Score One For Gene Therapy

Researchers are discovering safer, effective treatments

Gene therapy has taken a beating in the press since last September. That's when Jesse Gelsinger died of side effects from an experimental genetic drug. But in late April, scientists in this beleaguered field found reason to celebrate anew. A team of French researchers at the Necker hospital in Paris reported that they had successfully treated two infants with a deadly immune disease that once forced children to live their short lives trapped inside sterile plastic bubbles. Today, its young victims go in and out of the hospital. Thanks to the breakthrough therapy, both French infants returned home within months of receiving treatment.

While experts caution that it's too soon to declare victory, the results are very encouraging. "This is an important first step," says W. French Anderson, a gene therapist at the University of Southern California. "It's so nice to have something positive to report."

The two French infants, whose treatment was described in the Apr. 28 issue of Science, suffer from "severe combined immunodeficiency X1 (SCIDX1)." This is an inherited illness that prevents the immune system from developing, so that even benign infections become life-threatening. To treat the immune deficiency, the French biologists harvested the babies' bone marrow, isolated its stem cells, and then bathed them in a cocktail of biological factors. Those factors encourage the cells to absorb a correct copy of the diseased gene.

The cocktail is at the heart of the breakthrough reported in Science. The goal of gene therapy is to treat disease by inserting a gene that either corrects a genetic defect or provides treatment for scourges like cancer. In principle, the technique should work against a multitude of hard-to-treat illnesses. Despite 10 years of research and more than 200 trials, however, there have been few clinical successes.

The problem has been getting enough copies of the corrected gene into cells to effect a cure. Like other researchers, the French scientists spent most of the past decade identifying key biological molecules that boost the ability of cells to accept new genes, while still retaining their ability to repopulate the immune system. In this case, they found a potent combination. Eight months after modified cells were infused into the babies, their immune-cell numbers had surged to match those of healthy kids.

CAUTION. The beauty of this technique: Researchers don't have to get the corrected gene into every cell. It turns out that cells that can pick up a good version of the SCIDX1 gene have a survival advantage, which allows them to multiply so fast that they quickly outnumber the still-mutated versions. So even though less than 40% of the cells got the SCIDX1 gene while in the cocktail bath, it seems enough to cure the children.

Despite the apparent success, this gene-therapy trial is still at an early stage, notes R. Michael Blaese, head of human therapy at the biotech company ValiGen. "The caution comes when you ask just how far this can be extended," Blaese says.

That's partly due to the trial's limited scope. The French team reported results from only two patients. (A third, not described in the paper, also seems to be responding to treatment.) Moreover, the researchers did not prove that the therapy hit the most important target--the stem cells that control the whole immune system. If they didn't, and the repaired cells die off, the children may have to undergo the same procedure a few years down the road, with no guarantee of a repeat success.

But if this technique pans out, says Blaese, it could be harnessed to treat a range of diseases, including other anemias and AIDS. After years of struggle, scientists are finally learning how to harness gene therapy's potential.

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