Gene therapy's up ....

The recent roller-coaster ride of gene therapy's fortunes continues, with peaks and valleys occurring almost monthly. In September, two studies reporting failures in treating cystic fibrosis and muscular dystrophy unleashed a torrent of media hand wringing over the future of the technique. The pendulum swung back this month with the publication of three studies that demonstrate success in treating an immune disorder--though how much success is unclear.

The apparent good news comes from three efforts designed to help people with an inherited genetic defect that prevents them from making an enzyme called ADA. This usually fatal enzyme deficiency poisons the body's T cells, the specialized cells in the blood that mobilize part of the immune system's protective response against infection.

In 1990, in the first gene therapy experiment ever attempted in humans, researchers began treating two ADA-deficient girls. First, the investigators removed some of the girls' T cells and grew them in the laboratory. Then, they added working versions of the ADA gene into this population of T cells and began regular infusions of the altered immune cells back into the children. Both girls today appear healthy, have immune cells that make ADA, and possess functioning immune systems, report R. Michael Blaese of the National Institutes of Health's National Center for Human Genome Research in Bethesda, Md., and his colleagues in the Oct. 20 Science.

In the same issue, a collaboration of three research groups from Italy details a similar success story in two other children. In addition to injecting relatively short-lived T cells into their patients, the Italian group injected ADA-engineered bone marrow cells. Marrow cells can provide a permanent supply of ADA-making immune cells.

In a third report, detailed in the October Nature Medicine, Blaese and his colleagues discuss another strategy. They identified three fetuses that had inherited broken ADA genes. When the babies were delivered, the investigators obtained stem cells, similar to bone marrow cells, from blood in the umbilical cords. They added functional ADA genes to those cells and injected them into the babies 4 days after birth. The babies appear to have a permanent population of normal immune cells.

In all three efforts to cure ADA deficiency, the children treated now seem healthy. The effectiveness of the gene therapy remains open to question, however. That's largely because the patients also received regular injections of the ADA enzyme itself. Withholding that proven treatment would have been unethical, but the enzyme injections cloud any assessment of the gene therapy's impact, explain investigators.

"They're probably getting biological changes that help the patients, but you can't prove it, " says Ronald G. Crystal of the New York Hospital--Cornell Medical Center in New York City.