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Gene Therapy Cures Immune Disorder

Reverses 'bubble boy' disease in two children

THURSDAY, June 27, 2002 (HealthDayNews) -- A decade ago, American doctors made the first attempt at gene therapy when they tried to treat three children with a rare immune system disease that leaves patients defenseless against infections.

That effort was unsuccessful. However, a new group of scientists have now reversed the disorder with an updated version of the gene-modifying technique.

Researchers in Italy and Israel say they have corrected two cases of severe combined immune deficiency (SCID) using genetically altered bone marrow stem cells. Both of the patients, who were born without a key immune system enzyme called adenosine draminase (ADA), are living at home and appear healthy. The research appears in tomorrow's issue of Science.

Dr. Laurie Myers, a Duke University pediatrician who treats SCID with stem cell transplants, calls the work "very exciting," and says her group hopes to try it in the future. Although ADA-SCID accounts for only a fraction of SCID cases, Myers says there's no reason to think gene therapy wouldn't work for other forms of the disease.

SCID strikes between one in 50,000 to 100,000 newborns a year in the United States. In the ADA form of the disease, infection-fighting T-cells are killed off by toxic byproducts the enzyme normally clears.

John Travolta made SCID a popular phenomenon in his portrayal of a patient with the disorder in a 1976 TV film, "The Boy in the Plastic Bubble." Since then, the disease has drawn the focus of the most cutting-edge treatments, and protective shields are no longer necessary to protect patients from ravaging infections.

In the last two decades, doctors like Myers have been able to overcome SCID with transplants of stem cells derived from bone marrow or umbilical cord blood. The grafted cells migrate to the chest and seek out the thymus gland, which is defective in SCID babies.

Roughly one in five SCID patients can be treated with bone marrow transplants from siblings with a perfect match of immune proteins. For the rest, doctors must decide between less favorable transplants from parents or more aggressive procedures.

Enter gene therapy. Although the first experiments in the early 1990s ultimately flopped, scientists have remained committed to the approach.

Whereas stem cell therapy merely resettles diseased bone marrow with healthy donor cells, gene therapy corrects the offending defect in a child's own stem cells. Since marrow stem cells produce the specialized cells in the blood, including immune cells, the fix gets passed down the line.

In the latest work, a team led by Dr. Claudio Bordignon of the San Raffaele Telethon Institute for Gene Therapy in Milan tested a novel twist on gene therapy on two children with ADA-SCID.

The patients, 7 months old and 2.5 years old at the time of the procedure, had no available bone marrow donors and could not obtain ADA replacement therapy -- a cow-derived version of the enzyme called PEG-ADA, which costs up to $500,000 a year.

Bordignon's group first took bone marrow from the children and pulled out stem cells from the samples. They then treated these defective cells with a virus carrying a normal version of the ADA gene, which incorporated itself into the cells' damaged genetic code.

To clear "space" for the graft, the researchers gave the patients a drug to partially erase their bone marrow -- a method called non-myeloblative conditioning that's not generally used with gene treatments. They then infused the cells back into the children and waited for them to take hold.

Within weeks, the children were producing a variety of normal immune cells, including T-cells, B-cells and natural killer cells, the researchers say. Within a few months, their blood also began showing immune proteins, called antibodies, which help the body fight infections.

Both patients also had a normal immune response to tetanus vaccination. After a year, the older child, a girl, was no longer suffering from the respiratory ailments, chronic diarrhea and infectious rashes that had plagued her before the procedure. She also developed antibodies to chicken pox when the virus ran through her family, but didn't fall ill with the disease.

Dr. Fabio Candotti, a SCID expert at the National Human Genome Research Institute, calls the new study "very promising and very exciting." Candotti is currently testing a similar gene therapy approach in four patients with ADA-SCID, but with somewhat less success.

One reason for the difference may be the Italian group's decision to partially eradicate the bone marrow, something Candotti isn't doing in his trial.

"Chemotherapy creates space for the infused cells and gives them an advantage" over the remnants from the defective system, he says. The result is that while the Italian team got nearly total re-population with normal T-cells, his patients show only a single healthy T-cell for every 10,000 or 100,000 abnormal ones, he says.

Candiotti's patients are also receiving PEG-ADA after the transplant, which may blunt the effectiveness of the new cells. He and his colleagues are considering scaling down the enzyme, which, as in the Italian approach, would untie the hands of the gene-corrected cells.

Dr. Donald Kohn, a childhood immunity specialist at the Keck School of Medicine at the University of Southern California who is collaborating with Candotti, says the new approach could benefit patients with genetic diseases beyond SCID.

"It's definitely an important piece of work with implications for treating SCID and a whole variety of blood diseases," Kohn says. These include sickle cell anemia, thalassemia and Gaucher's disease.

What To Do

For more on the disease, try the Primary Immune Deficiency Webring. You can also check out the Immune Deficiency Foundation.

SOURCES: Laurie Myers, M.D., associate professor, pediatrics, Duke University, Durham, N.C.; Fabio Candotti, M.D., head, disorders of immunity section, National Human Genome Research Institute, Bethesda, Md.; Donald Kohn, M.D., professor, pediatrics, Keck School of Medicine, University of Southern California, Los Angeles; June 28, 2002, Science
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