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Suffer the Children New Scientist 14 Mar 98

TAMPERING with genes in human sperm and eggs is outlawed, since any unforeseen side effects would be passed on to future generations. But US health officials are worried that human reproductive cells may have accidentally been contaminated during gene therapy trials. Therapeutic genes are usually shuttled into the body inside "vectors" such as viruses or loops of bacterial DNA called plasmids. But researchers have no way of restricting these vectors to tissues that need gene therapy. So patients have always been warned that germ line contamination is a potential danger and been advised to use barrier methods of contraception. Most of those treated so far have been terminally ill, and were not very likely to consider having children. But as researchers develop gene therapies for less serious conditions (This Week, 25 October 1997, p 20), the Food and Drug Administration (FDA) and the National Institutes of Health (NIH) have become alarmed at reports of vector DNA sequences showing up in the gonads of experimental animals-and, in one case, a human subject. This week at the NIH's headquarters near Washington DC, an advisory panel will discuss the first comprehensive survey of the problem. "This is not a rare thing," says Philip Noguchi of the division of cellular and gene therapies at the FDA. In January, when the NIH asked researchers for information, many confirmed they had seen vector sequences in gonadal tissue in animal studies. A team from Glaxo-Wellcome at Research Triangle Park in North Carolina, for example, used a nasal spray to treat rats for cystic fibrosis and found the therapeutic plasmid in the rats' ovaries, testes and seminal vesicles. At the University of Pennsylvania in Philadelphia, a team led by Nelson Wivel use gene therapy to treat liver-enzyme deficiencies. When they used the polymerase chain reaction to look for their adenovirus vector in rat tissue, "just about everything in the house lit up, including gonads'. Most worryingly, researchers at Introgen Therapeutics in Houston say testicular tissue from a man who died after taking part in a trial of gene therapy for cancer initiaey tested positive for their gene vector. The big question is whether vector sequences are getting into sperm and eggs, or merely the surrounding tissues. The Introgen team told the NIH panel that there was 'a high probability that the samples were cross-contaminated during collection or processing", since tissue from within the testes tested negative. Animal experiments also provide some reassurance that sperm and eggs are not being contaminated. Wivel gave male and female rats large doses of his viral vector and then mated the rats and analysed their offspring. "Out of more than 800 fetuses, we did not get any positives," he says. Esmail Zanjani of Nevada University in Reno injected sheep fetuses with a retrovirus containing a genetic marker. The males' semen later tested positive for the marker, but purified sperm were negative. Nevertheless, the FDA wants researchers to find better methods for testing the germ cells of human patients. "No one's taking up the gauntlet," complains Noguchi. "This isn't something that we have to deal with tomorrow." Nell Boyce, Washington DC