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"You can do spectacular things with cells in a laboratory dish," explains Anderson. "You can easily get the genes in, change the cell's properties and do other things that ought to enable you to treat disease successfully." That is precisely what Anderson and his colleagues did eight years ago in the first approved use of gene therapy, when they removed blood cells from a young patient, genetically altered them with a viral vector and infused them back into her bloodstream. (See box.)
But could the same be done directly to cells within the human body? "That's where we hit the wall in the early 1990s," recalls Dr. James Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania. One problem was that the body's immune system regarded the viral carriers as foreign invaders, and its response caused inflammation and swelling at the injection site. The antibodies that developed in response to the virus caused further difficulties. "In a very unfortunate turn of events," Wilson explains, "the patients would become immune against the therapy."
In an early gene-therapy trial for cystic fibrosis, inflammation caused by the viral carrier, an altered adenovirus, was so severe that the FDA ordered a halt to the effort, casting a pall over all the other trials--and the field in general. More problems plagued the researchers. In many cases the implanted genes failed to "turn on," or express themselves, and were unable to command the cells to produce the protein they were supposed to provide. Some operated for a while and then inexplicably shut down.
As a result, many gene-therapy trials failed during what the FDA calls Phase I, in which the safety of the procedure is evaluated on a handful of patients. Others proved ineffective and faltered during Phase II trials, which test a larger group to determine the efficacy of the therapy. And apparently only one trial has so far weathered Phase III, which calls for a larger number of patients and a statistical analysis of the results before the FDA gives its approval for general use.
That trial, being conducted by GTI-Novartis in Gaithersburg, Md., uses an ingenious technique to attack brain tumors. After re-engineering a retrovirus--an RNA virus that invades only cells that are in the process of dividing--the doctors outfitted it with a gene from the herpes virus and injected it into the brain. Because virtually the only cells that divide in the brain are tumor cells, the retroviruses infected them alone, inserting the herpes gene into their nuclei. As this gene expressed itself, it made the tumor cells sensitive to the herpes drug ganciclovir. When the drug was then administered to the patient, says Anderson, it "made the tumor cells commit suicide." But here there were troublesome side effects.
Clearly, gene therapy is not yet a panacea. Anderson concedes that except for reports of individual patients being helped, "there is still no conclusive evidence that a gene-therapy protocol has been successful in the treatment of a human disease."