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Seeking the best candidate, Verma zeroed in on the most notorious of the retroviruses--HIV, the virus that causes AIDS. He eliminated the protein envelope that allows the virus entry into T cells, substituted one enabling it to infect a greater variety of cells, and removed the six genes that make the virus dangerous.
Can the lentivirus, as Verma dubbed his creation, ever recombine to generate a virus that has the ability to cause disease? "We have done 115 such preparations," he says reassuringly, "and to date we have never seen a virus that is capable of infecting new cells." Later this year he plans to ask the FDA for permission to begin a Phase I trial for hemophilia.
Gene therapists are looking even further ahead. Pennsylvania's Wilson predicts that the next advance will be a mechanism built into the vector to regulate the expression of a therapeutic gene, turning it on or off. "Most diseases and most drugs require modifying the dose," he explains, "but the genes carried into cells by currently used vectors are either on or off."
This means gene therapy cannot now be used to treat, for example, diabetics. If they were provided with a normal insulin gene that was always turned on, their insulin level would soon be dangerously high. "But the mechanism we have in mind," Wilson says, "will be like a genetic rheostat. The gene will not work until you take a pill, and the more pills you take, the more the gene will be expressed--and if you want to cut off the supply, you simply stop taking the pill."
Some researchers look forward to the day when gene therapy is used to repair damaged genes. With the new vectors, they would infect cells with small molecules that combine DNA and RNA. These hybrid molecules would seek out and bind to the defective gene, enabling it to function normally. "It would be like a repair mechanism," Wilson explains, "rather than a replacement."
French Anderson, ever pushing the envelope, last September asked the National Institutes of Health to begin considering gene therapy in the womb for fetuses found to be afflicted with a hemoglobin deficiency that would kill them before birth and for fetuses with ADA deficiency, the "bubble boy" disorder he treated in his pioneering 1990 trial.
To critics of gene therapy dismayed by what seems to be the slow pace of progress, Anderson urges patience. "People don't understand that the development of an ordinary drug from time of concept to product is 10 years," he says. "We're talking about a revolutionary approach to therapy, and we're only eight years into it."
Floyd Stokes, recovered, vigorous and hard at work on his Texas ranch last week, needs no convincing. "Dr. Isner and these fellows had to do some really far-out thinking to come up with this treatment," he says. "I owe my life to them."
--With reporting by Alice Park/New York