genetics:

Copyright 2003 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.