Severe combined immunodeficiency

SEVERE COMBINED IMMUNODEFICIENCY DISEASES, OR SCIDS, ARE A GROUP OF DEVASTATING GENETIC DISORDERS THAT AFFLICT ONE IN EVERY 100,000 BABIES. FOR ONE REASON OR ANOTHER--SEVERAL gene defects are at fault--these babies are eventually left without the T cells that normally coordinate the body's response to invaders, leaving them with no immune system to speak of. In the past such babies often died within a year, unable to cope with the simplest colds or ear infections. But recent advances in genetics have improved prospects for some of these children. In fact, in 1993 researchers dared to talk for the first time not merely of treating children with one form of the disease but even of curing them.

Children with this kind of SCID have a defect in the gene for an enzyme, made by T cells, called adenosine deaminase, or ADA. This enzyme breaks down chemicals that, though normally made by the body, can poison T cells is allowed to build up. In the mid-1980s physicians began injecting children who lack the enzyme with ADA derived from cows. But for the treatment to be effective, children have to receive twice-weekly injections for the rest of their life.

A better, more long-lasting solution, some researchers believe, would be to provide cells with a good copy of the ADA gene. A first shot at such gene therapy was tried in 1990 on two young girls from Ohio. Reseachers from the National Institutes of Health removed T cells from each girl, inserted a normal copy of the gene inside the cells, then reinjected the cells. The altered T cells began making ADA, and the girls regained immune function. Yet the therapy falls short of the ideal: T cells live only a few months, so the engineered cells must be routinely replaced. As a safety net, the girls are also injected with twice-weekly enzyme supplements.

Donald Kohn, director of the gene therapy program at Childrens Hospital in Los Angeles, thinks a still better approach might be to stick the ADA gene into the blood's stem cells--precursor cells that give rise to T cells and live essentially forever. That's what Kohn and his colleagues tried in three SCID newborns this past May and June. At the babies' delivery, doctors retrieved a small amount of

umbilical cord blood, which is known to be rich in stem cells, and rushed it to Kohn's lab. Using an antibody that targets stem cells, Kohn's team separated the desired cells from the rest of the blood. The researchers then grew the stem cells in a lab dish and inserted a normal version of the ADA gene inside them, using a retrovirus as a carrier.

"Retroviruses are very efficient gene delivery vehicles," explains Kohn. "Unlike most viruses, they insert their genetic material directly into the cell's own genes." There was a snag, though. Cord blood is unusual in that it contains two types of stem cells: "baby" cells, which are active at birth but die within six months, and "permanent" stem cells, the real McCoys, which are initially quiescent. Since retroviruses can enter only active cells, Kohn added growth factors to prod the permanent cells into a brief growth spurt. Finally, all the stem cells--each carrying, Kohn hopes, a payload of ADA genes--were injected back into the babies.

It's still too early to tell if the startegy worked--Kohn's team is just getting the first hints that permanent stem cells might be producing T cells. Kohn suspects that most of the babies' current T cells are still the residual effect of their baby stem cells. To boost these T cells, the babies are also getting ADA enzyme shots. "What we're waiting to see," Kohn says cautiously, "is whether the T cells made by the babies' mature stem cells have the ADA gene. Then if we can show that having the gene makes T cells work better, and if the number of T cells with the gene increases, we may stop giving the babies extra ADA." All that may be too much to hope for at the very first attempt. But if the babies can make enough of their own ADA not to need extra treatment, they'd essentially be cured.

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